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

• Published in: Acta pharmaceutica Sinica. B Vol. 14; no. 2; pp. 765 - 780
• Main Authors: He, Siqin, Wang, Lulu, Wu, Dongxu, Tong, Fan, Zhao, Huan, Li, Hanmei, Gong, Tao, Gao, Huile, Zhou, Yang
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2024; Elsevier
• Subjects: Checkpoint blockade; Dual-responsive; Immunomodulator; Immunosuppressive microenvironment; Original; Photodynamic therapy; Supramolecular assembly; Immunomodulator; Photodynamic therapy; Supramolecular assembly; Checkpoint blockade; Dual-responsive; Immunosuppressive microenvironment
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2023.10.006

A major challenge facing photodynamic therapy (PDT) is that the activity of the immune-induced 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 Tregs. The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase 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. Dual-responsive cyclodextrin-based supramolecular self-assembly system co-delivers photosensitizer and immunomodulator to induce tumor cell apoptosis and reverse the immunosuppressive microenvironment with PD-1 antibody for effective treatment of metastatic breast cancer. [Display omitted]