ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

Figure 1Loading Img

Micellar Stability in Biological Media Dictates Internalization in Living Cells

View Author Information
Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 15-21, 08028 Barcelona, Spain
Department of Organic Chemistry, School of Chemistry, Faculty of Exact Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel
§ Tel Aviv University Center for Nanoscience and Nanotechnology, Tel-Aviv University, Tel-Aviv 6997801, Israel
BLAVATNIK CENTER for Drug Discovery, Tel-Aviv University, Tel-Aviv 6997801, Israel
Cite this: J. Am. Chem. Soc. 2017, 139, 46, 16677–16687
Publication Date (Web):October 27, 2017
Copyright © 2017 American Chemical Society

    Article Views





    Other access options
    Supporting Info (1)»


    Abstract Image

    The dynamic nature of polymeric assemblies makes their stability in biological media a crucial parameter for their potential use as drug delivery systems in vivo. Therefore, it is essential to study and understand the behavior of self-assembled nanocarriers under conditions that will be encountered in vivo such as extreme dilutions and interactions with blood proteins and cells. Herein, using a combination of fluorescence spectroscopy and microscopy, we studied four amphiphilic PEG–dendron hybrids and their self-assembled micelles in order to determine their structure–stability relations. The high molecular precision of the dendritic block enabled us to systematically tune the hydrophobicity and stability of the assembled micelles. Using micelles that change their fluorescent properties upon disassembly, we observed that serum proteins bind to and interact with the polymeric amphiphiles in both their assembled and monomeric states. These interactions strongly affected the stability and enzymatic degradation of the micelles. Finally, using spectrally resolved confocal imaging, we determined the relations between the stability of the polymeric assemblies in biological media and their cell entry. Our results highlight the important interplay between molecular structure, micellar stability, and cell internalization pathways, pinpointing the high sensitivity of stability–activity relations to minor structural changes and the crucial role that these relations play in designing effective polymeric nanostructures for biomedical applications.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.


    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Supporting Information

    Jump To

    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b08351.

    • Detailed experimental information, characterization data, CMC measurements, UV and fluorescence spectra, HPLC degradation/stability data, cytotoxicity, and confocal imaging (PDF)

    Terms & Conditions

    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:

    Cited By

    This article is cited by 43 publications.

