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Nonequilibrium Reshaping of Polymersomes via Polymer AdditionClick to copy article linkArticle link copied!
- Yongjun MenYongjun MenInstitute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The NetherlandsMore by Yongjun Men
- Wei LiWei LiInstitute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The NetherlandsMore by Wei Li
- Yingfeng TuYingfeng TuInstitute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The NetherlandsMore by Yingfeng Tu
- Fei PengFei PengInstitute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The NetherlandsMore by Fei Peng
- Geert-Jan A. JanssenGeert-Jan A. JanssenInstitute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The NetherlandsMore by Geert-Jan A. Janssen
- Roeland J. M. NolteRoeland J. M. NolteInstitute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The NetherlandsMore by Roeland J. M. Nolte
- Daniela A. Wilson*Daniela A. Wilson*Tel.: +31 (0)24 36 52185. E-mail: [email protected]Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The NetherlandsMore by Daniela A. Wilson
Abstract
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Polymersomes are a class of artificial liposomes, assembled from amphiphilic synthetic block copolymers, holding great promise toward applications in nanomedicine. The diversity in polymersome morphological shapes and, in particular, the precise control of these shapes, which is an important aspect in drug delivery studies, remains a great challenge. This is due to a lack of general methodologies that can be applied and the inability to capture the morphologies at the nanometer scale. Here, we present a methodology that can accurately control the shape of polymersomes via the addition of polyethylene glycol (PEG) under nonequilibrium conditions. Various shapes including spheres, ellipsoids, tubes, discs, stomatocytes, nests, stomatocyte-in-stomatocytes, disc-in-discs, and large compound vesicles (LCVs) can be uniformly captured by adjusting the water content and the PEG concentration. Moreover, these shapes undergo nonequilibrium changes in time, which is reflected in their phase diagram changes. This research provides a universal tool to fabricate all shapes of polymersomes by controlling three variables: water content, PEG concentration, and time. The use of the biofriendly polymer PEG enables the application of this methodology in the field of nanomedicine.
Copyright © 2019 American Chemical Society
Cell shape is of key importance in cell growth and cell differentiation and, as such, has been crucial in the evolution of life. For instance, it is important in the morphogenesis of tissue during the development of the living body. Furthermore, it may help a species escape from its predators. (1) The dynamic assembly of the cytoskeleton is the result of out-of-equilibrium reactions in the cell and is accompanied by shape changes, which are needed for environmental adaptation. (1) Out-of-equilibrium assemblies are systems that require a continuous supply energy to persist. If the energy supply stops, the system would fall apart and end up in a thermodynamic minimum state nearby. (2−4) Liposomes can spontaneously exhibit various shapes, which are reminiscent of biological cell morphologies, which have inspired scientists to fabricate vesicles (synthetic liposomes) of different shapes and compositions as cell mimetic systems in order to understand the mechanism of liposomal shape change. (5) Variations in mechanical stress, temperature, pH, or osmotic shocks and in membrane composition are capable of inducing drastic changes in liposomes, ranging from nearly spherical shapes to discocytes, stomatocytes, starfish, or pears. (6,7) However, the dynamic nature of the phospholipid membrane makes these shape transitions transient due to the lack of stabilization by the cytoplasm in the cell and the fact that the cytoskeleton has glassy properties, limiting an accurate shape control.
Polymersomes assembled from amphiphilic synthetic block copolymers demonstrate enhanced membrane stiffness and provide great possibilities for tailoring both the chemical design of the membrane and its physical properties (such as stiffness, zeta-potential, and adhesiveness), which allows for good control over the shape and function of the aggregate. (8−16) The shape of a polymersome is expected to affect its interaction with the cell, which is important for its flow properties, its cellular uptake, and immune regulation, as is the case for the biconcave disc-like red blood cell. (17−21) Therefore, it is of great importance to be able to accurately reshape a polymersome and to understand the mechanism of the interconversions of the various shapes. Several studies have explored the possibilities to reshape polymersomes via osmotic pressure or a change in chemical structure. (22−35) Block copolymers bearing liquid-crystalline side chains assembled to ellipsoids, tubes, and polyhedral shapes of polymersomes via solvent control. (33,34) Spherical polymersomes, assembled from poly(ethylene glycol)-block-polystyrene (PEG-b-PS) block copolymers, deflate into flat discs and bowl-shaped stomatocytes via dialysis of the polymersome suspensions in mixtures of organic solvents against pure water, leading to a decrease of the inner volume of the aggregates. (29) Chemical cross-linking of the polymersomes induced a shape transformation from spheres to rods. (36) Our group has previously reported on the shaping of polymersomes into predictable morphologies via nonequilibrium self-assembly with the objective to mechanistically understand and predict polymersome shape changes to low-energy states. Unfortunately, only a few morphologies, such as discs, rods, and stomatocytes, were observed. (37) Hence, a complete overview of the shape transformations of polymersomes and their transition from low to high energy states in order to capture unique morphologies in the nanometer range that have not been observed before is still lacking.
Herein, we report a new nonequilibrium methodology to transform spherical PEG-b-PS polymersomes into a variety of shapes, such as rods, tubes, discs, stomatocytes, nests, disc-in-discs, stomatocytes-in-stomatocytes (sto-in-sto), and large compound vesicles, which can be kinetically trapped at any stage of their transformation. Our former approach for obtaining a controlled shape transformation was only based on osmotic pressure changes to push further the polymersome transformation beyond the low-energy stomatocyte state to generate other shapes. (37) In the present methodology, we combined additives, time, and nonequilibrium conditions as parameters for shape control. The polymersomes are initially formed by adding water to a block copolymer solution in a mixture of tetrahydrofuran (THF) and dioxane. Our approach for obtaining a controlled shape transformation is to ensure that the polymersomes only experience one single equilibrium state at the moment they are formed. Extra addition of water pushes the polymersome out of osmotic equilibrium by storing energy in the membrane. The membrane flexibility and permeability can be tuned by the water fraction in the polymersome solution, which is possible because of the amorphous glassy nature of the PS part. The PS membrane used in our studies is composed of 230 repeating units, which limits its mobility, resulting in much longer transition time scales (i.e., on the order of hours) than in the case of liposomes (seconds). This prolonged time scale gives the possibility to kinetically trap every intermediate morphology by freezing the PS membrane via quickly adding excess water. The use of PEG as a fusogen has been recently demonstrated by our group, and its ability to induce a shape change in the polymersome can already be realized with a trace amount (0.005 wt %) of this compound, compared to >15 wt % for the liposome system, which is possible because the low permeability of the membrane amplifies the osmotic pressure. (31) In this paper, we show that the bending energy of the polymersome can be regulated by tuning the rigidity of the PS membrane, allowing good control of the nonequilibrium shape transformation and the possibility to capture various morphologies over time, leading to a complete phase diagram of the shape transformations.
Results and Discussion
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Self-Assembly via Water Addition
Polymersomes were made by first dissolving 10 mg of PEG45-b-PS230 in 1 mL of THF/dioxane = 4:1 (v/v), followed by slowly adding water at a rate of 1 mL/h (Figure 1a,b). The assembled polymersomes were formed when the ratio of water and organic solvent approached 1:4 (v/v). At this point, the solvent compositions inside and outside the polymersomes are equal (i.e., the inner and outer osmotic pressures are equal), setting this as the equilibrium point. Continuous addition of water into the solution will push the self-assembled system to nonequilibrium as an osmotic pressure builds up over the membrane. The extra water addition makes the PS membrane more rigid and less permeable. As previously observed, (21) when the water content is 50 vol %, most of the spherical polymersomes change into rods after 4 days because the organic solvent flows out faster than water flows in, resulting in a volume decrease. The system changes back to a spherical morphology after 8 days (inflow of water releases the bending energy), indicating that the nonequilibrium shape change is driven by osmotic pressure. However, the increase of water addition leads to an increase of the membrane rigidity and a decrease of the permeability, which limits the range over which the osmotic pressure can be built up. This small range indicates that only very limited morphologies (rods, discs, and stomatocytes) are accessible with this method. Furthermore, the flexibility and mobility of the polymer chains are considerably reduced, preventing spontaneous curvature from changing and membrane fusion from taking place.
Figure 1
Figure 1. Overview of the nonequilibrium self-assembly approach. (a) Structure of the PEG-b-PS block copolymer and the formation of a polymersome from this compound. The red and blue dots represent organic solvent and water molecules, respectively. (b) Scheme of the self-assembly and PEG-induced shape transformation process. (c) Shapes captured after addition of PEG 2000 at the time of 1 min. Light blue arrow points to higher water content, and the dark blue arrow represents the PEG2000 concentration, which gradually changes from 0.01 to 5 g/L. (d) All of the shapes show different equilibrium behavior over time (red arrow).
Shape Transformation via PEG Addition
To explore new paths of polymersome shape change, PEG was selected for enhancing the osmotic pressure and the interaction with the polymersome membrane, as it has been demonstrated before to act as a fusogen of liposomes due to its osmophobic association effect. (38) This effect demonstrates that the PEG molecules are excluded from the region adjacent to the lipid vesicle surface (exclusion layer), which induces osmotic stress onto the vesicles, resulting in membrane fusion. Based on our previous report, (29) PEG with a molecular weight of 2000 was chosen as the fusogen as relatively large molecules can be excluded more effectively from the exclusion layer adjacent to the membrane surface than small molecules, which is seen as the “mechanical stress model”. (39) As shown in Figure 1b, when the volume of water reached a certain value (0.3–2 mL), 200 μL of the polymersome suspension was transferred to a centrifuge tube, followed by the addition of 10 μL of an aqueous PEG2000 solution to the suspension. The shape of polymersomes immediately changed to a variety of morphologies depending on the PEG2000 concentration and water content (Figure 1c). We expect that the added PEG2000 polymer molecules in the solution will mostly stay outside of the polymersome membranes due to their inability to penetrate the thick hydrophobic PS membranes. This PEG addition procedure pushes the polymersomes even further away from the equilibrium situation when compared to the experiments in which only water is added. The morphology was fixed by quenching 200 μL of polymersome solution with 1 mL of water for transmission electron microscopy (TEM) measurement. All shapes that were captured are presented in Figure 2, together with the preparation conditions, such as water content and PEG2000 concentration that were used for the shape transformation. This information on the morphologies was used to construct a phase diagram, which is shown in Figure 3. The solid line in this figure means that only one type of shape was observed in the particular region, and the dashed line is a mixture of both shapes.
Figure 2
Figure 2. TEM and cryo-TEM (insets) images of polymersome morphologies recorded after 1 min, as obtained after the addition of different concentrations of PEG2000. (a) Spherical vesicles (PEG2000 concentration, water content: 0.005 g/L, 23 vol %), (b) ellipsoids (0.02 g/L, 23 vol %), (c) tubes (0.05 g/L, 33 vol %), (d) discs (0.1 g/L, 50 vol %), (e) stomatocytes (0.5 g/L, 33 vol %), (f) nests (1 g/L, 23 vol %), (g) sto-in-stos (5 g/L, 23 vol %), (h) disc-in-discs (5 g/L, 33 vol %), (i) large compound vesicles (25 g/L, 23 vol %). The colors of the symbols match the ones in the phase diagram in Figure 3. Scale bar: black, 1 μm; white, 500 nm.
Figure 3
Figure 3. Phase diagram of polymersome morphologies before equilibrium. The points in the picture correspond to the images in Figure 2. The solid line means that only one shape is observed in the region; the dashed line means a mixture of two shapes in that area. The red line is defined as being the threshold concentration line for fusion.
The observed morphology changes can be categorized into two classes: (i) shape transitions with membrane fusion and (ii) transitions without membrane fusion, mainly depending on the PEG2000 concentration. When the PEG2000 concentration was above a threshold value (see the upward pointing line of the nested vesicles in the phase diagram; Figure 3, red line), the membranes started to fuse, forming nested vesicles, stomatocyte-in-stomatocytes (sto-in-stos), discocyte-in-discocytes (disc-in-discs), and large compound vesicles (LCVs) (Figure 2f–i). Below the PEG2000 threshold value, the membranes remained stable, forming ellipsoids, tubes, discs, and stomatocytes (Figure 2b–e). The different shape changes can be explained in terms of osmotic pressure and membrane permeability.
Spherical shapes (Figure 2a) are stable and sustained in the region of the phase diagram, where the PEG2000 concentration remains below 0.01 g/L and the water content is low (the situation of a highly permeable membrane) because such PEG concentrations generate very small osmotic pressures, which can easily equilibrate due to the high permeability of the membrane. Spherical shapes are also found at high PEG2000 concentrations and high water contents (the situation of a low permeable membrane) when the rigid membrane prevents water and organic solvent to leak out. A slight increase of the PEG2000 concentration at low water content leads to an increase in the induced osmotic pressure, resulting in a shape transformation from sphere to ellipsoid. The ellipsoid shape will gradually elongate to a tube by continuous increasing the osmotic pressure and water content. In the region of high organic solvent content (leading to a membrane with high permeability and low rigidity), the osmotic pressure is high enough to increase the curvature, meanwhile pushing much more organic solvent out, resulting in a shape transformation to stomatocytes. In the region of low organic solvent, the shape changes to a disc as it requires a higher bending energy for the transformation to a stomatocyte, whereas only a small volume of organic solvent is available to leak out. As can be seen in Figure 3, stomatocytes are obtained over a large region and are well under control as they are situated at the lowest energy state. Moreover, we found that the size of the opening of stomatocytes can be manipulated by adjusting the water content. As shown in Figure S1, the average diameters of the open mouth of the stomatocytes decreased from 414 to 177 nm and further to 21 nm when the water content fell from 60 to 50 vol % and then to 33.3 vol %.
Nested shape structures were formed when, with the assistance of the PEG2000, a larger reduction of the inner volume was possible, coupled with a fusion of the mouth. During this fusion process, a part of the PEG2000 solution would be entrapped inside the nested shape, leading to an increase in the organic solvent content. Higher osmotic pressure will push the organic solvent out for the second time, forming a disc-in-disc shaped structure. As demonstrated in the phase diagram, this disc-in-disc shape possesses a high bending energy, hence, capture of such morphologies is only possible when the membrane is relatively rigid. When the membrane is too flexible (water content 23 vol %), these disc and disc-in-disc shapes are not obtainable; instead, stomatocytes and sto-in-sto shapes are formed directly. If the concentration of PEG2000 is greater than 10 g/L, the polymersome corona cannot be stabilized by electrostatic and steric effects, leading to membrane fusion and to large compound vesicles. Shorter PS chain (PEG45-PS190) polymersome transformed to similar shapes as PEG45-PS230 at the same concentration (Figure S3), but the PEG45-b-PS160 polymersome membrane is too flexible to be fused to irregular shapes even at low PEG2000 concentrations (Figure S2).
