Light-activatable liposomes for repetitive on-demand drug release and immunopotentiation in hypoxic tumor therapy

• Published in: Biomaterials Vol. 265; p. 120456
• Main Authors: Yang, Yuanyuan, Liu, Xin, Ma, Wen, Xu, Qing, Chen, Gui, Wang, Yufei, Xiao, Haihua, Li, Nan, Liang, Xing-Jie, Yu, Meng, Yu, Zhiqiang
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.01.2021
• Subjects: antineoplastic activity; biocompatible materials; Cell Line, Tumor; cisplatin; Drug Liberation; glutathione; hepatoma; Humans; Hydrogen Peroxide; hypoxia; Hypoxia - drug therapy; Hypoxia alleviation; Immunopotentiation; irradiation; Light-activatable liposomes; Liposomes; macrophages; nanomedicine; Oxidative equilibrium; phospholipids; Photochemotherapy; Photosensitizing Agents - therapeutic use; platinum; Repetitive drug release; xenotransplantation; Hypoxia alleviation; Immunopotentiation; Light-activatable liposomes; Oxidative equilibrium; Repetitive drug release
• ISSN: 0142-9612; 1878-5905; 1878-5905
• DOI: 10.1016/j.biomaterials.2020.120456

External stimuli-responsive nanomedicine with desirable repetitive on-demand drug release character is postulated to greatly accommodate patients' flexible medication regime. To this object, light-activatable liposomes (Pt/Ce6-LP) integrated with both a Ce6 photodynamic component and a tetravalent platinum prodrug (Pt(IV)) chemotherapeutic component are engineered. This multifunctional system was rationally designed using unsaturated phospholipid to achieve repetitive on-demand drug release under discontinuous light irradiation, thus performing chemo-photodynamic therapy effect and immunopotentiation in hypoxic tumor. Furthermore, glutathione (GSH) consumption during transformation from Pt(IV) prodrug to Pt(II) can avoid depletion of reactive oxygen species (ROS) in photodynamic therapy (PDT). Note this positive feedback loop appears to remodel the redox balance of H2O2 and GSH in tumors, alleviating the hypoxic tumor microenvironment. The alleviated hypoxia is found to be critical to the enhancement of PDT efficacy, reversal of cisplatin resistance in tumors, and polarization of tumor-associated macrophages (TAMs) to the immunocompetent M1-phynotype. Pt/Ce6-LP with light radiation demonstrates significant antitumor effect and persistent post-medication inhibition in patient-derived tumor xenograft model of hepatocellular carcinoma. A light-activatable liposome (Pt/Ce6-LP) was constructed to realize repetitive on-demand drug release and intensified PDT/chemotherapy on patient-derived tumor xenograft model of hepatocellular carcinoma. Pt/Ce6-LP with light irradiation overcame hypoxia-relative therapeutic resistance via a positive feedback loop and increased M1-TAMs populations to potentiate immune activity for hypoxic tumor treatment. [Display omitted]