A theranostic photosensitizer-conjugated albumin co-loading with resiquimod for cancer-targeted imaging and robust photo-immunotherapy

• Published in: Pharmacological research 2024-12, Vol.210, p.107489, Article 107489
• Main Authors: Tan, Xu, Wang, Yu, Long, Lei, Chen, Hongdan, Qu, Langfan, Cao, Xiaohui, Li, Huijuan, Chen, Zelin, Luo, Shenglin, Shi, Chunmeng
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cancer immunotherapy; Cell Line, Tumor; CTLA-4 blockade therapy; Dual-modal phototherapy; Female; Human serum albumin; Humans; Imidazoles - administration & dosage; Imidazoles - chemistry; Imidazoles - pharmacology; Immunotherapy - methods; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - therapy; Photochemotherapy - methods; Photosensitizing Agents - administration & dosage; Photosensitizing Agents - chemistry; Photosensitizing Agents - pharmacology; Photosensitizing Agents - therapeutic use; Phototherapy - methods; Serum Albumin, Human - chemistry; Theranostic Nanomedicine - methods; Tumor microenvironment; Tumor Microenvironment - drug effects
• ISSN: 1043-6618; 1096-1186; 1096-1186
• DOI: 10.1016/j.phrs.2024.107489

Cancer immunotherapy remains a low immune response rate in clinic because of dominant immunosuppressive tumor microenvironment (TME) and lack of effective drug to specifically remodel the TME. In this work, we introduced a tumor-seeking human serum albumin (HSA) based delivery platform by covalently conjugating with a tumor-targeting near-infrared (NIR) photosensitizer (IR-DBI) and non-covalently loading of immune modulator Resiquimod (R848). HSA exhibited tumor-preferential accumulation after covalent conjugation with IR-DBI. Meanwhile, HSA restricted the rotation of IR-DBI, narrowed the HOMO-LUMO energy gap, significantly enhanced fluorescent intensity and dual-modal phototherapy (PTT/PDT). The enhanced phototherapeutic effect further induced robust ICD effect. More importantly, non-covalent loading of R848 could be released from HSA at tumor sites by laser irradiation-induced heat. The in-situ release of R848 in TME efficiently promoted the maturation of DC cells and repolarized M2 macrophages to M1 macrophages. Consequently, robust photo-induced antitumor immunity was triggered in the different mice models bearing primary and distant tumors or lung metastasis, which was further enhanced by combining with CTLA-4 blockade therapy. Taken together, this work may present a versatile albumin composite which exhibits tumor-preferential accumulation and imaging-guided PDT/PTT/immunotherapy. [Display omitted] •A tumor-targeting near-infrared photosensitizer (IR-DBI) was covalently conjugated to human serum albumin (HSA) via chlorine substitution.•An immunoadjuvant (R848) was non-covalently loaded into HSA at subdomain IIIA via hydrophobic interaction and hydrogen bonds.•Covalent conjugation in HSA restricted IR-DBI rotation, narrowed its HOMO-LUMO energy gap, significantly enhanced dual-modal phototherapy (PTT/PDT)•HSA-DBI@848 exhibited tumor-preferential accumulation and imaging-guided precise phototherapy because of covalent conjugation with IR-DBI.•The in situ release of R848 in tumors promoted by photo-induced heat, repolarized M2 macrophages to M1 macrophages and triggered antitumor immunity.•Robust photo-induced antitumor immunity was further amplified by combining with CTLA-4 blockade therapy.