ATP-Responsive Liposomes via Screening of Lipid Switches Designed to Undergo Conformational Changes upon Binding Phosphorylated Metabolites
- Jinchao LouJinchao LouDepartment of Chemistry, University of Tennessee, Knoxville, Tennessee 37996, United StatesMore by Jinchao Lou
- ,
- Jennifer A. SchusterJennifer A. SchusterDepartment of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee 37996, United StatesMore by Jennifer A. Schuster
- ,
- Francisco N. BarreraFrancisco N. BarreraDepartment of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee 37996, United StatesMore by Francisco N. Barrera
- , and
- Michael D. Best*Michael D. Best*Email: [email protected]Department of Chemistry, University of Tennessee, Knoxville, Tennessee 37996, United StatesMore by Michael D. Best
Abstract
Liposomal delivery vehicles can dramatically enhance drug transport. However, their clinical application requires enhanced control over content release at diseased sites. For this reason, triggered release strategies have been explored, although a limited toolbox of stimuli has thus far been developed. Here, we report a novel strategy for stimuli-responsive liposomes that release encapsulated contents in the presence of phosphorylated small molecules. Our formulation efforts culminated in selective cargo release driven by ATP, a universal energy source that is upregulated in diseases such as cancer. Specifically, we developed lipid switches 1a–b bearing two ZnDPA units designed to undergo substantial conformational changes upon ATP binding, thereby disrupting membrane packing and triggering the release of encapsulated contents. Dye leakage assays using the hydrophobic dye Nile red validated that ATP-driven release was selective over 11 similar phosphorylated metabolites, and release of the hydrophilic dye calcein was also achieved. Multiple alternative lipid switch structures were synthesized and studied (1c–d and 2), which provided insights into the structural features that render 1a–b selective toward ATP-driven release. Importantly, analysis of cellular delivery using fluorescence microscopy in conjunction with pharmacological ATP manipulation showed that liposome delivery was specific, as it increased upon intracellular ATP accumulation, and was inhibited by ATP downregulation. Our new approach shows strong prospects for enhancing the selectivity of release and payload delivery to diseased cells driven by metabolites such as ATP, providing an exciting new paradigm for controlled release.
Cited By
This article is cited by 8 publications.
- Deborah Lee, Seoyoon Song, Suheon Kim, Mina Lee, Eunsu Kim, Sunhee Yoon, Han-Ul Kim, Sejin Son, Hyun Suk Jung, Yun Suk Huh, Sun Min Kim, Tae-Joon Jeon. Multicomponent-Loaded Vesosomal Drug Carrier for Controlled and Sustained Compound Release. Biomacromolecules 2023, 24 (8) , 3898-3907. https://doi.org/10.1021/acs.biomac.3c00528
- Joana N. Martins, Beatriz Raimundo, Alicia Rioboo, Yeray Folgar-Cameán, Javier Montenegro, Nuno Basílio. Photoswitchable Calixarene Activators for Controlled Peptide Transport across Lipid Membranes. Journal of the American Chemical Society 2023, 145 (24) , 13126-13133. https://doi.org/10.1021/jacs.3c01829
- Jinchao Lou, Ruhani Sagar, Michael D. Best. Metabolite-Responsive Liposomes Employing Synthetic Lipid Switches Driven by Molecular Recognition Principles. Accounts of Chemical Research 2022, 55 (20) , 2882-2891. https://doi.org/10.1021/acs.accounts.2c00446
- Jinchao Lou, Macy M. Hudson, Christelle F. Ancajas, Michael D. Best. Development of GTP-responsive liposomes by exchanging the metal-DPA binding site in a synthetic lipid switch. Chemical Communications 2023, 59 (22) , 3285-3288. https://doi.org/10.1039/D3CC00288H
- Ruhani Sagar, Emily A. Jaremba, Jinchao Lou, Michael D. Best. Copper-responsive liposomes for triggered cargo release employing a picolinamide−lipid conjugate. Organic & Biomolecular Chemistry 2023, 21 (5) , 955-959. https://doi.org/10.1039/D2OB01977A
- Da-Yuan Wang, Guang Yang, Xiao-Xiao Zhang, Henny C. van der Mei, Yijin Ren, Henk J. Busscher, Linqi Shi. Proton-mediated burst of dual-drug loaded liposomes for biofilm dispersal and bacterial killing. Journal of Controlled Release 2022, 352 , 460-471. https://doi.org/10.1016/j.jconrel.2022.10.049
- Megan L. Qualls, Jinchao Lou, Dillon P. McBee, Joshua A. Baccile, Michael D. Best. Cyclic Disulfide Liposomes for Membrane Functionalization and Cellular Delivery. Chemistry – A European Journal 2022, 28 (45) https://doi.org/10.1002/chem.202201164
- Sydney E. Bottcher, Jinchao Lou, Michael D. Best. Liposome triggered content release through molecular recognition of inositol trisphosphate. Chemical Communications 2022, 58 (28) , 4520-4523. https://doi.org/10.1039/D2CC00951J