Journal
BIOMATERIALS
Volume 265, Issue -, Pages -Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2020.120456
Keywords
Light-activatable liposomes; Repetitive drug release; Oxidative equilibrium; Hypoxia alleviation; Immunopotentiation
Funding
- National Natural Science Foundation of China [81773642, 81701817]
- Natural Science Foundation of Guangdong Province [2019A1515011619, 2019A1515011498]
- Guangdong-Hong Kong Technology Cooperation Fund [2017A050506016]
- Key Laboratory of Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, ACS [NSKF201819]
- Guangdong Basic and Applied Basic Research Foundation [2019A1515110877]
- China Postdoctoral Science Foundation [2020M672542]
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A multifunctional light-activatable liposome has been engineered for repetitive on-demand drug release under discontinuous light irradiation, allowing for chemo-photodynamic therapy and immunopotentiation in hypoxic tumors. This system effectively remodels the redox balance in tumors, alleviating hypoxia and enhancing PDT efficacy, reversing cisplatin resistance, and polarizing tumor-associated macrophages to the immunocompetent M1 phenotype.
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.
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