Introducing Targeting Units or pH-Releasable Immunodrugs into Core-Clickable Nanogels
European Polymer Journal, vol. 214, pp. 113150
Abstract
The development of nano-sized carrier systems plays a fundamental role in immunodrug delivery and the treatment of cancer. Especially functional materials, coupled with a stimuli-responsive drug release, control the selective delivery of small molecular drugs to the target site and avoid systemic side effects. Based on this, we introduce a DBCO core-functionalized nanogel platform for pH-reversible conjugation of highly potent TLR7/8-activating imidazoquinolines and the selective targeting of macrophage mannose receptor (MMR/ CD206) expressed by immunosuppressive macrophages. DBCO-PEG4-amine functionalized polymethacrylates are synthesized by controlled RAFT polymerization and self-assembled into precursor micelles in polar aprotic solvents. Corresponding nanogels are generated via reactive ester chemistry, while conjugated DBCO–units are incorporated into the core, still accessible for click reaction with azide-functionalized structures. Regarding the preparation of targeted nanogels, trimannose equipped with azide moieties can be conjugated to the DBCO nanogels, revealing the efficient targeting of macrophages’ mannose receptor in vitro. Moreover, the broad applicability of the DBCO nanogel is demonstrated by the synthesis of an azide–containing 2-propionic-3-methylmaleic anhydride-based linker sensitive for the pH–reversible conjugation of secondary amine-modified immune modulators, such as IMDQ-Me. Via bioorthogonal DBCO click reaction, the immune modulator can reversibly be conjugated, affording pH-responsive drug-loaded nanogels that conserve the desired immune stimulatory effect in vitro. Overall, these findings highlight the potential of core–functionalized DBCO nanogels, a promising carrier system for pH–sensitive conjugated immunodrugs as well as an attractive platform for controlled targeting of MMR. Altogether, the versatile application of core-functionalized DBCO nanogels may pave the way for enhancing bioorthogonal multifunctionality inside nanocarrier systems that assist in addressing multiple targets in cancer immunotherapy.
Authors 8
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Max Planck Institute for Polymer Research
Affiliation as printed
Max Planck Institute for Polymer Research, 55128 Mainz, Germany
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Affiliation as printed
Biotherapeutics Division, Leiden Academic Centre for Drug Research (LACDR), Leiden University, 2333CC Leiden, the Netherlands
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Max Planck Institute for Polymer Research
Affiliation as printed
Max Planck Institute for Polymer Research, 55128 Mainz, Germany
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Max Planck Institute for Polymer Research
Affiliation as printed
Max Planck Institute for Polymer Research, 55128 Mainz, Germany
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Max Planck Institute for Polymer Research
Affiliation as printed
Max Planck Institute for Polymer Research, 55128 Mainz, Germany
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Johannes Gutenberg University Mainz
Affiliation as printed
Johannes Gutenberg-University Mainz, Department of Chemistry, 55128 Mainz, Germany
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Vrije Universiteit Brussel · VIB-VUB Laboratory Myeloid Cell Immunology
Affiliation as printed
Brussels Center for Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium
Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, 1050 Brussels, Belgium
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Lutz Nuhn corresponding
University of Würzburg · Max Planck Institute for Polymer Research
Affiliation as printed
Chair of Macromolecular Chemistry, Julius-Maximilians-Universität Würzburg, 97070 Würzburg, Germany
Max Planck Institute for Polymer Research, 55128 Mainz, Germany
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