    1. Alis R. Olea, Alicia Jurado, Gadi Slor, Shahar Tevet, Silvia Pujals, Victor R. De La Rosa, Richard Hoogenboom, Roey J. Amir, Lorenzo Albertazzi. Reaching the Tumor: Mobility of Polymeric Micelles Inside an In Vitro Tumor-on-a-Chip Model with Dual ECM. ACS Applied Materials & Interfaces 2023, 15 (51) , 59134-59144.
    2. Parul Rathee, Nicole Edelstein-Pardo, Francesca Netti, Lihi Adler-Abramovich, Amit Sitt, Roey J. Amir. Architecture-Based Programming of Polymeric Micelles to Undergo Sequential Mesophase Transitions. ACS Macro Letters 2023, 12 (6) , 814-820.
    3. D. Paul Mallory, Abegel Freedman, Megan J. Kaliszewski, Gladys Rocío Montenegro-Galindo, Coleen Pugh, Adam W. Smith. Direct Quantification of Serum Protein Interactions with PEGylated Micelle Nanocarriers. Biomacromolecules 2023, 24 (6) , 2479-2488.
    4. Edgar Fuentes, Yeray Gabaldón, Mario Collado, Shikha Dhiman, José Augusto Berrocal, Silvia Pujals, Lorenzo Albertazzi. Supramolecular Stability of Benzene-1,3,5-tricarboxamide Supramolecular Polymers in Biological Media: Beyond the Stability–Responsiveness Trade-off. Journal of the American Chemical Society 2022, 144 (46) , 21196-21205.
    5. Michael J. Poellmann, Kaila Javius-Jones, Caroline Hopkins, Jin Woong Lee, Seungpyo Hong. Dendritic–Linear Copolymer and Dendron Lipid Nanoparticles for Drug and Gene Delivery. Bioconjugate Chemistry 2022, 33 (11) , 2008-2017.
    6. Gadi Slor, Shahar Tevet, Roey J. Amir. Stimuli-Induced Architectural Transition as a Tool for Controlling the Enzymatic Degradability of Polymeric Micelles. ACS Polymers Au 2022, 2 (5) , 380-386.
    7. Ge Gao, Xianbao Sun, Xiaoyang Liu, Runqun Tang, Manli Wang, Wenjun Zhan, Junnian Zheng, Gaolin Liang. FAP-α-Instructed Coumarin Excimer Formation for High Contrast Fluorescence Imaging of Tumor. Nano Letters 2022, 22 (16) , 6782-6786.
    8. Yanan Li, Menghuan Li, Li Liu, Chencheng Xue, Yang Fei, Xuan Wang, Yuchen Zhang, Kaiyong Cai, Yanli Zhao, Zhong Luo. Cell-Specific Metabolic Reprogramming of Tumors for Bioactivatable Ferroptosis Therapy. ACS Nano 2022, 16 (3) , 3965-3984.
    9. Linlin Deng, Lorenzo Albertazzi, Anja R. A. Palmans. Elucidating the Stability of Single-Chain Polymeric Nanoparticles in Biological Media and Living Cells. Biomacromolecules 2022, 23 (1) , 326-338.
    10. Gadi Slor, Alis R. Olea, Sílvia Pujals, Ali Tigrine, Victor R. De La Rosa, Richard Hoogenboom, Lorenzo Albertazzi, Roey J. Amir. Judging Enzyme-Responsive Micelles by Their Covers: Direct Comparison of Dendritic Amphiphiles with Different Hydrophilic Blocks. Biomacromolecules 2021, 22 (3) , 1197-1210.
    11. Natalia Feiner-Gracia, Adrianna Glinkowska Mares, Marina Buzhor, Romen Rodriguez-Trujillo, Josep Samitier Marti, Roey J. Amir, Silvia Pujals, Lorenzo Albertazzi. Real-Time Ratiometric Imaging of Micelles Assembly State in a Microfluidic Cancer-on-a-Chip. ACS Applied Bio Materials 2021, 4 (1) , 669-681.
    12. Merav Segal, Lihi Ozery, Gadi Slor, Shreyas Shankar Wagle, Tamara Ehm, Roy Beck, Roey J. Amir. Architectural Change of the Shell-Forming Block from Linear to V-Shaped Accelerates Micellar Disassembly, but Slows the Complete Enzymatic Degradation of the Amphiphiles. Biomacromolecules 2020, 21 (10) , 4076-4086.
    13. Shixian Lv, Hojun Kim, Ziyuan Song, Lin Feng, Yingfeng Yang, Ryan Baumgartner, Kuan-Ying Tseng, Shen J. Dillon, Cecilia Leal, Lichen Yin, Jianjun Cheng. Unimolecular Polypeptide Micelles via Ultrafast Polymerization of N-Carboxyanhydrides. Journal of the American Chemical Society 2020, 142 (19) , 8570-8574.
    14. Zhe Tan, Yaming Jiang, Wenjia Zhang, Logan Karls, Timothy P. Lodge, Theresa M. Reineke. Polycation Architecture and Assembly Direct Successful Gene Delivery: Micelleplexes Outperform Polyplexes via Optimal DNA Packaging. Journal of the American Chemical Society 2019, 141 (40) , 15804-15817.