Equilibration after PEG Addition
The process after PEG addition continuously induces a shape change until equilibrium is reached (Figure 1d). This shape change mainly involves three processes. First, after the first balancing of the osmotic pressure, the polymersome will reinflate by the simultaneous inflow of water and organic solvent to decrease the bending energy, while maintaining the osmotic balance. Second, PEG molecules diffusing in and out of the polymersome will continuously assist in the fusing/aggregation of the polymersomes. Third, the polymer chains will rearrange in order to release the bending energy. These three factors synergistically work on the self-assembled system through a nonequilibrium process via different morphologies to adapt to the minimum energy path. Figure 4a,b presents the phase diagram change after 2 days and 30 days. At low water content, the membrane is flexible and slightly permeable to water, allowing inflow of both water and organic solvent, resulting in the shape transformation from long/narrow tubes (∼5 μm long) to shorter/wider tubes (∼2 μm long). The shorter/wider tubes cannot transform back to spheres because they reached the kinetic equilibrium state (Figure 4c). As the shape change from sphere to disc is discontinuous, the excess energy generated from the osmotic pressure is stored in the PS membrane via polymer chain tension. This tension is then slowly alleviated in time by chain rearrangements, which can also be seen as bending energy. Thus, a high concentration of PEG creates a high osmotic pressure, which flattens the polymersome to a disc shape. The extra bending energy can be slowly released via a shape change to stomatocyte (Figure 4d). In the same context, but when PEG is present in high concentration and the membrane is plasticized by the large amount of organic solvent, all morphologies, such as sto-in-sto, disc-in-disc, and nest shapes, equilibrate to large composite vesicles, due to the interaction of PEG with the membrane of the polymersome (Figure 4f). Smaller PEG concentrations and a highly flexible membrane will push the stomatocytes to form multiopened stomatocytes (Figure 4e). Furthermore, once the membranes are fused together, it is impossible at this condition to separate them back to polymersomes again, which would need the system to overcome extremely high surface energies.
Figure 4
Figure 4. Morphology changes of polymersomes after equilibration. The phase diagrams of polymersome morphologies after equilibration for 2 days (a) and 30 days (b). At selected conditions, which are the same as in Figure 2, the long tubes (c), discs (d), stomatocytes (e), and nests (f) change to short/wide tubes, multiopened stomatocytes, and LCVs, after equilibration times of 2 days and 30 days. The colors match the labels in Figures 2 and 3. Scale bar: 1 μm.
Conclusion
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In summary, we have demonstrated a universal methodology for reshaping nanometer-scale polymersomes into various new morphologies in a controllable manner via PEG-guided nonequilibrium self-assembly. Furthermore, we have constructed the complete phase diagrams of all transitions. Each of the produced morphologies is highly uniform, and the structures are fully reproducible, including the stomatocyte openings, which can be strictly controlled. The latter is of great importance and can be used as a soft method for encapsulation purposes (e.g., of drug molecules). All structures started from a spherical morphology and transformed to various shapes via different routes whose mechanisms have been investigated. Low concentrations of PEG2000 below the threshold concentration (red line in Figure 3) induce only osmotic pressure over the membrane, resulting in the transition from the spherical shape to ellipsoid, tube, disc, and stomatocyte. Above the threshold concentration, PEG2000 not only creates a high osmotic pressure but also acts as a fusogen of the membrane due to the effect of osmophobic association, which assists the shape change to nest, sto-in-sto, disc-in-disc, and LCV. The rigidity of the membrane, which is tuned by the ratio of water and organic solvent regulates the path of the shape changes and the kinetics, allowing each shape during the transformation to be to captured in time spans varying from hours to days. We demonstrated that all of these shape transformation procedures are kinetic traps and nonequilibrium at short time scales. The kinetic pathway strongly depends on parameters such as the organic solvent (THF and dioxane) type, ratio, and water content, as well the added PEG2000. These differently shaped polymersomes are promising candidates for applications as nanocontainers or nanomachines. As we already demonstrated, the nonbiodegradable PS could be replaced by other biodegradable polymers such as poly(d,l-lactide), which exhibits a similar glassy behavior at room temperature as PS, offering opportunities for the practical application of the aggregates in drug delivery.
Experimental Methods
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Materials
All reagents and chemicals were purchased from Sigma-Aldrich and used as received. Milli-Q water (18.1 MΩ) was used throughout the experiments. The molecular weights of the block copolymers were measured with a Shimadzu Prominence GPC system equipped with a PL gel 5 μm mixed D column (Polymer Laboratories) and differential refractive index and UV (254 nm) detectors. THF was used as an eluent with a flow rate of 1 mL/min. NMR spectra were performed on a Varian Inova 400 spectrometer with CDCl3 as a solvent. Transmission electron microscopy samples were prepared in the following way: a solution of a sample (6 μL) was air-dried on a carbon-coated Cu TEM grid (200 mesh). A TEM JEOL 1010 microscope at an acceleration voltage of 60 kV was used to perform the measurements. A sonicator VWR USC300TH was used for the sonication experiments at room temperature. A JEOL 2100 cryo-transmission electron microscope was used for a detailed characterization. PEG-b-PS was synthesized as described in our previous paper. (31)
Preparation of Polymersomes
The procedure as described in our previous literature report was used. (22) A typical procedure is as follows: PEG45-b-PS230 (10 mg) was dissolved in a solvent mixture of tetrahydrofuran (THF) and 1,4-dioxane (dioxane) (1 mL, 4:1 by volume) in a 15 mL capped vial with a magnetic stirrer. After the compounds were dissolved for 1 h at room temperature, a syringe pump equipped with a syringe with a needle was calibrated to deliver water at a speed of 1 mL/h. The needle from the syringe was inserted into the vial of which the cap was replaced with a rubber septum. An amount of 0.3 mL of water was pumped into the organic solution with vigorous stirring (900 rpm). After the water addition was finished, 50 μL of the suspension was dropped at once into 1 mL of pure water with stirring, which ensured a rapid quenching of the PS domain within the bilayer of the polymersomes.
PEG Addition Methodology
A polymersome solution (200 μL, 0.8 g/L) in a mixture of THF/dioxane water = 10:3 (or 10:5, 10:10, 10:20, 10:30 and 10:40) by volume was loaded in a 1.5 mL Eppendorf centrifugation tube. An amount of 10 μL (or another amount) of a PEG2000 aqueous solution (1, 10, 100 g/L) was added to the polymersome suspension (200 μL) with a frequency of 1200. After 1 min, 20 μL of the polymersome suspension was taken out to be quenched by 1 mL of ultrapure water.
Equilibrium
The polymersome suspension was left in the shaker while the temperature was kept constant (20 °C). At the desired time, 20 μL of the polymersome suspension was quenched into 1 mL of water located in a 1.5 mL centrifuge tube. The tube was centrifuged at 10 000 rpm for 5 min to remove the added PEG. The polymersomes aggregated at the bottom of the tube were redispersed by addition of 1 mL of water, then one drop of the suspension was taken to prepare the TEM sample.
Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsnano.9b04740.
Materials and instrumentation; synthesis methods of PEG-b-PS and polymersomes, as well shape transformation via PEG addition methodology; TEM images of stomatocytes with various mouth openings; shape change of polymersomes assembled from different PS lengths (PDF)
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Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.
Author Information
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- Daniela A. Wilson - Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands;
http://orcid.org/0000-0002-8796-2274;
- Roeland J. M. Nolte - Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands;http://orcid.org/0000-0002-5612-7815
Y.M. and W.L. contributed equally. Y.M. and D.A.W. designed the experiments and wrote the manuscript. Y.M., W.L., Y.T., and F.P. performed the experiments and analyzed the results. G.-J.A.J. performed the cryo-transmission electron microscope measurements. Y.M., W.L., Y.T., F.P., R.J.M.N., and D.A.W. interpreted the results.
Acknowledgments
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This research was supported by the European Research Council via an ERC Starting grant (307679 StomaMotors) and NWO Chemische Wetenschappen (VIDI Grant 723.015.001) to D.A.W. Further support was received from the Ministry of Education, Culture and Science (Gravitation program 024.001.035). W.L. acknowledges funding from the China Scholarship Council. Y.M. acknowledges fruitful discussions with Prof. Jan van Hest.
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- 7Hotani, H. Transformation Pathways of Liposomes. J. Mol. Biol. 1984, 178, 113– 120, DOI: 10.1016/0022-2836(84)90234-1Google Scholar7Transformation pathways of liposomesHotani, HirokazuJournal of Molecular Biology (1984), 178 (1), 113-20CODEN: JMOBAK; ISSN:0022-2836.Liposomes undergoing transformation were obsd. by dark-field light microscopy to study the role of lipid in morphogenesis of biol. vesicular structures. Liposomes were found to transform sequentially in a well-defined manner through one of several transformation pathways. A circular biconcave form was an initial shape in all the pathways, and it transformed into a stable thin flexible filament or small spheres via a variety of regularly shaped vesicles which possessed geometrical symmetry. The transformation was reversible up to a certain point in each pathway. Osmotic pressure was the driving force for the transformations. Biol. membrane vesicles, such as trypsinized red cell ghosts, also transformed by similar pathways.
- 8Ahmed, F.; Photos, P. J.; Discher, D. E. Polymersomes as Viral Capsid Mimics. Drug Dev. Res. 2006, 67, 4– 14, DOI: 10.1002/ddr.20062Google Scholar8Polymersomes as viral capsid mimicsAhmed, Fariyal; Photos, Peter J.; Discher, Dennis E.Drug Development Research (2006), 67 (1), 4-14CODEN: DDREDK; ISSN:0272-4391. (Wiley-Liss, Inc.)A review. Polymersomes are self-assembled polymer shells composed of block copolymer amphiphiles. These synthetic amphiphiles have a similar amphiphilicity to lipids, but they have much larger mol. wts. and so for this reason, plus many others reviewed here, comparisons of polymersomes to viral capsids composed of large polypeptide chains seem increasingly more appropriate. The wide range of polymers being used to make polymersomes is summarized together with descriptions of phys. properties such as stability and permeability. Emerging studies of in vivo stealthiness and programmed disassembly for controlled release are also elaborated here together with a summary of targeting in vitro. Comparisons of polymersomes to viral capsids are shown to encompass many aspects of current designs.
- 9Thevenot, J.; de Oliveira, H.; Sandre, O.; Pourtau, L.; Andres, E.; Miraux, S.; Thiaudiere, E.; Berra, E.; Lecommandoux, S. Multifunctional Polymersomes for Cancer Theranostics. J. Controlled Release 2013, 172, e44– e45, DOI: 10.1016/j.jconrel.2013.08.094Google Scholar9Multifunctional polymersomes for cancer theranosticsThevenot, Julie; de Oliveira, Hugo; Sandre, Olivier; Pourtau, Line; Andres, Encarnacion; Miraux, Sylvain; Thiaudiere, Eric; Berra, Edurne; Lecommandoux, SebastienJournal of Controlled Release (2013), 172 (1), e44-e45CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A multicomponent, targeted polymersome system was designed for treatment and imaging of metastatic breast cancer. An amphiphilic block copolymer was functionalized with HER2-specific antibody for targeting. Polymersomes loaded with iron oxide also were good MRI contrast agents.
- 10Wang, J.; Liu, K.; Xing, R.; Yan, X. Peptide Self-Assembly: Thermodynamics and Kinetics. Chem. Soc. Rev. 2016, 45, 5589– 5604, DOI: 10.1039/C6CS00176AGoogle Scholar10Peptide self-assembly: thermodynamics and kineticsWang, Juan; Liu, Kai; Xing, Ruirui; Yan, XuehaiChemical Society Reviews (2016), 45 (20), 5589-5604CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)Self-assembling systems play a significant role in physiol. functions and have therefore attracted tremendous attention due to their great potential for applications in energy, biomedicine and nanotechnol. Peptides, consisting of amino acids, are among the most popular building blocks and programmable mol. motifs. Nanostructures and materials assembled using peptides exhibit important potential for green-life new technol. and biomedical applications mostly because of their bio-friendliness and reversibility. The formation of these ordered nanostructures pertains to the synergistic effect of various intermol. non-covalent interactions, including hydrogen-bonding, π-π stacking, electrostatic, hydrophobic, and van der Waals interactions. Therefore, the self-assembly process is mainly driven by thermodn.; however, kinetics is also a crit. factor in structural modulation and function integration. In this review, we focus on the influence of thermodn. and kinetic factors on structural assembly and regulation based on different types of peptide building blocks, including arom. dipeptides, amphiphilic peptides, polypeptides, and amyloid-relevant peptides.
- 11Zhang, L.; Eisenberg, A. Morphogenic Effect of Added Ions on Crew-Cut Aggregates of Polystyrene-b-Poly(acrylic acid) Block Copolymers in Solutions. Macromolecules 1996, 29, 8805– 8815, DOI: 10.1021/ma961376tGoogle Scholar11Morphogenic Effect of Added Ions on Crew-Cut Aggregates of Polystyrene-b-poly(acrylic acid) Block Copolymers in SolutionsZhang, Lifeng; Eisenberg, AdiMacromolecules (1996), 29 (27), 8805-8815CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)The morphol. of crew-cut aggregates of amphiphilic block copolymers in dil. solns. can be controlled by the addn. of ions in micromolar (HCl, NaOH, CaCl2, Ca(Ac)2) or millimolar (NaCl) concns. The copolymers are highly asym. polystyrene-b-poly(acrylic acid) diblocks, PS-b-PAA, in which the lengths of the insol. PS blocks are much longer than those of the sol. PAA blocks. In addn. to spherical, rodlike, and univesicular or lamellar aggregates, large compd. vesicles (LCVs), a new morphol., can be obtained from a single block copolymer. The morphogenic effect of different added ions on the crew-cut aggregates can be ascribed to the changed repulsive interactions among the hydrophilic PAA segments, due to neutralization by NaOH, protonation by HCl, ion-binding or bridging by Ca2+, and electrostatic screening by NaCl, resp. The formation of the LCVs may involve a secondary aggregation of individual vesicles and a subsequent fusion process. Some features of the spontaneously formed LCVs may make them esp. useful as drug delivering vehicles, and as models of biol. cells.
- 12Discher, B. M.; Won, Y.-Y.; Ege, D. S.; Lee, J. C.-M.; Bates, F. S.; Discher, D. E.; Hammer, D. A. Polymersomes: Tough Vesicles Made from Diblock Copolymers. Science 1999, 284, 1143– 1146, DOI: 10.1126/science.284.5417.1143Google Scholar12Polymersomes: Tough vesicles made from diblock copolymersDischer, Bohdana M.; Won, You-Yeon; Ege, David S.; Lee, James C.-M.; Bates, Frank S.; Discher, Dennis E.; Hammer, Daniel A.Science (Washington, D. C.) (1999), 284 (5417), 1143-1146CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Vesicles were made from amphiphilic diblock copolymers and characterized by micromanipulation. The av. mol. wt. of the specific polymer studied, polyethylene oxide-polyethylethylene (EO40-EE37), is several times greater than that of typical phospholipids in natural membranes. Both the membrane bending and area expansion moduli of electroformed polymersomes (polymer-based liposomes) fell within the range of lipid membrane measurements, but the giant polymersomes proved to be almost an order of magnitude tougher and sustained far greater areal strain before rupture. The polymersome membrane was also at least 10 times less permeable to water than common phospholipid bilayers. The results suggest a new class of synthetic thin-shelled capsules based on block copolymer chem.
- 13Pochan, D. J.; Chen, Z.; Cui, H.; Hales, K.; Qi, K.; Wooley, K. L. Toroidal Triblock Copolymer Assemblies. Science 2004, 306, 94– 97, DOI: 10.1126/science.1102866Google Scholar13Toroidal Triblock Copolymer AssembliesPochan, Darrin J.; Chen, Zhiyun; Cui, Honggang; Hales, Kelly; Qi, Kai; Wooley, Karen L.Science (Washington, DC, United States) (2004), 306 (5693), 94-97CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)A stable phase of toroidal, or ringlike, supramol. assemblies was formed by combining dil. soln. characteristics crit. for both bundling of like-charged biopolymers and block copolymer micelle formation. The key to toroid vs. classic cylinder micelle formation is the interaction of the neg. charged hydrophilic block of an amphiphilic triblock copolymer with a pos. charged divalent org. counterion. This produces a self-attraction of cylindrical micelles that leads to toroid formation, a mechanism akin to the toroidal bundling of semiflexible charged biopolymers such as DNA. The toroids can be kinetically trapped or chem. cross-linked. Insight into the mechanism of toroid formation can be gained by observation of intermediate structures kinetically trapped during film casting.
