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Dual-responsive supramolecular photodynamic nanomedicine with activatable immunomodulation for enhanced antitumor therapy

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Acta Pharmaceutica Sinica B 2024年第2期14卷 765-780页

作者： Siqin He Lulu Wang Dongxu Wu Fan Tong Huan Zhao Hanmei Li Tao Gong Huile Gao Yang Zhou Key Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical SciencesHainan UniversityHaikou 570200China Key Laboratory of Drug-Targeting and Drug Delivery System West China School of PharmacySichuan UniversityChengdu 610041China revvity inc. WalthamMA 02451USA School of Food and Biological Engineering Chengdu UniversityChengdu 610106China

A major challenge facing photodynamic therapy(PDT) is that the activity of the immuneinduced infiltrating CD8^(+)T cells is subject to the regulatory T lymphocytes(Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment(TME), a supramolecular photodynamic nanoparticle(DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated β-cyclodextrin(DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration(Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile β-carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of *** guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and inc.easing photosensitizer retention in the tumor. With a significant inc.ease in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.

关键词： Photodynamic therapy Immunosuppressive microenvironment Immunomodulator Dual-responsive Supramolecularassembly Checkpointblockade

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