    15. Nathalia Rodrigues de Almeida, Yuchun Han, Jesus Perez, Sydney Kirkpatrick, Yilin Wang, Martin Conda Sheridan. Design, Synthesis, and Nanostructure-Dependent Antibacterial Activity of Cationic Peptide Amphiphiles. ACS Applied Materials & Interfaces 2019, 11 (3) , 2790-2801.
    16. Kanaparedu P. C. Sekhar, Harikrishna Adicherla, Rati Ranjan Nayak. Impact of Glycolipid Hydrophobic Chain Length and Headgroup Size on Self-Assembly and Hydrophobic Guest Release. Langmuir 2018, 34 (30) , 8875-8886.
    17. Shubhashis Datta, Annamária Jutková, Petra Šrámková, Lenka Lenkavská, Veronika Huntošová, Dušan Chorvát, Pavol Miškovský, Daniel Jancura, Juraj Kronek. Unravelling the Excellent Chemical Stability and Bioavailability of Solvent Responsive Curcumin-Loaded 2-Ethyl-2-oxazoline-grad-2-(4-dodecyloxyphenyl)-2-oxazoline Copolymer Nanoparticles for Drug Delivery. Biomacromolecules 2018, 19 (7) , 2459-2471.
    18. Xuanrong Sun, Guowei Wang, Hao Zhang, Shiqi Hu, Xin Liu, Jianbin Tang, Youqing Shen. The Blood Clearance Kinetics and Pathway of Polymeric Micelles in Cancer Drug Delivery. ACS Nano 2018, 12 (6) , 6179-6192.
    19. Weizhi Chen, Sensen Zhou, Lei Ge, Wei Wu, Xiqun Jiang. Translatable High Drug Loading Drug Delivery Systems Based on Biocompatible Polymer Nanocarriers. Biomacromolecules 2018, 19 (6) , 1732-1745.
    20. Thomas Allam, Dominick E. Balderston, Mandeep K. Chahal, Kira L. F. Hilton, Charlotte K. Hind, Olivia B. Keers, Rebecca J. Lilley, Chandni Manwani, Alix Overton, Precious I. A. Popoola, Lisa R. Thompson, Lisa J. White, Jennifer R. Hiscock. Tools to enable the study and translation of supramolecular amphiphiles. Chemical Society Reviews 2023, 52 (20) , 6892-6917.
    21. Amit Sarder, Chanchal Mandal. Amphiphilic Nanocarriers to Fight Against Pathogenic Bacteria. 2023, 76-100.
    22. Xiaotong Wang, Shizhu Chen, Yaru Jia, Kaihan Zhang, Lili Ma, Luwei Li, Xingjie Liang, Jinchao Zhang. Construction of AIEgen functionalized nanomicelles and their stability study through ‘seesaw-like’ fluorescence changes. Chinese Chemical Letters 2023, 34 (6) , 107866.
    23. Yifan Cai, Xin Ji, Yunsen Zhang, Chang Liu, Zichen Zhang, Yongjiu Lv, Xiaochun Dong, Haisheng He, Jianping Qi, Yi Lu, Defang Ouyang, Weili Zhao, Wei Wu. Near‐infrared fluorophores with absolute aggregation‐caused quenching and negligible fluorescence re‐illumination for in vivo bioimaging of nanocarriers. Aggregate 2023, 4 (2)
    24. Yifan Cai, Jianping Qi, Yi Lu, Haisheng He, Wei Wu. The in vivo fate of polymeric micelles. Advanced Drug Delivery Reviews 2022, 188 , 114463.
    25. W. Chen, P. Liu. Dendritic polyurethane-based prodrug as unimolecular micelles for precise ultrasound-activated localized drug delivery. Materials Today Chemistry 2022, 24 , 100819.
    26. Qiaoyu Zhou, Tiancong Zhao, Mengli Liu, Dongrui Yin, Minchao Liu, Ahmed A. Elzatahry, Fan Zhang, Dongyuan Zhao, Xiaomin Li. Highly stable hybrid single-micelle: a universal nanocarrier for hydrophobic bioimaging agents. Nano Research 2022, 15 (5) , 4582-4589.
    27. Alvja Mali, Eric L. Kaijzel, Hildo J. Lamb, Luis J. Cruz. 19F-nanoparticles: Platform for in vivo delivery of fluorinated biomaterials for 19F-MRI. Journal of Controlled Release 2021, 338 , 870-889.
    28. Ahmed M. Abdelsalam, Ahmed Somaida, Ghazala Ambreen, Abdallah M. Ayoub, Imran Tariq, Konrad Engelhardt, Patrick Garidel, Ibrahim Fawaz, Muhammed U. Amin, Matthias Wojcik, Udo Bakowsky. Surface tailored zein as a novel delivery system for hypericin: Application in photodynamic therapy. Materials Science and Engineering: C 2021, 129 , 112420.