- 14van Hest, J. C. M.; Delnoye, D. A. P.; Baars, M. W. P. L.; van Genderen, M. H. P.; Meijer, E. W. Polystyrene-Dendrimer Amphiphilic Block Copolymers with a Generation-Dependent Aggregation. Science 1995, 268, 1592– 1595, DOI: 10.1126/science.268.5217.1592Google Scholar14Polystyrene-dendrimer amphiphilic block copolymers with a generation-dependent aggregationvan Hest, J. C. M.; Delnoye, D. A. P.; Baars, M. W. P. L.; van Genderen, M. H. P.; Meijer, E. W.Science (Washington, D. C.) (1995), 268 (5217), 1592-5CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)A class of amphiphilic macromols. has been synthesized by combining well-defined polystyrene (PS) with poly(propylene imine) dendrimers. Five different generations, from PS-dendr-NH2 up to Ps-dendr-(NH2)32, were prepd. in yields of 70 to 90 percent. Dynamic light scattering, cond. measurements, and transmission electron microscopy show that in aq. phases, PS-dendr-(NH2)32 forms spherical micelles, PS-dendr-(NH2)16 forms micellar rods, and PS-dendr-(NH2)8 forms vesicular structures. The lower generations of this class of macromols. show inverted micellar behavior. The obsd. effect of amphiphile geometry on aggregation behavior is in qual. agreement with the theory of J. N. Israelachvili, et al. (1976). The amphiphiles presented here are similar in shape but different in size as compared with traditional surfactants, whereas they are similar in size but different in shape as compared with traditional block copolymers.
- 15Zhang, L.; Eisenberg, A. Multiple Morphologies of ″Crew-Cut″ Aggregates of Polystyrene-b-Poly(acrylic acid) Block Copolymers. Science 1995, 268, 1728– 1731, DOI: 10.1126/science.268.5218.1728Google Scholar15Multiple morphologies of "crew-cut" aggregates of polystyrene-b-poly(acrylic acid) block copolymersZhang, Lifeng; Eisenberg, AdiScience (Washington, D. C.) (1995), 268 (5218), 1728-31CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)The observation by transmission electron microscopy of six different stable aggregate morphologies is reported for the same family of highly asym. styrene-acrylic acid diblock copolymers prepd. in a low-mol.-wt. solvent system. Four of the morphologies consist of spheres, rods, lamellae, and vesicles in aq. soln., whereas the fifth consists of simple reverse micelle-like aggregates. The sixth consists of up to micrometer-size spheres in aq. soln. that have hydrophilic surfaces and are filled with the reverse micelle-like aggregates. In addn., a needle-like solid, which is highly birefringent, is obtained on drying of aq. solns. of the spherical micelles. This range of morphologies is believed to be unprecedented for a block copolymer system.
- 16Zhang, L.; Yu, K.; Eisenberg, A. Ion-Induced Morphological Changes in “Crew-Cut” Aggregates of Amphiphilic Block Copolymers. Science 1996, 272, 1777– 1779, DOI: 10.1126/science.272.5269.1777Google Scholar16Ion-induced morphological changes in "crew-cut" aggregates of amphiphilic block copolymersZhang, Lifeng; Yu, Kui; Eisenberg, AdiScience (Washington, D. C.) (1996), 272 (5269), 1777-1779CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)The addn. of ions in micromolar (CaCl2 or HCl) or millimolar (NaCl) concns. can change the morphol. of "crew-cut" aggregates of amphiphilic block copolymers in dil. solns. In addn. to spherical, rodlike, and univesicular or lamellar aggregates, an unusual large compd. vesicle morphol. can be obtained from a single block copolymer. Some features of the spontaneously formed large compd. vesicles may make them esp. useful as vehicles for delivering drugs and as models of biol. cells. Gelation of a dil. spherical micelle soln. can also be induced by ions as the result of the formation of a cross-linked "pearl necklace" morphol.
- 17Balmert, S. C.; Little, S. R. Biomimetic Delivery with Micro- and Nanoparticles. Adv. Mater. 2012, 24, 3757– 3778, DOI: 10.1002/adma.201200224Google Scholar17Biomimetic Delivery with Micro- and NanoparticlesBalmert, Stephen C.; Little, Steven R.Advanced Materials (Weinheim, Germany) (2012), 24 (28), 3757-3778CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The nascent field of biomimetic delivery with micro- and nanoparticles (MNP) has advanced considerably in recent years. Drawing inspiration from the ways that cells communicate in the body, several different modes of "delivery" (i.e., temporospatial presentation of biol. signals) have been investigated in a no. of therapeutic contexts. In particular, this review focuses on (1) controlled release formulations that deliver natural sol. factors with physiol. relevant temporal context, (2) presentation of surface-bound ligands to cells, with spatial organization of ligands ranging from isotropic to dynamically anisotropic, and (3) phys. properties of particles, including size, shape and mech. stiffness, which mimic those of natural cells. Importantly, the context provided by multimodal, or multifactor delivery represents a key element of most biomimetic MNP systems, a concept illustrated by an analogy to human interpersonal communication. Regulatory implications of increasingly sophisticated and "cell-like" biomimetic MNP systems are also discussed.
- 18Kolhar, P.; Anselmo, A. C.; Gupta, V.; Pant, K.; Prabhakarpandian, B.; Ruoslahti, E.; Mitragotri, S. Using Shape Effects to Target Antibody-Coated Nanoparticles to Lung and Brain Endothelium. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 10753– 10758, DOI: 10.1073/pnas.1308345110Google Scholar18Using shape effects to target antibody-coated nanoparticles to lung and brain endotheliumKolhar, Poornima; Anselmo, Aaron C.; Gupta, Vivek; Pant, Kapil; Prabhakarpandian, Balabhaskar; Ruoslahti, Erkki; Mitragotri, SamirProceedings of the National Academy of Sciences of the United States of America (2013), 110 (26), 10753-10758,S10753/1-S10753/6CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Vascular endothelium offers a variety of therapeutic targets for the treatment of cancer, cardiovascular diseases, inflammation, and oxidative stress. Significant research has been focused on developing agents to target the endothelium in diseased tissues. This includes identification of antibodies against adhesion mols. and neovascular expression markers or peptides discovered using phage display. Such targeting mols. also have been used to deliver nanoparticles to the endothelium of the diseased tissue. Here we report, based on in vitro and in vivo studies, that the specificity of endothelial targeting can be enhanced further by engineering the shape of ligand-displaying nanoparticles. In vitro studies performed using microfluidic systems that mimic the vasculature (synthetic microvascular networks) showed that rod-shaped nanoparticles exhibit higher specific and lower nonspecific accumulation under flow at the target compared with their spherical counterparts. Math. modeling of particle-surface interactions suggests that the higher avidity and specificity of nanorods originate from the balance of polyvalent interactions that favor adhesion and entropic losses as well as shear-induced detachment that reduce binding. In vivo expts. in mice confirmed that shape-induced enhancement of vascular targeting is also obsd. under physiol. conditions in lungs and brain for nanoparticles displaying anti-intracellular adhesion mol. 1 and anti-transferrin receptor antibodies.
- 19Petros, R. A.; DeSimone, J. M. Strategies in the Design of Nanoparticles for Therapeutic Applications. Nat. Rev. Drug Discovery 2010, 9, 615– 627, DOI: 10.1038/nrd2591Google Scholar19Strategies in the design of nanoparticles for therapeutic applicationsPetros, Robby A.; De Simone, Joseph M.Nature Reviews Drug Discovery (2010), 9 (8), 615-627CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Engineered nanoparticles have the potential to revolutionize the diagnosis and treatment of many diseases; for example, by allowing the targeted delivery of a drug to particular subsets of cells. However, so far, such nanoparticles have not proved capable of surmounting all of the biol. barriers required to achieve this goal. Nevertheless, advances in nanoparticle engineering, as well as advances in understanding the importance of nanoparticle characteristics such as size, shape and surface properties for biol. interactions, are creating new opportunities for the development of nanoparticles for therapeutic applications. This Review focuses on recent progress important for the rational design of such nanoparticles and discusses the challenges to realizing the potential of nanoparticles.
- 20Perry, J. L.; Herlihy, K. P.; Napier, M. E.; DeSimone, J. M. PRINT: A Novel Platform Toward Shape and Size Specific Nanoparticle Theranostics. Acc. Chem. Res. 2011, 44, 990– 998, DOI: 10.1021/ar2000315Google Scholar20PRINT: A Novel Platform Toward Shape and Size Specific Nanoparticle TheranosticsPerry, Jillian L.; Herlihy, Kevin P.; Napier, Mary E.; DeSimone, Joseph M.Accounts of Chemical Research (2011), 44 (10), 990-998CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. Nanotheranostics represents the next generation of medicine, fusing nanotechnol., therapeutics, and diagnostics. By integrating therapeutic and imaging agents into one nanoparticle, this new treatment strategy has the potential not only to detect and diagnose disease but also to treat and monitor the therapeutic response. This capability could have a profound impact in both the research setting as well as in a clin. setting. In the research setting, such a capability will allow research scientists to rapidly assess the performance of new therapeutics in an effort to iterate their designs for increased therapeutic index and efficacy. In the clin. setting, theranostics offers the ability to det. whether patients enrolling in clin. trials are responding, or are expected to respond, to a given therapy based on the hypothesis assocd. with the biol. mechanisms being tested. If not, patients can be more quickly removed from the clin. trial and shifted to other therapeutic options. To be effective, these theranostic agents must be highly site specific. Optimally, they will carry relevant cargo, demonstrate controlled release of that cargo, and include imaging probes with a high signal-to-noise ratio. There are many biol. barriers in the human body that challenge the efficacy of nanoparticle delivery vehicles. These barriers include, but are not limited to, the walls of blood vessels, the phys. entrapment of particles in organs, and the removal of particles by phagocytic cells. The rapid clearance of circulating particles during systemic delivery is a major challenge; current research seeks to define key design parameters that govern the performance of nanocarriers, such as size, surface chem., elasticity, and shape. The effect of particle size and surface chem. on in vivo biodistribution of nanocarriers has been extensively studied, and general guidelines have been established. Recently it has been documented that shape and elasticity can have a profound effect on the behavior of delivery vehicles. Thus, having the ability to independently control shape, size, matrix, surface chem., and modulus is crucial for designing successful delivery agents. In this Account, we describe the use of particle replication in nonwetting templates (PRINT) to fabricate shape- and size-specific microparticles and nanoparticles. A particular strength of the PRINT method is that it affords precise control over shape, size, surface chem., and modulus. We have demonstrated the loading of PRINT particles with chemotherapeutics, magnetic resonance contrast agents, and fluorophores. The surface properties of the PRINT particles can be easily modified with "stealth" poly(ethylene glycol) chains to increase blood circulation time, with targeting moieties for targeted delivery or with radiolabels for nuclear imaging. These particles have tremendous potential for applications in nanomedicine and diagnostics.
- 21Rothenbuhler, J. R.; Huang, J.-R.; DiDonna, B. A.; Levine, A. J.; Mason, T. G. Mesoscale Structure of Diffusion-Limited Aggregates of Colloidal Rods and Disks. Soft Matter 2009, 5, 3639– 3645, DOI: 10.1039/b909740fGoogle Scholar21Mesoscale structure of diffusion-limited aggregates of colloidal rods and disksRothenbuhler, Jacob R.; Huang, Jung-Ren; DiDonna, Brian A.; Levine, Alex J.; Mason, Thomas G.Soft Matter (2009), 5 (19), 3639-3645CODEN: SMOABF; ISSN:1744-683X. (Royal Society of Chemistry)We explore the dependence of the non-universal mesoscale structure of diffusion-limited aggregates upon the shape of their constituent particles. Using random-walk simulations that model anisotropic diffusion in a viscous fluid, we study diffusion-limited aggregation (DLA) of right-circular cylinders having a wide range of length-to-diam. aspect ratios. This single-parameter family of particle shapes allows us to det. the role of particle quasi-dimensionality on the structure of DLA clusters that are composed of effectively 1D thin rods and 2D thin plates. We compare these clusters to those formed by traditional DLA of compact objects by studying the local nature of the interparticle contacts (end-end, end-body, or body-body), the distribution of the no. of interparticle contacts, and the wavevector-dependent structure factor S(q) of the resulting clusters. Clusters of rods are less dense than those of disks or compact objects of equal vol., yet the long length-scale structure of the DLA clusters conforms to the expected DLA scaling relations. However, the local structure at the particle scale, including the nearest-neighbor distribution functions and dominant collision types, depend strongly on the particle's quasi-dimensionality. We explain the non-universal local structure by introducing the concept of a diffusing particle's touch space', which incorporates both the particle's geometry and its anisotropic diffusion.
- 22Men, Y.; Peng, F.; Tu, Y.; van Hest, J. C. M.; Wilson, D. A. Methods for Production of Uniform Small-Sized Polymersome with Rigid Membrane. Polym. Chem. 2016, 7, 3977– 3982, DOI: 10.1039/C6PY00668JGoogle Scholar22Methods for production of uniform small-sized polymersome with rigid membraneMen, Yongjun; Peng, Fei; Tu, Yingfeng; van Hest, Jan C. M.; Wilson, Daniela A.Polymer Chemistry (2016), 7 (24), 3977-3982CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)We report a facile methodol. for the formation of uniform small-sized poly(ethylene glycol)-block-polystyrene (PEG-b-PS) polymersomes, via extrusion and sonication methods by using org. solvent as plasticizing agent. The obtained polymersomes have diams. less than 100 nm. The size and size distribution depend on the org. solvent content and sonication time. The small-sized polymersomes are able to carry both hydrophobic and hydrophilic dyes.
- 23Salva, R.; Le Meins, J.-F.; Sandre, O.; Brûlet, A.; Schmutz, M.; Guenoun, P.; Lecommandoux, S. Polymersome Shape Transformation at the Nanoscale. ACS Nano 2013, 7, 9298– 9311, DOI: 10.1021/nn4039589Google Scholar23Polymersome Shape Transformation at the NanoscaleSalva, Romain; Le Meins, Jean-Francois; Sandre, Olivier; Brulet, Annie; Schmutz, Marc; Guenoun, Patrick; Lecommandoux, SebastienACS Nano (2013), 7 (10), 9298-9311CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Polymer vesicles, also named polymersomes, are valuable candidates for drug delivery and micro- or nanoreactor applications. As far as drug delivery is concerned, the shape of the carrier is believed to have a strong influence on the biodistribution and cell internalization. Polymersomes can be submitted to an osmotic imbalance when injected in physiol. media leading to morphol. changes. To understand these osmotic stress-induced variations in membrane properties and shapes, several nanovesicles made of the graft polymer poly(dimethylsiloxane)-g-poly(ethylene oxide) (PDMS-g-PEO) or the triblock copolymer PEO-b-PDMS-b-PEO were osmotically stressed and obsd. by light scattering, neutron scattering (SANS), and cryo-transmission electron microscopy (cryo-TEM). Hypotonic shock leads to a swelling of the vesicles, comparable to optically observable giant polymersomes, and hypertonic shock leads to collapsed structures such as stomatocytes and original nested vesicles, the latter being only obsd. for bilayers classically formed by amphiphilic copolymers. Complementary SANS and cryo-TEM expts. are shown to be in quant. agreement and highlight the importance of the membrane structure on the behavior of these nanopolymersomes under hypertonic conditions as the final morphol. reached depends whether or not the copolymers assemble into a bilayer. The vesicle radius and membrane curvature are also shown to be crit. parameters for such transformations: the shape evolution trajectory agrees with theor. models only for large enough vesicle radii above a threshold value around 4 times the membrane thickness.
