Squaric Ester-Based, pH-Degradable Nanogels: Modular Nanocarriers for Safe, Systemic Administration of Toll-like Receptor 7/8 Agonistic Immune Modulators
| Autor: | Jana De Vrieze, Carolina Medina-Montano, Bruno G. De Geest, Niklas Choteschovsky, Niek N. Sanders, Stefan Lienenklaus, Bart N. Lambrecht, Matthias Bros, Kim Deswarte, Anne Huppertsberg, Christian Czysch, Kaloian Koynov, Lutz Nuhn, Judith Stickdorn, Detlef Schuppan, Francis Combes, Adrian Klefenz, Sascha Schmitt, Leonard Kaps, Sabah Kasmi, Chaojian Chen, Sunil A. David, Zifu Zhong, Pia Winterwerber |
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| Přispěvatelé: | Pulmonary Medicine |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Polymers
medicine.medical_treatment Nanogels VACCINE Pharmacology 010402 general chemistry 01 natural sciences Biochemistry Micelle Catalysis Article Polymerization chemistry.chemical_compound Colloid and Surface Chemistry Adjuvants Immunologic SDG 3 - Good Health and Well-being medicine Medicine and Health Sciences Animals Humans Reversible addition−fragmentation chain-transfer polymerization Micelles TLR8 AMIDES Drug Carriers Mice Inbred BALB C Chemistry Optical Imaging Biology and Life Sciences Esters General Chemistry TLR7 Hydrogen-Ion Concentration 0104 chemical sciences Imidazoquinoline Drug Liberation CONJUGATION Toll-Like Receptor 7 Toll-Like Receptor 8 Systemic administration Immunotherapy Nanocarriers ADJUVANTS Adjuvant Nanogel |
| Zdroj: | Journal of the American Chemical Society Journal of the American Chemical Society, 143(26), 9872-9883. American Chemical Society JOURNAL OF THE AMERICAN CHEMICAL SOCIETY |
| ISSN: | 0002-7863 1520-5126 |
| Popis: | Small-molecular Toll-like receptor 7/8 (TLR7/8) agonists hold promise as immune modulators for a variety of immune therapeutic purposes including cancer therapy or vaccination. However, due to their rapid systemic distribution causing difficult-to-control inflammatory off-target effects, their application is still problematic, in particular systemically. To address this problem, we designed and robustly fabricated pH-responsive nanogels serving as versatile immunodrug nanocarriers for safe delivery of TLR7/8-stimulating imidazoquinolines after intravenous administration. To this aim, a primary amine-reactive methacrylamide monomer bearing a pendant squaric ester amide is introduced, which is polymerized under controlled RAFT polymerization conditions. Corresponding PEG-derived squaric ester amide block copolymers self-assemble into precursor micelles in polar protic solvents. Their cores are amine-reactive and can sequentially be transformed by acid-sensitive cross-linkers, dyes, and imidazoquinolines. Remaining squaric ester amides are hydrophilized affording fully hydrophilic nanogels with profound stability in human plasma but stimuli-responsive degradation upon exposure to endolysosomal pH conditions. The immunomodulatory behavior of the imidazoquinolines alone or conjugated to the nanogels was demonstrated by macrophages in vitro. In vivo, however, we observed a remarkable impact of the nanogel: After intravenous injection, a spatially controlled immunostimulatory activity was evident in the spleen, whereas systemic off-target inflammatory responses triggered by the small-molecular imidazoquinoline analogue were absent. These findings underline the potential of squaric ester-based, pH-degradable nanogels as a promising platform to permit intravenous administration routes of small-molecular TLR7/8 agonists and, thus, the opportunity to explore their adjuvant potency for systemic vaccination or cancer immunotherapy purposes. |
| Databáze: | OpenAIRE |
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