    29. Hongxu Liu, Jenna Westley, S. Thayumanavan. Excimer–monomer fluorescence changes by supramolecular disassembly for protein sensing and quantification. Chemical Communications 2021, 57 (76) , 9776-9779.
    30. Sha Bao, Yanqin Zhang, Jing Ye, Yujin Zhu, Rui Li, Xiaohong Xu, Quan Zhang. Self-assembled micelles enhance the oral delivery of curcumin for the management of alcohol-induced tissue injury. Pharmaceutical Development and Technology 2021, 26 (8) , 880-889.
    31. Pravalika Butreddy, Selina Laws, Premitha Pansalawatte, Eric Laws, Hemali Rathnayake. Supramolecular Chemistry of Folic Acid — Experimental and Computational Investigation. Biophysical Reviews and Letters 2021, 16 (03) , 95-109.
    32. Hongxu Liu, Chiara Lionello, Jenna Westley, Annalisa Cardellini, Uyen Huynh, Giovanni M. Pavan, S. Thayumanavan. Understanding functional group and assembly dynamics in temperature responsive systems leads to design principles for enzyme responsive assemblies. Nanoscale 2021, 13 (26) , 11568-11575.
    33. Aurora Pinazo, Ramon Pons, Ana Marqués, Maribel Farfan, Anderson da Silva, Lourdes Perez. Biocompatible Catanionic Vesicles from Arginine-Based Surfactants: A New Strategy to Tune the Antimicrobial Activity and Cytotoxicity of Vesicular Systems. Pharmaceutics 2020, 12 (9) , 857.
    34. Houbing Zhang, Hongjun Li, Zhiting Cao, Jinzhi Du, Lifeng Yan, Jun Wang. Investigation of the in vivo integrity of polymeric micelles via large Stokes shift fluorophore-based FRET. Journal of Controlled Release 2020, 324 , 47-54.
    35. Haoxiang Zeng, Luke Stewart‐Yates, Louis M. Casey, Nick Bampos, Derrick A. Roberts. Covalent Post‐Assembly Modification: A Synthetic Multipurpose Tool in Supramolecular Chemistry. ChemPlusChem 2020, 85 (6) , 1249-1269.
    36. Yizhou Wang, Bin Lei, Minjia Sun, Xia Han, Shouhong Xu, Honglai Liu. Accurate Targeting and Controllable Release of Hybrid Liposome Containing a Stretchable Copolymer. Macromolecular Chemistry and Physics 2020, 221 (7)
    37. Nan Du, Ying Tan, Chen Zhang, Chunyan Tan. Poly(fluorenone- co -thiophene)-based nanoparticles for two-photon fluorescence imaging in living cells and tissues. RSC Advances 2020, 10 (21) , 12373-12377.
    38. Hao Su, Feihu Wang, Wei Ran, Weijie Zhang, Wenbing Dai, Han Wang, Caleb F. Anderson, Zongyuan Wang, Chao Zheng, Pengcheng Zhang, Yaping Li, Honggang Cui. The role of critical micellization concentration in efficacy and toxicity of supramolecular polymers. Proceedings of the National Academy of Sciences 2020, 117 (9) , 4518-4526.
    39. Zhengyu Deng, Shuai Yuan, Ronald X. Xu, Haojun Liang, Shiyong Liu. Reduction‐Triggered Transformation of Disulfide‐Containing Micelles at Chemically Tunable Rates. Angewandte Chemie 2018, 130 (29) , 9034-9038.
    40. Zhengyu Deng, Shuai Yuan, Ronald X. Xu, Haojun Liang, Shiyong Liu. Reduction‐Triggered Transformation of Disulfide‐Containing Micelles at Chemically Tunable Rates. Angewandte Chemie International Edition 2018, 57 (29) , 8896-8900.
    41. Tingbin Zhang, Qian Zhang, Jian-Hua Tian, Jin-Feng Xing, Weisheng Guo, Xing-Jie Liang. Perfluorocarbon-based nanomedicine: emerging strategy for diagnosis and treatment of diseases. MRS Communications 2018, 8 (2) , 303-313.
    42. Natalia Feiner-Gracia, Sílvia Pujals, Pietro Delcanale, Lorenzo Albertazzi. Advanced Optical Microscopy Techniques for the Investigation of Cell-Nanoparticle Interactions. 2018, 219-236.
    43. Abraham J. P. Teunissen, Carlos Pérez-Medina, Andries Meijerink, Willem J. M. Mulder. Investigating supramolecular systems using Förster resonance energy transfer. Chemical Society Reviews 2018, 47 (18) , 7027-7044.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Your Mendeley pairing has expired. Please reconnect