- 24Meeuwissen, S. A.; Kim, K. T.; Chen, Y.; Pochan, D. J.; van Hest, J. C. M. Controlled Shape Transformation of Polymersome Stomatocytes. Angew. Chem., Int. Ed. 2011, 50, 7070– 7073, DOI: 10.1002/anie.201102167Google Scholar24Controlled Shape Transformation of Polymersome StomatocytesMeeuwissen, Silvie A.; Kim, Kyoung-Taek; Chen, Ying-Chao; Pochan, Darrin J.; van Hest, Jan C. M.Angewandte Chemie, International Edition (2011), 50 (31), 7070-7073, S7070/1-S7070/14CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)We report here a controllable shape transformation of polymer vesicles (polymersomes) constructed from block copolymers of which the hydrophobic part is a high-mol.-wt. glassy segment. Control over the shape transformation is obtained by kinetic manipulation of the phase behavior of this glassy hydrophobic segment. Kinetic manipulation of the phase behavior of polymer membranes allows for different shapes of polymersomes to be captured at specific times, which directly translates into phys. robust nanostructures that are otherwise unobtainable. Combining the morphol. diversity of giant liposomes and the phys. robustness of polymersomes, our finding can be a general way to realize unusual nanostructures in a predictable manner.
- 25Abdelmohsen, L. K. E. A.; Williams, D. S.; Pille, J.; Ozel, S. G.; Rikken, R. S. M.; Wilson, D. A.; van Hest, J. C. M. Formation of Well-Defined, Functional Nanotubes via Osmotically Induced Shape Transformation of Biodegradable Polymersomes. J. Am. Chem. Soc. 2016, 138, 9353– 9356, DOI: 10.1021/jacs.6b03984Google Scholar25Formation of Well-Defined, Functional Nanotubes via Osmotically Induced Shape Transformation of Biodegradable PolymersomesAbdelmohsen, Loai K. E. A.; Williams, David S.; Pille, Jan; Ozel, Sema G.; Rikken, Roger S. M.; Wilson, Daniela A.; van Hest, Jan C. M.Journal of the American Chemical Society (2016), 138 (30), 9353-9356CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Polymersomes are robust, versatile nanostructures that can be tailored by varying the chem. structure of copolymeric building blocks, giving control over their size, shape, surface chem., and membrane permeability. In particular, the generation of nonspherical nanostructures has attracted much attention recently, as it has been demonstrated that shape affects function in a biomedical context. Until now, nonspherical polymersomes have only been constructed from nondegradable building blocks, hampering a detailed investigation of shape effects in nanomedicine for this category of nanostructures. Herein, we demonstrate the spontaneous elongation of spherical polymersomes comprising the biodegradable copolymer poly(ethylene glycol)-b-poly(D,L-lactide) into well-defined nanotubes. The size of these tubes is osmotically controlled using dialysis, which makes them very easy to prep. To confirm their utility for biomedical applications, we have demonstrated that, alongside drug loading, functional proteins can be tethered to the surface utilizing bio-orthogonal "click" chem. In this way the present findings establish a novel platform for the creation of biocompatible, high-aspect ratio nanoparticles for biomedical research.
- 26Blanazs, A.; Madsen, J.; Battaglia, G.; Ryan, A. J.; Armes, S. P. Mechanistic Insights for Block Copolymer Morphologies: How Do Worms Form Vesicles?. J. Am. Chem. Soc. 2011, 133, 16581– 16587, DOI: 10.1021/ja206301aGoogle Scholar26Mechanistic Insights for Block Copolymer Morphologies: How Do Worms Form Vesicles?Blanazs, Adam; Madsen, Jeppe; Battaglia, Giuseppe; Ryan, Anthony J.; Armes, Steven P.Journal of the American Chemical Society (2011), 133 (41), 16581-16587CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Amphiphilic diblock copolymers composed of two covalently linked, chem. distinct chains can be considered to be biol. mimics of cell membrane-forming lipid mols., but with typically more than an order of magnitude increase in mol. wt. These macromol. amphiphiles are known to form a wide range of nanostructures (spheres, worms, vesicles, etc.) in solvents that are selective for one of the blocks. However, such self-assembly is usually limited to dil. copolymer solns. (<1%), which is a significant disadvantage for potential com. applications such as drug delivery and coatings. In principle, this problem can be circumvented by polymn.-induced block copolymer self-assembly. Here the authors detail the synthesis and subsequent in situ self-assembly of amphiphilic AB diblock copolymers in a one pot concd. aq. dispersion polymn. formulation. The authors show that spherical micelles, wormlike micelles, and vesicles can be predictably and efficiently obtained (within 2 h of polymn., >99% monomer conversion) at relatively high solids in purely aq. soln. Furthermore, careful monitoring of the in situ polymn. by transmission electron microscopy reveals various novel intermediate structures (including branched worms, partially coalesced worms, nascent bilayers, "octopi", "jellyfish", and finally pure vesicles) that provide important mechanistic insights regarding the evolution of the particle morphol. during the sphere-to-worm and worm-to-vesicle transitions. This environmentally benign approach (which involves no toxic solvents, is conducted at relatively high solids, and requires no addnl. processing) is readily amenable to industrial scale-up, since it is based on com. available starting materials.
- 27Deng, Z.; Qian, Y.; Yu, Y.; Liu, G.; Hu, J.; Zhang, G.; Liu, S. Engineering Intracellular Delivery Nanocarriers and Nanoreactors from Oxidation-Responsive Polymersomes via Synchronized Bilayer Cross-Linking and Permeabilizing Inside Live Cells. J. Am. Chem. Soc. 2016, 138, 10452– 10466, DOI: 10.1021/jacs.6b04115Google Scholar27Engineering Intracellular Delivery Nanocarriers and Nanoreactors from Oxidation-Responsive Polymersomes via Synchronized Bilayer Cross-Linking and Permeabilizing Inside Live CellsDeng, Zhengyu; Qian, Yinfeng; Yu, Yongqiang; Liu, Guhuan; Hu, Jinming; Zhang, Guoying; Liu, ShiyongJournal of the American Chemical Society (2016), 138 (33), 10452-10466CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Reactive oxygen species (ROS) and oxidative stress are implicated in various physiol. and pathol. processes and this feature provides a vital biochem. basis for designing novel therapeutic and diagnostic nanomedicines. Among them, oxidn.-responsive micelles and vesicles (polymersomes) of amphiphilic block copolymers have been extensively explored; however, in previous works, oxidn. by ROS including H2O2 exclusively leads to microstructural destruction of polymeric assemblies. For oxidn.-responsive polymersomes, fast release of encapsulated hydrophilic drugs and bioactive macromols. will occur upon microstructural disintegration. Under certain application circumstances, this does not meet design requirements for sustained-release drug nanocarriers and long-acting in vivo nanoreactors. Also note that conventional polymersomes possess thick hydrophobic bilayers and compromised membrane permeability, rendering them as ineffective nanocarriers and nanoreactors. We herein report the fabrication of oxidn.-responsive multifunctional polymersomes exhibiting intracellular milieu-triggered vesicle bilayer crosslinking, permeability switching, and enhanced imaging/drug release features. Mitochondria-targeted H2O2 reactive polymersomes were obtained through the self-assembly of amphiphilic block copolymers contg. arylboronate ester-capped self-immolative side linkages in the hydrophobic block, followed by surface functionalization with targeting peptides. Upon cellular uptake, intracellular H2O2 triggers cascade decaging reactions and generates primary amine moieties; prominent amidation reaction then occurs within hydrophobic bilayer membranes, resulting in concurrent crosslinking and hydrophobic-to-hydrophilic transition of polymersome bilayers inside live cells. This process was further utilized to achieve integrated functions such as sustained drug release, (combination) chemotherapy monitored by fluorescence and magnetic resonance (MR) imaging turn-on, and to construct intracellular fluorogenic nanoreactors for cytosolic thiol-contg. bioactive mols.
- 28Du, J.; Tang, Y.; Lewis, A. L.; Armes, S. P. pH-Sensitive Vesicles Based on a Biocompatible Zwitterionic Diblock Copolymer. J. Am. Chem. Soc. 2005, 127, 17982– 17983, DOI: 10.1021/ja056514lGoogle Scholar28pH-Sensitive vesicles based on a biocompatible zwitterionic diblock copolymerDu, Jianzhong; Tang, Yiqing; Lewis, Andrew L.; Armes, Steven P.Journal of the American Chemical Society (2005), 127 (51), 17982-17983CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Highly biocompatible pH-sensitive diblock copolymer vesicles were prepd. from the self-assembly of a biocompatible zwitterionic copolymer, poly[2-(methacryloyloxy)ethyl phosphorylcholine-block-2-(diisopropylamino)ethyl methacrylate], PMPC-b-PDPA. Vesicle formation occurred spontaneously by adjusting the soln. pH from pH 2 to above 6, with the hydrophobic PDPA chains forming the vesicle walls. Transmission electron microscopy (TEM), dynamic laser light scattering (DLS), and UV-visible absorption spectrophotometry were used to characterize these vesicles. Gold nanoparticle-decorated vesicles were also obtained by treating the vesicles with HAuCl4, followed by NaBH4.
- 29Kim, K. T.; Zhu, J.; Meeuwissen, S. A.; Cornelissen, J. J. L. M.; Pochan, D. J.; Nolte, R. J. M.; van Hest, J. C. M. Polymersome Stomatocytes: Controlled Shape Transformation in Polymer Vesicles. J. Am. Chem. Soc. 2010, 132, 12522– 12524, DOI: 10.1021/ja104154tGoogle Scholar29Polymersome Stomatocytes: Controlled Shape Transformation in Polymer VesiclesKim, Kyoung Taek; Zhu, Jiahua; Meeuwissen, Silvie A.; Cornelissen, Jeroen J. L. M.; Pochan, Darrin J.; Nolte, Roeland J. M.; van Hest, Jan C. M.Journal of the American Chemical Society (2010), 132 (36), 12522-12524CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)We report here a controllable shape transformation of polymer vesicles (polymersomes) constructed from block copolymers of which the hydrophobic part is a high-mol.-wt. glassy segment. Control over the shape transformation is obtained by kinetic manipulation of the phase behavior of this glassy hydrophobic segment. Kinetic manipulation of the phase behavior of polymer membranes allows for different shapes of polymersomes to be captured at specific times, which directly translates into phys. robust nanostructures that are otherwise unobtainable. Combining the morphol. diversity of giant liposomes and the phys. robustness of polymersomes, our finding can be a general way to realize unusual nanostructures in a predictable manner.
- 30Ladmiral, V.; Semsarilar, M.; Canton, I.; Armes, S. P. Polymerization-Induced Self-Assembly of Galactose-Functionalized Biocompatible Diblock Copolymers for Intracellular Delivery. J. Am. Chem. Soc. 2013, 135, 13574– 13581, DOI: 10.1021/ja407033xGoogle Scholar30Polymerization-Induced Self-Assembly of Galactose-Functionalized Biocompatible Diblock Copolymers for Intracellular DeliveryLadmiral, Vincent; Semsarilar, Mona; Canton, Irene; Armes, Steven P.Journal of the American Chemical Society (2013), 135 (36), 13574-13581CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Recent advances in polymer science are enabling substantial progress in nanobiotechnol., particularly in the design of new tools for enhanced understanding of cell biol. and for smart drug delivery formulations. Herein, a range of novel galactosylated diblock copolymer nano-objects is prepd. directly in concd. aq. soln. via reversible addn.-fragmentation chain transfer polymn. using polymn.-induced self-assembly. The resulting nanospheres, worm-like micelles, or vesicles interact in vitro with galectins as judged by a turbidity assay. In addn., galactosylated vesicles are highly biocompatible and allow intracellular delivery of an encapsulated mol. cargo.
- 31Men, Y.; Li, W.; Janssen, G.-J.; Rikken, R. S. M.; Wilson, D. A. Stomatocyte in Stomatocyte: A New Shape of Polymersome Induced via Chemical-Addition Methodology. Nano Lett. 2018, 18, 2081– 2085, DOI: 10.1021/acs.nanolett.8b00187Google Scholar31Stomatocyte in Stomatocyte: A New Shape of Polymersome Induced via Chemical-Addition MethodologyMen, Yongjun; Li, Wei; Janssen, Geert-Jan; Rikken, Roger S. M.; Wilson, Daniela A.Nano Letters (2018), 18 (3), 2081-2085CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)Accurate control of the shape transformation of polymersome is an important and interesting challenge that spans across disciplines such as nanomedicine and nanomachine. Here, we report a fast and facile methodol. of shape manipulation of polymersome via out-of-equil. polymer self-assembly and shape change by chem. addn. of additives. Due to its increased permeability, hydrophilicity, and fusogenic properties, poly(ethylene oxide) was selected as the additive for bringing the system out of equil. via fast addn. into the polymersome org. soln. A new shape, stomatocyte-in-stomatocyte (sto-in-sto), is obtained for the first time. Moreover, fast shape transformation within less than 1 min to other relevant shapes such as stomatocyte and large compd. vesicles was also obtained and accurately controlled in a uniform dispersion. This methodol. is demonstrated as a general strategy with which to push the assembly further out of equil. to generate unusual nanostructures in a controllable and fast manner.
- 32Zhu, J.; Zhang, S.; Zhang, K.; Wang, X.; Mays, J. W.; Wooley, K. L.; Pochan, D. J. Disk-Cylinder and Disk-Sphere Nanoparticles via A Block Copolymer Blend Solution Construction. Nat. Commun. 2013, 4, 2297, DOI: 10.1038/ncomms3297Google Scholar32Disk-cylinder and disk-sphere nanoparticles via a block copolymer blend solution constructionZhu Jiahua; Zhang Shiyi; Zhang Ke; Wang Xiaojun; Mays Jimmy W; Wooley Karen L; Pochan Darrin JNature communications (2013), 4 (), 2297 ISSN:.Researchers strive to produce nanoparticles with complexity in composition and structure. Although traditional spherical, cylindrical and membranous, or planar, nanostructures are ubiquitous, scientists seek more complicated geometries for potential functionality. Here we report the simple solution construction of multigeometry nanoparticles, disk-sphere and disk-cylinder, through a straightforward, molecular-level, blending strategy with binary mixtures of block copolymers. The multigeometry nanoparticles contain disk geometry in the core with either spherical patches along the disk periphery in the case of disk-sphere particles or cylindrical edges and handles in the case of the disk-cylinder particles. The portions of different geometry in the same nanoparticles contain different core block chemistry, thus also defining multicompartments in the nanoparticles. Although the block copolymers chosen for the blends are important for the definition of the final hybrid particles, the control of the kinetic pathway of assembly is critical for successful multigeometry particle construction.
- 33Wong, C. K.; Mason, A. F.; Stenzel, M. H.; Thordarson, P. Formation of Non-Spherical Polymersomes Driven by Hydrophobic Directional Aromatic Perylene Interactions. Nat. Commun. 2017, 8, 1240, DOI: 10.1038/s41467-017-01372-zGoogle Scholar33Formation of non-spherical polymersomes driven by hydrophobic directional aromatic perylene interactionsWong Chin Ken; Mason Alexander F; Stenzel Martina H; Thordarson Pall; Wong Chin Ken; Mason Alexander F; Thordarson Pall; Wong Chin Ken; Stenzel Martina HNature communications (2017), 8 (1), 1240 ISSN:.Polymersomes, made up of amphiphilic block copolymers, are emerging as a powerful tool in drug delivery and synthetic biology due to their high stability, chemical versatility, and surface modifiability. The full potential of polymersomes, however, has been hindered by a lack of versatile methods for shape control. Here we show that a range of non-spherical polymersome morphologies with anisotropic membranes can be obtained by exploiting hydrophobic directional aromatic interactions between perylene polymer units within the membrane structure. By controlling the extent of solvation/desolvation of the aromatic side chains through changes in solvent quality, we demonstrate facile access to polymersomes that are either ellipsoidal or tubular-shaped. Our results indicate that perylene aromatic interactions have a great potential in the design of non-spherical polymersomes and other structurally complex self-assembled polymer structures.
