PH-Triggered, Lymph Node Focused Immunodrug Release by Polymeric 2-Propionic-3-Methyl-maleic Anhydrides with Cholesteryl End Groups.

Autor: Heck AG; Chair of Macromolecular Chemistry, Julius-Maximilians-Universität Würzburg, 97070, Würzburg, Germany.; Max Planck Institute for Polymer Research, 55128, Mainz, Germany., Medina-Montano C; Department of Dermatology, University Medical Center (UMC) of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany., Zhong Z; Department of Pharmaceutics and Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, 9000, Belgium., Deswarte K; Department of Internal Medicine and Pediatrics, VIB Center for Inflammation Research, Ghent University, Ghent, 9052, Belgium., Eigen K; Chair of Macromolecular Chemistry, Julius-Maximilians-Universität Würzburg, 97070, Würzburg, Germany., Stickdorn J; Max Planck Institute for Polymer Research, 55128, Mainz, Germany., Kockelmann J; Chair of Macromolecular Chemistry, Julius-Maximilians-Universität Würzburg, 97070, Würzburg, Germany., Scherger M; Max Planck Institute for Polymer Research, 55128, Mainz, Germany., Sanders NN; Laboratory of Gene Therapy, Department of Nutrition, Genetics and Ethology, Ghent University, Merelbeke, 9820, Belgium., Lienenklaus S; Institute for Laboratory Animal Science and Institute of Immunology, Hannover Medical School, 30625, Hanover, Germany., Lambrecht BN; Department of Internal Medicine and Pediatrics, VIB Center for Inflammation Research, Ghent University, Ghent, 9052, Belgium., Grabbe S; Department of Dermatology, University Medical Center (UMC) of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany., De Geest BG; Department of Pharmaceutics and Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, 9000, Belgium., Nuhn L; Chair of Macromolecular Chemistry, Julius-Maximilians-Universität Würzburg, 97070, Würzburg, Germany.; Max Planck Institute for Polymer Research, 55128, Mainz, Germany.
Jazyk: angličtina
Zdroj: Advanced healthcare materials [Adv Healthc Mater] 2024 Dec; Vol. 13 (32), pp. e2402875. Date of Electronic Publication: 2024 Sep 23.
DOI: 10.1002/adhm.202402875
Abstrakt: Gaining spatial control over innate immune activation is of great relevance during vaccine delivery and anticancer therapy, where one aims at activating immune cells at draining lymphoid tissue while avoiding systemic off-target innate immune activation. Lipid-polymer amphiphiles show high tendency to drain to lymphoid tissue upon local administration. Here, pH-sensitive, cholesteryl end group functionalized polymers as stimuli-responsive carriers are introduced for controlled immunoactivation of draining lymph nodes. Methacrylamide-based monomers bearing pendant 2-propionic-3-methylmaleic anhydride groups are polymerized by Reversible Addition-Fragmentation Chain Transfer (RAFT) polymerization using a cholesterol chain-transfer agent (chol-CTA). The amine-reactive anhydrides are conjugated with various amines, however, while primary amines afforded irreversible imides, secondary amines provided pH-responsive conjugates that are released upon acidification. This can be applied to fluorescent dyes for irreversibly carrier labeling or immunostimulatory Toll-like receptor (TLR) 7/8 agonists as cargos for pH-responsive delivery. Hydrophilization of remaining anhydride repeating units with short PEG-chains yielded cholesteryl-polymer amphiphiles that showed efficient cellular uptake and increased drug release at endosomal pH. Moreover, reversibly conjugated TLR 7/8 agonist amphiphiles efficiently drained to lymph nodes and increased the number of effectively maturated antigen-presenting cells after subcutaneous injection in vivo. Consequently, cholesteryl-linked methacrylamide-based polymers with pH-sensitive 2-propionic-3-methylmaleic anhydride side groups provide ideal features for immunodrug delivery.
(© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)
Databáze: MEDLINE
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