Unfolding and Degradation of Micellar Immunodrug Carriers Derived From End Group Modified Aliphatic Poly(Carbonate)s with Acid‐Responsive Ketal Side Groups
Abstract
Abstract Small‐molecule immunodrugs hold significant promise for immunotherapeutic applications including vaccination and cancer therapy. However, their clinical use is limited by severe side effects resulting from systemic distribution. To address this challenge, a biodegradable, acid‐responsive nanocarrier system designed for controlled immunodrug delivery in vivo is presented. It is based on polymeric micelles that disassemble in response to acidic environments, enabling site‐specific particle unfolding following endocytosis by antigen‐presenting cells. Its core structure features a hydrolysable aliphatic poly(carbonate) backbone, promoting both biocompatibility and biodegradability. The high precision of the applied ring‐opening polymerization allows for polymer end group functionalization, including the integration of fluorophores for Förster resonance energy transfer (FRET)‐based monitoring of particle integrity and unfolding. The observations reveal a pH‐dependent disassembly profile both in vitro and in vivo. Comparative studies with non‐responsive poly(carbonate)s demonstrate the superior performance of the acid‐responsive design in selectively disassembling under acidic conditions and enhancing polymer backbone degradation. Furthermore, covalent conjugation of a small molecule Toll‐like receptor 7/8 agonist promotes its controlled delivery in vitro and in vivo, resulting in improved immune cell uptake and regulated cytokine production. The findings underscore the potential of this biodegradable, acid‐responsive micellar nanocarrier system as precision delivery platform for safer and effective immunotherapeutics.
Article Details
Authors (17)
Adrian V. Hauck
Institute of Functional Materials and Biofabrication, Center of Polymers for Life, Department of Chemistry and Pharmacy Julius‐Maximilians‐Universität Würzburg 97074 Würzburg Germany
Michael Fichter
Department of Dermatology University Medical Center (UMC) of the Johannes Gutenberg‐University Mainz 55131 Mainz Germany
Laura J. Rosenberger
Department of Dermatology University Medical Center (UMC) of the Johannes Gutenberg‐University Mainz 55131 Mainz Germany
Jannis Willig
Institute of Functional Materials and Biofabrication, Center of Polymers for Life, Department of Chemistry and Pharmacy Julius‐Maximilians‐Universität Würzburg 97074 Würzburg Germany
Alexander Fuchs
Institute of Functional Materials and Biofabrication, Center of Polymers for Life, Department of Chemistry and Pharmacy Julius‐Maximilians‐Universität Würzburg 97074 Würzburg Germany
Felicia Schön
Paul Schneider
Department of Dermatology University Medical Center (UMC) of the Johannes Gutenberg‐University Mainz 55131 Mainz Germany
Carolina Medina‐Montano
Department of Dermatology University Medical Center (UMC) of the Johannes Gutenberg‐University Mainz 55131 Mainz Germany
Taufiq Ahmad
Jessica Erlenbusch
Department of Chemistry Johannes Gutenberg‐University Mainz 55122 Mainz Germany
Pol Besenius
Department of Chemistry University of Mainz Duesbergweg 10–14 55128 Mainz Germany
Leonard Kaps
Department of Dermatology University Medical Center (UMC) of the Johannes Gutenberg‐University Mainz 55131 Mainz Germany
Matthias Bros
University Medical Centre
Stephan Grabbe
Volker Mailänder
Department of Dermatology University Medical Center of the Johannes Gutenberg‐University Mainz Germany
Jürgen Groll
Lutz Nuhn
Institute of Functional Materials and Biofabrication, Center of Polymers for Life, Department of Chemistry and Pharmacy Julius‐Maximilians‐Universität Würzburg 97074 Würzburg Germany