- 34Wong, C. K.; Martin, A. D.; Floetenmeyer, M.; Parton, R. G.; Stenzel, M. H.; Thordarson, P. Faceted Polymersomes: A Sphere-to-Polyhedron Shape Transformation. Chem. Sci. 2019, 10, 2725– 2731, DOI: 10.1039/C8SC04206CGoogle Scholar34Faceted polymersomes: a sphere-to-polyhedron shape transformationWong, Chin Ken; Martin, Adam D.; Floetenmeyer, Matthias; Parton, Robert G.; Stenzel, Martina H.; Thordarson, PallChemical Science (2019), 10 (9), 2725-2731CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)The creation of "soft" deformable hollow polymeric nanoparticles with complex non-spherical shapes via block copolymer self-assembly remains a challenge. In this work, we show that a perylene-bearing block copolymer can self-assemble into polymeric membrane sacs (polymersomes) that not only possess uncommonly faceted polyhedral shapes but are also intrinsically fluorescent. Here, we further reveal for the first time an exptl. visualization of the entire polymersome faceting process. We uncover how our polymersomes facet through a sphere-to-polyhedron shape transformation pathway that is driven by perylene aggregation confined within a topol. spherical polymersome shell. Finally, we illustrate the importance in understanding this shape transformation process by demonstrating our ability to controllably isolate different intermediate polymersome morphologies. The findings presented herein should provide opportunities for those who utilize non-spherical polymersomes for drug delivery, nanoreactor or templating applications, and those who are interested in the fundamental aspects of polymersome self-assembly.
- 35Wong, C. K.; Stenzel, M. H.; Thordarson, P. Non-Spherical Polymersomes: Formation and Characterization. Chem. Soc. Rev. 2019, 48, 4019– 4035, DOI: 10.1039/C8CS00856FGoogle Scholar35Non-spherical polymersomes: formation and characterizationWong, Chin Ken; Stenzel, Martina H.; Thordarson, PallChemical Society Reviews (2019), 48 (15), 4019-4035CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. Polymersomes are self-assembled hollow membrane sacs that are not only able to encapsulate hydrophobic and/or hydrophilic mols., but also possess exceptional chem. and phys. stability, structural versatility, and surface modifiability. For the above reasons, polymersomes have in recent years emerged as a powerful tool for a wide range of applications in the fields of biomimicry and drug delivery. The full potential of polymersomes, however, has yet to be harnessed due to a lack of appreciation of existing shape control methods. This very much contrasts the field of inorg. nanoparticle synthesis where non-spherical hollow metal nanoparticles are routinely prepd. and used. Here, we summarize recent efforts over the past decade to study the morphol. transformation of conventionally spherical polymersomes into non-spherical polymersomes.
- 36van Oers, M. C. M.; Rutjes, F. P. J. T.; van Hest, J. C. M. Tubular Polymersomes: A Cross-Linker-Induced Shape Transformation. J. Am. Chem. Soc. 2013, 135, 16308– 16311, DOI: 10.1021/ja408754zGoogle Scholar36Tubular Polymersomes: A Cross-Linker-Induced Shape Transformationvan Oers, Matthijs C. M.; Rutjes, Floris P. J. T.; van Hest, Jan C. M.Journal of the American Chemical Society (2013), 135 (44), 16308-16311CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Polymersomes, polymeric vesicles constructed of block copolymers, can undergo a sphere-to-tubule transition under the influence of a chem. modification of the polymeric bilayer. A strain-promoted alkyne-azide cycloaddn. (SPAAC) reaction between azide handles inside the hydrophobic domain of the membrane and an excess of a bicyclo[6.1.0]-nonyne (BCN)-cross-linker causes the vesicle to stretch in one dimension. Tubular polymersomes up to 2 μm in length can be obtained with this shape transformation. The introduction of a cleavable cross-linker makes this process reversible and opens the way for future drug delivery applications.
- 37Rikken, R. S. M.; Engelkamp, H.; Nolte, R. J. M.; Maan, J. C.; van Hest, J. C. M.; Wilson, D. A.; Christianen, P. C. M. Shaping Polymersomes into Predictable Morphologies via Out-of-Equilibrium Self-Assembly. Nat. Commun. 2016, 7, 12606, DOI: 10.1038/ncomms12606Google Scholar37Shaping polymersomes into predictable morphologies via out-of-equilibrium self-assemblyRikken, R. S. M.; Engelkamp, H.; Nolte, R. J. M.; Maan, J. C.; van Hest, J. C. M.; Wilson, D. A.; Christianen, P. C. M.Nature Communications (2016), 7 (), 12606CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)Polymersomes are bilayer vesicles, self-assembled from amphiphilic block copolymers. They are versatile nanocapsules with adjustable properties, such as flexibility, permeability, size and functionality. However, so far no methodol. approach to control their shape exists. Here we demonstrate a mechanistically fully understood procedure to precisely control polymersome shape via an out-of-equil. process. Carefully selecting osmotic pressure and permeability initiates controlled deflation, resulting in transient capsule shapes, followed by reinflation of the polymersomes. The shape transformation towards stomatocytes, bowl-shaped vesicles, was probed with magnetic birefringence, permitting us to stop the process at any intermediate shape in the phase diagram. Quant. electron microscopy anal. of the different morphologies reveals that this shape transformation proceeds via a long-predicted hysteretic deflation-inflation trajectory, which can be understood in terms of bending energy. Because of the high degree of controllability and predictability, this study provides the design rules for accessing polymersomes with all possible different shapes.
- 38Yamazaki, M.; Ito, T. Deformation and Instability of Membrane Structure of Phospholipid Vesicles Caused by Osmophobic Association: Mechanical Stress Model for the Mechanism of Poly(Ethylene Glycol)-Induced Membrane Fusion. Biochemistry 1990, 29, 1309– 1314, DOI: 10.1021/bi00457a029Google Scholar38Deformation and instability of membrane structure of phospholipid vesicles caused by osmophobic association: mechanical stress model for the mechanism of poly(ethylene glycol)-induced membrane fusionYamazaki, Masahito; Ito, TadanaoBiochemistry (1990), 29 (5), 1309-14CODEN: BICHAW; ISSN:0006-2960.The mechanism of poly(ethylene glycol)-induced fusion of phospholipid vesicles was studied based on the osmophobic assocn. theory which was recently proposed both theor. (Ito, T., et al., 1989) and exptl. (Yamazaki, M., et al., 1989). Osmophobic assocn. and fusion were detected by measuring the light scattering of the vesicle suspension; the former was detected from the increase in light scattering induced by the addn. of PEG, and the latter was from the irreversibility of the increase in light scattering. Threshold concns. of PEG were required not only for osmophobic assocn. but also for fusion. The threshold concn. for fusion depended on the mol. wt. of PEG and also on the electrostatic repulsive interaction between phospholipid vesicles, which was manipulated by the use of vesicles with neg. surface charge; increasing the mol. wt. of PEG lowered the threshold concn., and increasing the electrostatic repulsive interaction raised it. In addn., a transient leakage of internal contents from the vesicles was obsd. at the concn. that caused fusion. When the surface charge of the vesicle was varied, the threshold for fusion coincided with that for osmophobic assocn., provided that the latter was >22 wt % of PEG 6000. However, when the threshold for osmophobic assocn. was <22 wt %, the threshold for fusion remained ∼22 wt %, irresp. of the difference in the threshold for osmophobic assocn. Electron microphotographs of quick-frozen replicas of egg yolk phosphatidylcholine vesicles showed that the vesicles in the aggregate caused by PEG-induced osmophobic assocn. were deformed to increase their area of contact with the adjacent vesicles. According to the anal. based on the osmophobic assocn. theory, the mech. force (f) that causes the deformation of the vesicle (deformation force) is counterbalanced by the thermodn. force due to osmophobic assocn., increasing with increased concns. of PEG, but it is little affected by the electrostatic repulsive interaction between the vesicles. On the basis of the results described above, a mech. stress model is proposed for the mechanism of PEG-induced fusion. Membranes that are tightly assocd. by osmophobic assocn. are mech. strained by the deformation force f. Consequently, the membrane structure becomes unstable at increased concns. of PEG, and above a crit. concn., ∼22 wt % of PEG 6000, destruction of the bilayer structure into a leaky membrane structure may cause fusion.
- 39Yamazaki, M.; Ohnishi, S.; Ito, T. Osmoelastic Coupling in Biological Structures: Decrease in Membrane Fluidity and Osmophobic Association of Phospholipid Vesicles in Response to Osmotic Stress. Biochemistry 1989, 28, 3710– 3715, DOI: 10.1021/bi00435a013Google Scholar39Osmoelastic coupling in biological structures: decrease in membrane fluidity and osmophobic association of phospholipid vesicles in response to osmotic stressYamazaki, Masahito; Ohnishi, Shunichi; Ito, TadanaoBiochemistry (1989), 28 (9), 3710-15CODEN: BICHAW; ISSN:0006-2960.PEG-induced changes in membrane fluidity and aggregation of phospholipid vesicles were studied. A threshold concn. of PEG was required to induce the aggregation. This concn. increased with a decrease in the mol. wt. of PEG, e.g., from 5% with PEG 6000 (PEG with an av. mol. wt. of 7500) to >30% with PEG 200. The aggregation was reversible upon diln. of PEG if the initial PEG concn. was smaller than a certain value, e.g., 22% for PEG 6000. Addn. of PEG caused a decrease in membrane fluidity of the vesicles detected by fluorescence anisotropy of diphenylhexatriene and by ESR of a spin-labeled fatty acid. The fluidity change (as detected by the diphenylhexatriene anisotropy change) had an inflection point at ∼5% of PEG 6000, which suggests that the aggregation would make the decrease of membrane fluidity smaller. Transfer of lipid mols. between phospholipid vesicles was enhanced by the PEG-induced aggregation. The enhancement occurred not only upon direct addn. of PEG to the suspending medium, but also upon dialysis of the vesicle suspension against a high concn. of PEG. All these features are consistent with osmoelastic coupling in the phospholipid membranes and the subsequent osmophobic assocn. of the vesicles. The imbalance of osmolarity between the region adjacent to the vesicle surface (exclusion layer) and the bulk aq. phase, which results from the preferential exclusion of PEG from the exclusion layer in the case of direct addn. of PEG, exerts an osmotic stress on the vesicles. The osmotic stress would be counterbalanced by an elastic pressure resulting from elastic strain of the membrane, and it would increase the free energy of vesicles in the dispersed state (osmoelastic coupling). When the osmotic stress exceeds a threshold level, the vesicles would aggregate to avoid further increase in the free energy (osmophobic assocn.).
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Abstract
Figure 1
Figure 1. Overview of the nonequilibrium self-assembly approach. (a) Structure of the PEG-b-PS block copolymer and the formation of a polymersome from this compound. The red and blue dots represent organic solvent and water molecules, respectively. (b) Scheme of the self-assembly and PEG-induced shape transformation process. (c) Shapes captured after addition of PEG 2000 at the time of 1 min. Light blue arrow points to higher water content, and the dark blue arrow represents the PEG2000 concentration, which gradually changes from 0.01 to 5 g/L. (d) All of the shapes show different equilibrium behavior over time (red arrow).
Figure 2
Figure 2. TEM and cryo-TEM (insets) images of polymersome morphologies recorded after 1 min, as obtained after the addition of different concentrations of PEG2000. (a) Spherical vesicles (PEG2000 concentration, water content: 0.005 g/L, 23 vol %), (b) ellipsoids (0.02 g/L, 23 vol %), (c) tubes (0.05 g/L, 33 vol %), (d) discs (0.1 g/L, 50 vol %), (e) stomatocytes (0.5 g/L, 33 vol %), (f) nests (1 g/L, 23 vol %), (g) sto-in-stos (5 g/L, 23 vol %), (h) disc-in-discs (5 g/L, 33 vol %), (i) large compound vesicles (25 g/L, 23 vol %). The colors of the symbols match the ones in the phase diagram in Figure 3. Scale bar: black, 1 μm; white, 500 nm.
Figure 3
Figure 3. Phase diagram of polymersome morphologies before equilibrium. The points in the picture correspond to the images in Figure 2. The solid line means that only one shape is observed in the region; the dashed line means a mixture of two shapes in that area. The red line is defined as being the threshold concentration line for fusion.
Figure 4
Figure 4. Morphology changes of polymersomes after equilibration. The phase diagrams of polymersome morphologies after equilibration for 2 days (a) and 30 days (b). At selected conditions, which are the same as in Figure 2, the long tubes (c), discs (d), stomatocytes (e), and nests (f) change to short/wide tubes, multiopened stomatocytes, and LCVs, after equilibration times of 2 days and 30 days. The colors match the labels in Figures 2 and 3. Scale bar: 1 μm.
References
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- 8Ahmed, F.; Photos, P. J.; Discher, D. E. Polymersomes as Viral Capsid Mimics. Drug Dev. Res. 2006, 67, 4– 14, DOI: 10.1002/ddr.200628Polymersomes as viral capsid mimicsAhmed, Fariyal; Photos, Peter J.; Discher, Dennis E.Drug Development Research (2006), 67 (1), 4-14CODEN: DDREDK; ISSN:0272-4391. (Wiley-Liss, Inc.)A review. Polymersomes are self-assembled polymer shells composed of block copolymer amphiphiles. These synthetic amphiphiles have a similar amphiphilicity to lipids, but they have much larger mol. wts. and so for this reason, plus many others reviewed here, comparisons of polymersomes to viral capsids composed of large polypeptide chains seem increasingly more appropriate. The wide range of polymers being used to make polymersomes is summarized together with descriptions of phys. properties such as stability and permeability. Emerging studies of in vivo stealthiness and programmed disassembly for controlled release are also elaborated here together with a summary of targeting in vitro. Comparisons of polymersomes to viral capsids are shown to encompass many aspects of current designs.
- 9Thevenot, J.; de Oliveira, H.; Sandre, O.; Pourtau, L.; Andres, E.; Miraux, S.; Thiaudiere, E.; Berra, E.; Lecommandoux, S. Multifunctional Polymersomes for Cancer Theranostics. J. Controlled Release 2013, 172, e44– e45, DOI: 10.1016/j.jconrel.2013.08.0949Multifunctional polymersomes for cancer theranosticsThevenot, Julie; de Oliveira, Hugo; Sandre, Olivier; Pourtau, Line; Andres, Encarnacion; Miraux, Sylvain; Thiaudiere, Eric; Berra, Edurne; Lecommandoux, SebastienJournal of Controlled Release (2013), 172 (1), e44-e45CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A multicomponent, targeted polymersome system was designed for treatment and imaging of metastatic breast cancer. An amphiphilic block copolymer was functionalized with HER2-specific antibody for targeting. Polymersomes loaded with iron oxide also were good MRI contrast agents.
