title: Acid-Activatable Versatile Micelleplexes for PD-L1 Blockade-Enhanced Cancer Photodynamic Immunotherapy.
abstract: Photodynamic therapy (PDT) has emerged as a promising clinical modality for cancer therapy due to its ability to initiate an antitumor immune response. However, PDT-mediated cancer immunotherapy is severely impaired by tumor-cell immunosuppression of host T cell antitumor activity through the programmed cell death 1 ligand (PD-L1) and programmed cell death receptor 1 (PD-1) (PD-L1-PD-1) immune checkpoint pathway. Here, we demonstrate that PDT-mediated cancer immunotherapy can be augmented by PD-L1 knockdown (KD) in tumor cells. We rationally designed a versatile micelleplex by integrating an acid-activatable cationic micelle, photosensitizer (PS), and small interfering RNA (siRNA). The micelleplex was inert at physiological pH conditions and activated only upon internalization in the acidic endocytic vesicles of tumor cells for fluorescence imaging and PDT. Compared to PDT alone, the combination of PDT and PD-L1 KD showed significantly enhanced efficacy for inhibiting tumor growth and distant metastasis in a B16-F10 melanoma xenograft tumor model. These results suggest that acid-activatable micelleplexes utilizing PDT-induced cancer immunotherapy are more effective when combined with siRNA-mediated PD-L1 blockade. This study could provide a general strategy for enhancing the therapy efficacy of photodynamic cancer therapy.
authors.affiliation: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.|University of Chinese Academy of Sciences , Beijing 100049, China.
authors.forename: Dangge
authors.initials: D
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.|University of Chinese Academy of Sciences , Beijing 100049, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Haijun
authors.initials: H
authors.lastname: Yu
authors.affiliation: Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai 200031, China.
authors.forename: Shi
authors.initials: S
authors.lastname: Jiao
authors.affiliation: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.|University of Chinese Academy of Sciences , Beijing 100049, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Fangyuan
authors.initials: F
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Yuanlei
authors.initials: Y
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai 200031, China.
authors.forename: Zhaocai
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D007167:Immunotherapy; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010778:Photochemotherapy; D017319:Photosensitizing Agents; D061026:Programmed Cell Death 1 Receptor; D013601:T-Lymphocytes; D023041:Xenograft Model Antitumor Assays
chemical_list: D017319:Photosensitizing Agents; D061026:Programmed Cell Death 1 Receptor
keywords: Micelleplexes; RNA interference; acid-activatable; cancer immunotherapy; photodynamic therapy