- 10Wang, J.; Liu, K.; Xing, R.; Yan, X. Peptide Self-Assembly: Thermodynamics and Kinetics. Chem. Soc. Rev. 2016, 45, 5589– 5604, DOI: 10.1039/C6CS00176A10Peptide self-assembly: thermodynamics and kineticsWang, Juan; Liu, Kai; Xing, Ruirui; Yan, XuehaiChemical Society Reviews (2016), 45 (20), 5589-5604CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)Self-assembling systems play a significant role in physiol. functions and have therefore attracted tremendous attention due to their great potential for applications in energy, biomedicine and nanotechnol. Peptides, consisting of amino acids, are among the most popular building blocks and programmable mol. motifs. Nanostructures and materials assembled using peptides exhibit important potential for green-life new technol. and biomedical applications mostly because of their bio-friendliness and reversibility. The formation of these ordered nanostructures pertains to the synergistic effect of various intermol. non-covalent interactions, including hydrogen-bonding, π-π stacking, electrostatic, hydrophobic, and van der Waals interactions. Therefore, the self-assembly process is mainly driven by thermodn.; however, kinetics is also a crit. factor in structural modulation and function integration. In this review, we focus on the influence of thermodn. and kinetic factors on structural assembly and regulation based on different types of peptide building blocks, including arom. dipeptides, amphiphilic peptides, polypeptides, and amyloid-relevant peptides.
- 11Zhang, L.; Eisenberg, A. Morphogenic Effect of Added Ions on Crew-Cut Aggregates of Polystyrene-b-Poly(acrylic acid) Block Copolymers in Solutions. Macromolecules 1996, 29, 8805– 8815, DOI: 10.1021/ma961376t11Morphogenic Effect of Added Ions on Crew-Cut Aggregates of Polystyrene-b-poly(acrylic acid) Block Copolymers in SolutionsZhang, Lifeng; Eisenberg, AdiMacromolecules (1996), 29 (27), 8805-8815CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)The morphol. of crew-cut aggregates of amphiphilic block copolymers in dil. solns. can be controlled by the addn. of ions in micromolar (HCl, NaOH, CaCl2, Ca(Ac)2) or millimolar (NaCl) concns. The copolymers are highly asym. polystyrene-b-poly(acrylic acid) diblocks, PS-b-PAA, in which the lengths of the insol. PS blocks are much longer than those of the sol. PAA blocks. In addn. to spherical, rodlike, and univesicular or lamellar aggregates, large compd. vesicles (LCVs), a new morphol., can be obtained from a single block copolymer. The morphogenic effect of different added ions on the crew-cut aggregates can be ascribed to the changed repulsive interactions among the hydrophilic PAA segments, due to neutralization by NaOH, protonation by HCl, ion-binding or bridging by Ca2+, and electrostatic screening by NaCl, resp. The formation of the LCVs may involve a secondary aggregation of individual vesicles and a subsequent fusion process. Some features of the spontaneously formed LCVs may make them esp. useful as drug delivering vehicles, and as models of biol. cells.
- 12Discher, B. M.; Won, Y.-Y.; Ege, D. S.; Lee, J. C.-M.; Bates, F. S.; Discher, D. E.; Hammer, D. A. Polymersomes: Tough Vesicles Made from Diblock Copolymers. Science 1999, 284, 1143– 1146, DOI: 10.1126/science.284.5417.114312Polymersomes: Tough vesicles made from diblock copolymersDischer, Bohdana M.; Won, You-Yeon; Ege, David S.; Lee, James C.-M.; Bates, Frank S.; Discher, Dennis E.; Hammer, Daniel A.Science (Washington, D. C.) (1999), 284 (5417), 1143-1146CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Vesicles were made from amphiphilic diblock copolymers and characterized by micromanipulation. The av. mol. wt. of the specific polymer studied, polyethylene oxide-polyethylethylene (EO40-EE37), is several times greater than that of typical phospholipids in natural membranes. Both the membrane bending and area expansion moduli of electroformed polymersomes (polymer-based liposomes) fell within the range of lipid membrane measurements, but the giant polymersomes proved to be almost an order of magnitude tougher and sustained far greater areal strain before rupture. The polymersome membrane was also at least 10 times less permeable to water than common phospholipid bilayers. The results suggest a new class of synthetic thin-shelled capsules based on block copolymer chem.
- 13Pochan, D. J.; Chen, Z.; Cui, H.; Hales, K.; Qi, K.; Wooley, K. L. Toroidal Triblock Copolymer Assemblies. Science 2004, 306, 94– 97, DOI: 10.1126/science.110286613Toroidal Triblock Copolymer AssembliesPochan, Darrin J.; Chen, Zhiyun; Cui, Honggang; Hales, Kelly; Qi, Kai; Wooley, Karen L.Science (Washington, DC, United States) (2004), 306 (5693), 94-97CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)A stable phase of toroidal, or ringlike, supramol. assemblies was formed by combining dil. soln. characteristics crit. for both bundling of like-charged biopolymers and block copolymer micelle formation. The key to toroid vs. classic cylinder micelle formation is the interaction of the neg. charged hydrophilic block of an amphiphilic triblock copolymer with a pos. charged divalent org. counterion. This produces a self-attraction of cylindrical micelles that leads to toroid formation, a mechanism akin to the toroidal bundling of semiflexible charged biopolymers such as DNA. The toroids can be kinetically trapped or chem. cross-linked. Insight into the mechanism of toroid formation can be gained by observation of intermediate structures kinetically trapped during film casting.
- 14van Hest, J. C. M.; Delnoye, D. A. P.; Baars, M. W. P. L.; van Genderen, M. H. P.; Meijer, E. W. Polystyrene-Dendrimer Amphiphilic Block Copolymers with a Generation-Dependent Aggregation. Science 1995, 268, 1592– 1595, DOI: 10.1126/science.268.5217.159214Polystyrene-dendrimer amphiphilic block copolymers with a generation-dependent aggregationvan Hest, J. C. M.; Delnoye, D. A. P.; Baars, M. W. P. L.; van Genderen, M. H. P.; Meijer, E. W.Science (Washington, D. C.) (1995), 268 (5217), 1592-5CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)A class of amphiphilic macromols. has been synthesized by combining well-defined polystyrene (PS) with poly(propylene imine) dendrimers. Five different generations, from PS-dendr-NH2 up to Ps-dendr-(NH2)32, were prepd. in yields of 70 to 90 percent. Dynamic light scattering, cond. measurements, and transmission electron microscopy show that in aq. phases, PS-dendr-(NH2)32 forms spherical micelles, PS-dendr-(NH2)16 forms micellar rods, and PS-dendr-(NH2)8 forms vesicular structures. The lower generations of this class of macromols. show inverted micellar behavior. The obsd. effect of amphiphile geometry on aggregation behavior is in qual. agreement with the theory of J. N. Israelachvili, et al. (1976). The amphiphiles presented here are similar in shape but different in size as compared with traditional surfactants, whereas they are similar in size but different in shape as compared with traditional block copolymers.
- 15Zhang, L.; Eisenberg, A. Multiple Morphologies of ″Crew-Cut″ Aggregates of Polystyrene-b-Poly(acrylic acid) Block Copolymers. Science 1995, 268, 1728– 1731, DOI: 10.1126/science.268.5218.172815Multiple morphologies of "crew-cut" aggregates of polystyrene-b-poly(acrylic acid) block copolymersZhang, Lifeng; Eisenberg, AdiScience (Washington, D. C.) (1995), 268 (5218), 1728-31CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)The observation by transmission electron microscopy of six different stable aggregate morphologies is reported for the same family of highly asym. styrene-acrylic acid diblock copolymers prepd. in a low-mol.-wt. solvent system. Four of the morphologies consist of spheres, rods, lamellae, and vesicles in aq. soln., whereas the fifth consists of simple reverse micelle-like aggregates. The sixth consists of up to micrometer-size spheres in aq. soln. that have hydrophilic surfaces and are filled with the reverse micelle-like aggregates. In addn., a needle-like solid, which is highly birefringent, is obtained on drying of aq. solns. of the spherical micelles. This range of morphologies is believed to be unprecedented for a block copolymer system.
- 16Zhang, L.; Yu, K.; Eisenberg, A. Ion-Induced Morphological Changes in “Crew-Cut” Aggregates of Amphiphilic Block Copolymers. Science 1996, 272, 1777– 1779, DOI: 10.1126/science.272.5269.177716Ion-induced morphological changes in "crew-cut" aggregates of amphiphilic block copolymersZhang, Lifeng; Yu, Kui; Eisenberg, AdiScience (Washington, D. C.) (1996), 272 (5269), 1777-1779CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)The addn. of ions in micromolar (CaCl2 or HCl) or millimolar (NaCl) concns. can change the morphol. of "crew-cut" aggregates of amphiphilic block copolymers in dil. solns. In addn. to spherical, rodlike, and univesicular or lamellar aggregates, an unusual large compd. vesicle morphol. can be obtained from a single block copolymer. Some features of the spontaneously formed large compd. vesicles may make them esp. useful as vehicles for delivering drugs and as models of biol. cells. Gelation of a dil. spherical micelle soln. can also be induced by ions as the result of the formation of a cross-linked "pearl necklace" morphol.
- 17Balmert, S. C.; Little, S. R. Biomimetic Delivery with Micro- and Nanoparticles. Adv. Mater. 2012, 24, 3757– 3778, DOI: 10.1002/adma.20120022417Biomimetic Delivery with Micro- and NanoparticlesBalmert, Stephen C.; Little, Steven R.Advanced Materials (Weinheim, Germany) (2012), 24 (28), 3757-3778CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The nascent field of biomimetic delivery with micro- and nanoparticles (MNP) has advanced considerably in recent years. Drawing inspiration from the ways that cells communicate in the body, several different modes of "delivery" (i.e., temporospatial presentation of biol. signals) have been investigated in a no. of therapeutic contexts. In particular, this review focuses on (1) controlled release formulations that deliver natural sol. factors with physiol. relevant temporal context, (2) presentation of surface-bound ligands to cells, with spatial organization of ligands ranging from isotropic to dynamically anisotropic, and (3) phys. properties of particles, including size, shape and mech. stiffness, which mimic those of natural cells. Importantly, the context provided by multimodal, or multifactor delivery represents a key element of most biomimetic MNP systems, a concept illustrated by an analogy to human interpersonal communication. Regulatory implications of increasingly sophisticated and "cell-like" biomimetic MNP systems are also discussed.
- 18Kolhar, P.; Anselmo, A. C.; Gupta, V.; Pant, K.; Prabhakarpandian, B.; Ruoslahti, E.; Mitragotri, S. Using Shape Effects to Target Antibody-Coated Nanoparticles to Lung and Brain Endothelium. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 10753– 10758, DOI: 10.1073/pnas.130834511018Using shape effects to target antibody-coated nanoparticles to lung and brain endotheliumKolhar, Poornima; Anselmo, Aaron C.; Gupta, Vivek; Pant, Kapil; Prabhakarpandian, Balabhaskar; Ruoslahti, Erkki; Mitragotri, SamirProceedings of the National Academy of Sciences of the United States of America (2013), 110 (26), 10753-10758,S10753/1-S10753/6CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Vascular endothelium offers a variety of therapeutic targets for the treatment of cancer, cardiovascular diseases, inflammation, and oxidative stress. Significant research has been focused on developing agents to target the endothelium in diseased tissues. This includes identification of antibodies against adhesion mols. and neovascular expression markers or peptides discovered using phage display. Such targeting mols. also have been used to deliver nanoparticles to the endothelium of the diseased tissue. Here we report, based on in vitro and in vivo studies, that the specificity of endothelial targeting can be enhanced further by engineering the shape of ligand-displaying nanoparticles. In vitro studies performed using microfluidic systems that mimic the vasculature (synthetic microvascular networks) showed that rod-shaped nanoparticles exhibit higher specific and lower nonspecific accumulation under flow at the target compared with their spherical counterparts. Math. modeling of particle-surface interactions suggests that the higher avidity and specificity of nanorods originate from the balance of polyvalent interactions that favor adhesion and entropic losses as well as shear-induced detachment that reduce binding. In vivo expts. in mice confirmed that shape-induced enhancement of vascular targeting is also obsd. under physiol. conditions in lungs and brain for nanoparticles displaying anti-intracellular adhesion mol. 1 and anti-transferrin receptor antibodies.
- 19Petros, R. A.; DeSimone, J. M. Strategies in the Design of Nanoparticles for Therapeutic Applications. Nat. Rev. Drug Discovery 2010, 9, 615– 627, DOI: 10.1038/nrd259119Strategies in the design of nanoparticles for therapeutic applicationsPetros, Robby A.; De Simone, Joseph M.Nature Reviews Drug Discovery (2010), 9 (8), 615-627CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Engineered nanoparticles have the potential to revolutionize the diagnosis and treatment of many diseases; for example, by allowing the targeted delivery of a drug to particular subsets of cells. However, so far, such nanoparticles have not proved capable of surmounting all of the biol. barriers required to achieve this goal. Nevertheless, advances in nanoparticle engineering, as well as advances in understanding the importance of nanoparticle characteristics such as size, shape and surface properties for biol. interactions, are creating new opportunities for the development of nanoparticles for therapeutic applications. This Review focuses on recent progress important for the rational design of such nanoparticles and discusses the challenges to realizing the potential of nanoparticles.
- 20Perry, J. L.; Herlihy, K. P.; Napier, M. E.; DeSimone, J. M. PRINT: A Novel Platform Toward Shape and Size Specific Nanoparticle Theranostics. Acc. Chem. Res. 2011, 44, 990– 998, DOI: 10.1021/ar200031520PRINT: A Novel Platform Toward Shape and Size Specific Nanoparticle TheranosticsPerry, Jillian L.; Herlihy, Kevin P.; Napier, Mary E.; DeSimone, Joseph M.Accounts of Chemical Research (2011), 44 (10), 990-998CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. Nanotheranostics represents the next generation of medicine, fusing nanotechnol., therapeutics, and diagnostics. By integrating therapeutic and imaging agents into one nanoparticle, this new treatment strategy has the potential not only to detect and diagnose disease but also to treat and monitor the therapeutic response. This capability could have a profound impact in both the research setting as well as in a clin. setting. In the research setting, such a capability will allow research scientists to rapidly assess the performance of new therapeutics in an effort to iterate their designs for increased therapeutic index and efficacy. In the clin. setting, theranostics offers the ability to det. whether patients enrolling in clin. trials are responding, or are expected to respond, to a given therapy based on the hypothesis assocd. with the biol. mechanisms being tested. If not, patients can be more quickly removed from the clin. trial and shifted to other therapeutic options. To be effective, these theranostic agents must be highly site specific. Optimally, they will carry relevant cargo, demonstrate controlled release of that cargo, and include imaging probes with a high signal-to-noise ratio. There are many biol. barriers in the human body that challenge the efficacy of nanoparticle delivery vehicles. These barriers include, but are not limited to, the walls of blood vessels, the phys. entrapment of particles in organs, and the removal of particles by phagocytic cells. The rapid clearance of circulating particles during systemic delivery is a major challenge; current research seeks to define key design parameters that govern the performance of nanocarriers, such as size, surface chem., elasticity, and shape. The effect of particle size and surface chem. on in vivo biodistribution of nanocarriers has been extensively studied, and general guidelines have been established. Recently it has been documented that shape and elasticity can have a profound effect on the behavior of delivery vehicles. Thus, having the ability to independently control shape, size, matrix, surface chem., and modulus is crucial for designing successful delivery agents. In this Account, we describe the use of particle replication in nonwetting templates (PRINT) to fabricate shape- and size-specific microparticles and nanoparticles. A particular strength of the PRINT method is that it affords precise control over shape, size, surface chem., and modulus. We have demonstrated the loading of PRINT particles with chemotherapeutics, magnetic resonance contrast agents, and fluorophores. The surface properties of the PRINT particles can be easily modified with "stealth" poly(ethylene glycol) chains to increase blood circulation time, with targeting moieties for targeted delivery or with radiolabels for nuclear imaging. These particles have tremendous potential for applications in nanomedicine and diagnostics.
- 21Rothenbuhler, J. R.; Huang, J.-R.; DiDonna, B. A.; Levine, A. J.; Mason, T. G. Mesoscale Structure of Diffusion-Limited Aggregates of Colloidal Rods and Disks. Soft Matter 2009, 5, 3639– 3645, DOI: 10.1039/b909740f21Mesoscale structure of diffusion-limited aggregates of colloidal rods and disksRothenbuhler, Jacob R.; Huang, Jung-Ren; DiDonna, Brian A.; Levine, Alex J.; Mason, Thomas G.Soft Matter (2009), 5 (19), 3639-3645CODEN: SMOABF; ISSN:1744-683X. (Royal Society of Chemistry)We explore the dependence of the non-universal mesoscale structure of diffusion-limited aggregates upon the shape of their constituent particles. Using random-walk simulations that model anisotropic diffusion in a viscous fluid, we study diffusion-limited aggregation (DLA) of right-circular cylinders having a wide range of length-to-diam. aspect ratios. This single-parameter family of particle shapes allows us to det. the role of particle quasi-dimensionality on the structure of DLA clusters that are composed of effectively 1D thin rods and 2D thin plates. We compare these clusters to those formed by traditional DLA of compact objects by studying the local nature of the interparticle contacts (end-end, end-body, or body-body), the distribution of the no. of interparticle contacts, and the wavevector-dependent structure factor S(q) of the resulting clusters. Clusters of rods are less dense than those of disks or compact objects of equal vol., yet the long length-scale structure of the DLA clusters conforms to the expected DLA scaling relations. However, the local structure at the particle scale, including the nearest-neighbor distribution functions and dominant collision types, depend strongly on the particle's quasi-dimensionality. We explain the non-universal local structure by introducing the concept of a diffusing particle's touch space', which incorporates both the particle's geometry and its anisotropic diffusion.
- 22Men, Y.; Peng, F.; Tu, Y.; van Hest, J. C. M.; Wilson, D. A. Methods for Production of Uniform Small-Sized Polymersome with Rigid Membrane. Polym. Chem. 2016, 7, 3977– 3982, DOI: 10.1039/C6PY00668J22Methods for production of uniform small-sized polymersome with rigid membraneMen, Yongjun; Peng, Fei; Tu, Yingfeng; van Hest, Jan C. M.; Wilson, Daniela A.Polymer Chemistry (2016), 7 (24), 3977-3982CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)We report a facile methodol. for the formation of uniform small-sized poly(ethylene glycol)-block-polystyrene (PEG-b-PS) polymersomes, via extrusion and sonication methods by using org. solvent as plasticizing agent. The obtained polymersomes have diams. less than 100 nm. The size and size distribution depend on the org. solvent content and sonication time. The small-sized polymersomes are able to carry both hydrophobic and hydrophilic dyes.
- 23Salva, R.; Le Meins, J.-F.; Sandre, O.; Brûlet, A.; Schmutz, M.; Guenoun, P.; Lecommandoux, S. Polymersome Shape Transformation at the Nanoscale. ACS Nano 2013, 7, 9298– 9311, DOI: 10.1021/nn403958923Polymersome Shape Transformation at the NanoscaleSalva, Romain; Le Meins, Jean-Francois; Sandre, Olivier; Brulet, Annie; Schmutz, Marc; Guenoun, Patrick; Lecommandoux, SebastienACS Nano (2013), 7 (10), 9298-9311CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Polymer vesicles, also named polymersomes, are valuable candidates for drug delivery and micro- or nanoreactor applications. As far as drug delivery is concerned, the shape of the carrier is believed to have a strong influence on the biodistribution and cell internalization. Polymersomes can be submitted to an osmotic imbalance when injected in physiol. media leading to morphol. changes. To understand these osmotic stress-induced variations in membrane properties and shapes, several nanovesicles made of the graft polymer poly(dimethylsiloxane)-g-poly(ethylene oxide) (PDMS-g-PEO) or the triblock copolymer PEO-b-PDMS-b-PEO were osmotically stressed and obsd. by light scattering, neutron scattering (SANS), and cryo-transmission electron microscopy (cryo-TEM). Hypotonic shock leads to a swelling of the vesicles, comparable to optically observable giant polymersomes, and hypertonic shock leads to collapsed structures such as stomatocytes and original nested vesicles, the latter being only obsd. for bilayers classically formed by amphiphilic copolymers. Complementary SANS and cryo-TEM expts. are shown to be in quant. agreement and highlight the importance of the membrane structure on the behavior of these nanopolymersomes under hypertonic conditions as the final morphol. reached depends whether or not the copolymers assemble into a bilayer. The vesicle radius and membrane curvature are also shown to be crit. parameters for such transformations: the shape evolution trajectory agrees with theor. models only for large enough vesicle radii above a threshold value around 4 times the membrane thickness.
- 24Meeuwissen, S. A.; Kim, K. T.; Chen, Y.; Pochan, D. J.; van Hest, J. C. M. Controlled Shape Transformation of Polymersome Stomatocytes. Angew. Chem., Int. Ed. 2011, 50, 7070– 7073, DOI: 10.1002/anie.20110216724Controlled Shape Transformation of Polymersome StomatocytesMeeuwissen, Silvie A.; Kim, Kyoung-Taek; Chen, Ying-Chao; Pochan, Darrin J.; van Hest, Jan C. M.Angewandte Chemie, International Edition (2011), 50 (31), 7070-7073, S7070/1-S7070/14CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)We report here a controllable shape transformation of polymer vesicles (polymersomes) constructed from block copolymers of which the hydrophobic part is a high-mol.-wt. glassy segment. Control over the shape transformation is obtained by kinetic manipulation of the phase behavior of this glassy hydrophobic segment. Kinetic manipulation of the phase behavior of polymer membranes allows for different shapes of polymersomes to be captured at specific times, which directly translates into phys. robust nanostructures that are otherwise unobtainable. Combining the morphol. diversity of giant liposomes and the phys. robustness of polymersomes, our finding can be a general way to realize unusual nanostructures in a predictable manner.
- 25Abdelmohsen, L. K. E. A.; Williams, D. S.; Pille, J.; Ozel, S. G.; Rikken, R. S. M.; Wilson, D. A.; van Hest, J. C. M. Formation of Well-Defined, Functional Nanotubes via Osmotically Induced Shape Transformation of Biodegradable Polymersomes. J. Am. Chem. Soc. 2016, 138, 9353– 9356, DOI: 10.1021/jacs.6b0398425Formation of Well-Defined, Functional Nanotubes via Osmotically Induced Shape Transformation of Biodegradable PolymersomesAbdelmohsen, Loai K. E. A.; Williams, David S.; Pille, Jan; Ozel, Sema G.; Rikken, Roger S. M.; Wilson, Daniela A.; van Hest, Jan C. M.Journal of the American Chemical Society (2016), 138 (30), 9353-9356CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Polymersomes are robust, versatile nanostructures that can be tailored by varying the chem. structure of copolymeric building blocks, giving control over their size, shape, surface chem., and membrane permeability. In particular, the generation of nonspherical nanostructures has attracted much attention recently, as it has been demonstrated that shape affects function in a biomedical context. Until now, nonspherical polymersomes have only been constructed from nondegradable building blocks, hampering a detailed investigation of shape effects in nanomedicine for this category of nanostructures. Herein, we demonstrate the spontaneous elongation of spherical polymersomes comprising the biodegradable copolymer poly(ethylene glycol)-b-poly(D,L-lactide) into well-defined nanotubes. The size of these tubes is osmotically controlled using dialysis, which makes them very easy to prep. To confirm their utility for biomedical applications, we have demonstrated that, alongside drug loading, functional proteins can be tethered to the surface utilizing bio-orthogonal "click" chem. In this way the present findings establish a novel platform for the creation of biocompatible, high-aspect ratio nanoparticles for biomedical research.
- 26Blanazs, A.; Madsen, J.; Battaglia, G.; Ryan, A. J.; Armes, S. P. Mechanistic Insights for Block Copolymer Morphologies: How Do Worms Form Vesicles?. J. Am. Chem. Soc. 2011, 133, 16581– 16587, DOI: 10.1021/ja206301a26Mechanistic Insights for Block Copolymer Morphologies: How Do Worms Form Vesicles?Blanazs, Adam; Madsen, Jeppe; Battaglia, Giuseppe; Ryan, Anthony J.; Armes, Steven P.Journal of the American Chemical Society (2011), 133 (41), 16581-16587CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Amphiphilic diblock copolymers composed of two covalently linked, chem. distinct chains can be considered to be biol. mimics of cell membrane-forming lipid mols., but with typically more than an order of magnitude increase in mol. wt. These macromol. amphiphiles are known to form a wide range of nanostructures (spheres, worms, vesicles, etc.) in solvents that are selective for one of the blocks. However, such self-assembly is usually limited to dil. copolymer solns. (<1%), which is a significant disadvantage for potential com. applications such as drug delivery and coatings. In principle, this problem can be circumvented by polymn.-induced block copolymer self-assembly. Here the authors detail the synthesis and subsequent in situ self-assembly of amphiphilic AB diblock copolymers in a one pot concd. aq. dispersion polymn. formulation. The authors show that spherical micelles, wormlike micelles, and vesicles can be predictably and efficiently obtained (within 2 h of polymn., >99% monomer conversion) at relatively high solids in purely aq. soln. Furthermore, careful monitoring of the in situ polymn. by transmission electron microscopy reveals various novel intermediate structures (including branched worms, partially coalesced worms, nascent bilayers, "octopi", "jellyfish", and finally pure vesicles) that provide important mechanistic insights regarding the evolution of the particle morphol. during the sphere-to-worm and worm-to-vesicle transitions. This environmentally benign approach (which involves no toxic solvents, is conducted at relatively high solids, and requires no addnl. processing) is readily amenable to industrial scale-up, since it is based on com. available starting materials.
- 27Deng, Z.; Qian, Y.; Yu, Y.; Liu, G.; Hu, J.; Zhang, G.; Liu, S. Engineering Intracellular Delivery Nanocarriers and Nanoreactors from Oxidation-Responsive Polymersomes via Synchronized Bilayer Cross-Linking and Permeabilizing Inside Live Cells. J. Am. Chem. Soc. 2016, 138, 10452– 10466, DOI: 10.1021/jacs.6b0411527Engineering Intracellular Delivery Nanocarriers and Nanoreactors from Oxidation-Responsive Polymersomes via Synchronized Bilayer Cross-Linking and Permeabilizing Inside Live CellsDeng, Zhengyu; Qian, Yinfeng; Yu, Yongqiang; Liu, Guhuan; Hu, Jinming; Zhang, Guoying; Liu, ShiyongJournal of the American Chemical Society (2016), 138 (33), 10452-10466CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Reactive oxygen species (ROS) and oxidative stress are implicated in various physiol. and pathol. processes and this feature provides a vital biochem. basis for designing novel therapeutic and diagnostic nanomedicines. Among them, oxidn.-responsive micelles and vesicles (polymersomes) of amphiphilic block copolymers have been extensively explored; however, in previous works, oxidn. by ROS including H2O2 exclusively leads to microstructural destruction of polymeric assemblies. For oxidn.-responsive polymersomes, fast release of encapsulated hydrophilic drugs and bioactive macromols. will occur upon microstructural disintegration. Under certain application circumstances, this does not meet design requirements for sustained-release drug nanocarriers and long-acting in vivo nanoreactors. Also note that conventional polymersomes possess thick hydrophobic bilayers and compromised membrane permeability, rendering them as ineffective nanocarriers and nanoreactors. We herein report the fabrication of oxidn.-responsive multifunctional polymersomes exhibiting intracellular milieu-triggered vesicle bilayer crosslinking, permeability switching, and enhanced imaging/drug release features. Mitochondria-targeted H2O2 reactive polymersomes were obtained through the self-assembly of amphiphilic block copolymers contg. arylboronate ester-capped self-immolative side linkages in the hydrophobic block, followed by surface functionalization with targeting peptides. Upon cellular uptake, intracellular H2O2 triggers cascade decaging reactions and generates primary amine moieties; prominent amidation reaction then occurs within hydrophobic bilayer membranes, resulting in concurrent crosslinking and hydrophobic-to-hydrophilic transition of polymersome bilayers inside live cells. This process was further utilized to achieve integrated functions such as sustained drug release, (combination) chemotherapy monitored by fluorescence and magnetic resonance (MR) imaging turn-on, and to construct intracellular fluorogenic nanoreactors for cytosolic thiol-contg. bioactive mols.
- 28Du, J.; Tang, Y.; Lewis, A. L.; Armes, S. P. pH-Sensitive Vesicles Based on a Biocompatible Zwitterionic Diblock Copolymer. J. Am. Chem. Soc. 2005, 127, 17982– 17983, DOI: 10.1021/ja056514l28pH-Sensitive vesicles based on a biocompatible zwitterionic diblock copolymerDu, Jianzhong; Tang, Yiqing; Lewis, Andrew L.; Armes, Steven P.Journal of the American Chemical Society (2005), 127 (51), 17982-17983CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Highly biocompatible pH-sensitive diblock copolymer vesicles were prepd. from the self-assembly of a biocompatible zwitterionic copolymer, poly[2-(methacryloyloxy)ethyl phosphorylcholine-block-2-(diisopropylamino)ethyl methacrylate], PMPC-b-PDPA. Vesicle formation occurred spontaneously by adjusting the soln. pH from pH 2 to above 6, with the hydrophobic PDPA chains forming the vesicle walls. Transmission electron microscopy (TEM), dynamic laser light scattering (DLS), and UV-visible absorption spectrophotometry were used to characterize these vesicles. Gold nanoparticle-decorated vesicles were also obtained by treating the vesicles with HAuCl4, followed by NaBH4.
- 29Kim, K. T.; Zhu, J.; Meeuwissen, S. A.; Cornelissen, J. J. L. M.; Pochan, D. J.; Nolte, R. J. M.; van Hest, J. C. M. Polymersome Stomatocytes: Controlled Shape Transformation in Polymer Vesicles. J. Am. Chem. Soc. 2010, 132, 12522– 12524, DOI: 10.1021/ja104154t29Polymersome Stomatocytes: Controlled Shape Transformation in Polymer VesiclesKim, Kyoung Taek; Zhu, Jiahua; Meeuwissen, Silvie A.; Cornelissen, Jeroen J. L. M.; Pochan, Darrin J.; Nolte, Roeland J. M.; van Hest, Jan C. M.Journal of the American Chemical Society (2010), 132 (36), 12522-12524CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)We report here a controllable shape transformation of polymer vesicles (polymersomes) constructed from block copolymers of which the hydrophobic part is a high-mol.-wt. glassy segment. Control over the shape transformation is obtained by kinetic manipulation of the phase behavior of this glassy hydrophobic segment. Kinetic manipulation of the phase behavior of polymer membranes allows for different shapes of polymersomes to be captured at specific times, which directly translates into phys. robust nanostructures that are otherwise unobtainable. Combining the morphol. diversity of giant liposomes and the phys. robustness of polymersomes, our finding can be a general way to realize unusual nanostructures in a predictable manner.
- 30Ladmiral, V.; Semsarilar, M.; Canton, I.; Armes, S. P. Polymerization-Induced Self-Assembly of Galactose-Functionalized Biocompatible Diblock Copolymers for Intracellular Delivery. J. Am. Chem. Soc. 2013, 135, 13574– 13581, DOI: 10.1021/ja407033x30Polymerization-Induced Self-Assembly of Galactose-Functionalized Biocompatible Diblock Copolymers for Intracellular DeliveryLadmiral, Vincent; Semsarilar, Mona; Canton, Irene; Armes, Steven P.Journal of the American Chemical Society (2013), 135 (36), 13574-13581CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Recent advances in polymer science are enabling substantial progress in nanobiotechnol., particularly in the design of new tools for enhanced understanding of cell biol. and for smart drug delivery formulations. Herein, a range of novel galactosylated diblock copolymer nano-objects is prepd. directly in concd. aq. soln. via reversible addn.-fragmentation chain transfer polymn. using polymn.-induced self-assembly. The resulting nanospheres, worm-like micelles, or vesicles interact in vitro with galectins as judged by a turbidity assay. In addn., galactosylated vesicles are highly biocompatible and allow intracellular delivery of an encapsulated mol. cargo.
- 31Men, Y.; Li, W.; Janssen, G.-J.; Rikken, R. S. M.; Wilson, D. A. Stomatocyte in Stomatocyte: A New Shape of Polymersome Induced via Chemical-Addition Methodology. Nano Lett. 2018, 18, 2081– 2085, DOI: 10.1021/acs.nanolett.8b0018731Stomatocyte in Stomatocyte: A New Shape of Polymersome Induced via Chemical-Addition MethodologyMen, Yongjun; Li, Wei; Janssen, Geert-Jan; Rikken, Roger S. M.; Wilson, Daniela A.Nano Letters (2018), 18 (3), 2081-2085CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)Accurate control of the shape transformation of polymersome is an important and interesting challenge that spans across disciplines such as nanomedicine and nanomachine. Here, we report a fast and facile methodol. of shape manipulation of polymersome via out-of-equil. polymer self-assembly and shape change by chem. addn. of additives. Due to its increased permeability, hydrophilicity, and fusogenic properties, poly(ethylene oxide) was selected as the additive for bringing the system out of equil. via fast addn. into the polymersome org. soln. A new shape, stomatocyte-in-stomatocyte (sto-in-sto), is obtained for the first time. Moreover, fast shape transformation within less than 1 min to other relevant shapes such as stomatocyte and large compd. vesicles was also obtained and accurately controlled in a uniform dispersion. This methodol. is demonstrated as a general strategy with which to push the assembly further out of equil. to generate unusual nanostructures in a controllable and fast manner.
- 32Zhu, J.; Zhang, S.; Zhang, K.; Wang, X.; Mays, J. W.; Wooley, K. L.; Pochan, D. J. Disk-Cylinder and Disk-Sphere Nanoparticles via A Block Copolymer Blend Solution Construction. Nat. Commun. 2013, 4, 2297, DOI: 10.1038/ncomms329732Disk-cylinder and disk-sphere nanoparticles via a block copolymer blend solution constructionZhu Jiahua; Zhang Shiyi; Zhang Ke; Wang Xiaojun; Mays Jimmy W; Wooley Karen L; Pochan Darrin JNature communications (2013), 4 (), 2297 ISSN:.Researchers strive to produce nanoparticles with complexity in composition and structure. Although traditional spherical, cylindrical and membranous, or planar, nanostructures are ubiquitous, scientists seek more complicated geometries for potential functionality. Here we report the simple solution construction of multigeometry nanoparticles, disk-sphere and disk-cylinder, through a straightforward, molecular-level, blending strategy with binary mixtures of block copolymers. The multigeometry nanoparticles contain disk geometry in the core with either spherical patches along the disk periphery in the case of disk-sphere particles or cylindrical edges and handles in the case of the disk-cylinder particles. The portions of different geometry in the same nanoparticles contain different core block chemistry, thus also defining multicompartments in the nanoparticles. Although the block copolymers chosen for the blends are important for the definition of the final hybrid particles, the control of the kinetic pathway of assembly is critical for successful multigeometry particle construction.
- 33Wong, C. K.; Mason, A. F.; Stenzel, M. H.; Thordarson, P. Formation of Non-Spherical Polymersomes Driven by Hydrophobic Directional Aromatic Perylene Interactions. Nat. Commun. 2017, 8, 1240, DOI: 10.1038/s41467-017-01372-z33Formation of non-spherical polymersomes driven by hydrophobic directional aromatic perylene interactionsWong Chin Ken; Mason Alexander F; Stenzel Martina H; Thordarson Pall; Wong Chin Ken; Mason Alexander F; Thordarson Pall; Wong Chin Ken; Stenzel Martina HNature communications (2017), 8 (1), 1240 ISSN:.Polymersomes, made up of amphiphilic block copolymers, are emerging as a powerful tool in drug delivery and synthetic biology due to their high stability, chemical versatility, and surface modifiability. The full potential of polymersomes, however, has been hindered by a lack of versatile methods for shape control. Here we show that a range of non-spherical polymersome morphologies with anisotropic membranes can be obtained by exploiting hydrophobic directional aromatic interactions between perylene polymer units within the membrane structure. By controlling the extent of solvation/desolvation of the aromatic side chains through changes in solvent quality, we demonstrate facile access to polymersomes that are either ellipsoidal or tubular-shaped. Our results indicate that perylene aromatic interactions have a great potential in the design of non-spherical polymersomes and other structurally complex self-assembled polymer structures.
- 34Wong, C. K.; Martin, A. D.; Floetenmeyer, M.; Parton, R. G.; Stenzel, M. H.; Thordarson, P. Faceted Polymersomes: A Sphere-to-Polyhedron Shape Transformation. Chem. Sci. 2019, 10, 2725– 2731, DOI: 10.1039/C8SC04206C34Faceted polymersomes: a sphere-to-polyhedron shape transformationWong, Chin Ken; Martin, Adam D.; Floetenmeyer, Matthias; Parton, Robert G.; Stenzel, Martina H.; Thordarson, PallChemical Science (2019), 10 (9), 2725-2731CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)The creation of "soft" deformable hollow polymeric nanoparticles with complex non-spherical shapes via block copolymer self-assembly remains a challenge. In this work, we show that a perylene-bearing block copolymer can self-assemble into polymeric membrane sacs (polymersomes) that not only possess uncommonly faceted polyhedral shapes but are also intrinsically fluorescent. Here, we further reveal for the first time an exptl. visualization of the entire polymersome faceting process. We uncover how our polymersomes facet through a sphere-to-polyhedron shape transformation pathway that is driven by perylene aggregation confined within a topol. spherical polymersome shell. Finally, we illustrate the importance in understanding this shape transformation process by demonstrating our ability to controllably isolate different intermediate polymersome morphologies. The findings presented herein should provide opportunities for those who utilize non-spherical polymersomes for drug delivery, nanoreactor or templating applications, and those who are interested in the fundamental aspects of polymersome self-assembly.
- 35Wong, C. K.; Stenzel, M. H.; Thordarson, P. Non-Spherical Polymersomes: Formation and Characterization. Chem. Soc. Rev. 2019, 48, 4019– 4035, DOI: 10.1039/C8CS00856F35Non-spherical polymersomes: formation and characterizationWong, Chin Ken; Stenzel, Martina H.; Thordarson, PallChemical Society Reviews (2019), 48 (15), 4019-4035CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. Polymersomes are self-assembled hollow membrane sacs that are not only able to encapsulate hydrophobic and/or hydrophilic mols., but also possess exceptional chem. and phys. stability, structural versatility, and surface modifiability. For the above reasons, polymersomes have in recent years emerged as a powerful tool for a wide range of applications in the fields of biomimicry and drug delivery. The full potential of polymersomes, however, has yet to be harnessed due to a lack of appreciation of existing shape control methods. This very much contrasts the field of inorg. nanoparticle synthesis where non-spherical hollow metal nanoparticles are routinely prepd. and used. Here, we summarize recent efforts over the past decade to study the morphol. transformation of conventionally spherical polymersomes into non-spherical polymersomes.
- 36van Oers, M. C. M.; Rutjes, F. P. J. T.; van Hest, J. C. M. Tubular Polymersomes: A Cross-Linker-Induced Shape Transformation. J. Am. Chem. Soc. 2013, 135, 16308– 16311, DOI: 10.1021/ja408754z36Tubular Polymersomes: A Cross-Linker-Induced Shape Transformationvan Oers, Matthijs C. M.; Rutjes, Floris P. J. T.; van Hest, Jan C. M.Journal of the American Chemical Society (2013), 135 (44), 16308-16311CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Polymersomes, polymeric vesicles constructed of block copolymers, can undergo a sphere-to-tubule transition under the influence of a chem. modification of the polymeric bilayer. A strain-promoted alkyne-azide cycloaddn. (SPAAC) reaction between azide handles inside the hydrophobic domain of the membrane and an excess of a bicyclo[6.1.0]-nonyne (BCN)-cross-linker causes the vesicle to stretch in one dimension. Tubular polymersomes up to 2 μm in length can be obtained with this shape transformation. The introduction of a cleavable cross-linker makes this process reversible and opens the way for future drug delivery applications.
- 37Rikken, R. S. M.; Engelkamp, H.; Nolte, R. J. M.; Maan, J. C.; van Hest, J. C. M.; Wilson, D. A.; Christianen, P. C. M. Shaping Polymersomes into Predictable Morphologies via Out-of-Equilibrium Self-Assembly. Nat. Commun. 2016, 7, 12606, DOI: 10.1038/ncomms1260637Shaping polymersomes into predictable morphologies via out-of-equilibrium self-assemblyRikken, R. S. M.; Engelkamp, H.; Nolte, R. J. M.; Maan, J. C.; van Hest, J. C. M.; Wilson, D. A.; Christianen, P. C. M.Nature Communications (2016), 7 (), 12606CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)Polymersomes are bilayer vesicles, self-assembled from amphiphilic block copolymers. They are versatile nanocapsules with adjustable properties, such as flexibility, permeability, size and functionality. However, so far no methodol. approach to control their shape exists. Here we demonstrate a mechanistically fully understood procedure to precisely control polymersome shape via an out-of-equil. process. Carefully selecting osmotic pressure and permeability initiates controlled deflation, resulting in transient capsule shapes, followed by reinflation of the polymersomes. The shape transformation towards stomatocytes, bowl-shaped vesicles, was probed with magnetic birefringence, permitting us to stop the process at any intermediate shape in the phase diagram. Quant. electron microscopy anal. of the different morphologies reveals that this shape transformation proceeds via a long-predicted hysteretic deflation-inflation trajectory, which can be understood in terms of bending energy. Because of the high degree of controllability and predictability, this study provides the design rules for accessing polymersomes with all possible different shapes.
- 38Yamazaki, M.; Ito, T. Deformation and Instability of Membrane Structure of Phospholipid Vesicles Caused by Osmophobic Association: Mechanical Stress Model for the Mechanism of Poly(Ethylene Glycol)-Induced Membrane Fusion. Biochemistry 1990, 29, 1309– 1314, DOI: 10.1021/bi00457a02938Deformation and instability of membrane structure of phospholipid vesicles caused by osmophobic association: mechanical stress model for the mechanism of poly(ethylene glycol)-induced membrane fusionYamazaki, Masahito; Ito, TadanaoBiochemistry (1990), 29 (5), 1309-14CODEN: BICHAW; ISSN:0006-2960.The mechanism of poly(ethylene glycol)-induced fusion of phospholipid vesicles was studied based on the osmophobic assocn. theory which was recently proposed both theor. (Ito, T., et al., 1989) and exptl. (Yamazaki, M., et al., 1989). Osmophobic assocn. and fusion were detected by measuring the light scattering of the vesicle suspension; the former was detected from the increase in light scattering induced by the addn. of PEG, and the latter was from the irreversibility of the increase in light scattering. Threshold concns. of PEG were required not only for osmophobic assocn. but also for fusion. The threshold concn. for fusion depended on the mol. wt. of PEG and also on the electrostatic repulsive interaction between phospholipid vesicles, which was manipulated by the use of vesicles with neg. surface charge; increasing the mol. wt. of PEG lowered the threshold concn., and increasing the electrostatic repulsive interaction raised it. In addn., a transient leakage of internal contents from the vesicles was obsd. at the concn. that caused fusion. When the surface charge of the vesicle was varied, the threshold for fusion coincided with that for osmophobic assocn., provided that the latter was >22 wt % of PEG 6000. However, when the threshold for osmophobic assocn. was <22 wt %, the threshold for fusion remained ∼22 wt %, irresp. of the difference in the threshold for osmophobic assocn. Electron microphotographs of quick-frozen replicas of egg yolk phosphatidylcholine vesicles showed that the vesicles in the aggregate caused by PEG-induced osmophobic assocn. were deformed to increase their area of contact with the adjacent vesicles. According to the anal. based on the osmophobic assocn. theory, the mech. force (f) that causes the deformation of the vesicle (deformation force) is counterbalanced by the thermodn. force due to osmophobic assocn., increasing with increased concns. of PEG, but it is little affected by the electrostatic repulsive interaction between the vesicles. On the basis of the results described above, a mech. stress model is proposed for the mechanism of PEG-induced fusion. Membranes that are tightly assocd. by osmophobic assocn. are mech. strained by the deformation force f. Consequently, the membrane structure becomes unstable at increased concns. of PEG, and above a crit. concn., ∼22 wt % of PEG 6000, destruction of the bilayer structure into a leaky membrane structure may cause fusion.
- 39Yamazaki, M.; Ohnishi, S.; Ito, T. Osmoelastic Coupling in Biological Structures: Decrease in Membrane Fluidity and Osmophobic Association of Phospholipid Vesicles in Response to Osmotic Stress. Biochemistry 1989, 28, 3710– 3715, DOI: 10.1021/bi00435a01339Osmoelastic coupling in biological structures: decrease in membrane fluidity and osmophobic association of phospholipid vesicles in response to osmotic stressYamazaki, Masahito; Ohnishi, Shunichi; Ito, TadanaoBiochemistry (1989), 28 (9), 3710-15CODEN: BICHAW; ISSN:0006-2960.PEG-induced changes in membrane fluidity and aggregation of phospholipid vesicles were studied. A threshold concn. of PEG was required to induce the aggregation. This concn. increased with a decrease in the mol. wt. of PEG, e.g., from 5% with PEG 6000 (PEG with an av. mol. wt. of 7500) to >30% with PEG 200. The aggregation was reversible upon diln. of PEG if the initial PEG concn. was smaller than a certain value, e.g., 22% for PEG 6000. Addn. of PEG caused a decrease in membrane fluidity of the vesicles detected by fluorescence anisotropy of diphenylhexatriene and by ESR of a spin-labeled fatty acid. The fluidity change (as detected by the diphenylhexatriene anisotropy change) had an inflection point at ∼5% of PEG 6000, which suggests that the aggregation would make the decrease of membrane fluidity smaller. Transfer of lipid mols. between phospholipid vesicles was enhanced by the PEG-induced aggregation. The enhancement occurred not only upon direct addn. of PEG to the suspending medium, but also upon dialysis of the vesicle suspension against a high concn. of PEG. All these features are consistent with osmoelastic coupling in the phospholipid membranes and the subsequent osmophobic assocn. of the vesicles. The imbalance of osmolarity between the region adjacent to the vesicle surface (exclusion layer) and the bulk aq. phase, which results from the preferential exclusion of PEG from the exclusion layer in the case of direct addn. of PEG, exerts an osmotic stress on the vesicles. The osmotic stress would be counterbalanced by an elastic pressure resulting from elastic strain of the membrane, and it would increase the free energy of vesicles in the dispersed state (osmoelastic coupling). When the osmotic stress exceeds a threshold level, the vesicles would aggregate to avoid further increase in the free energy (osmophobic assocn.).
Supporting Information
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsnano.9b04740.
Materials and instrumentation; synthesis methods of PEG-b-PS and polymersomes, as well shape transformation via PEG addition methodology; TEM images of stomatocytes with various mouth openings; shape change of polymersomes assembled from different PS lengths (PDF)
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