Unimolecular Photodynamic O2-Economizer To Overcome Hypoxia Resistance in Phototherapeutics.

Abstract

Tumor hypoxia has proven to be the major bottleneck of photodynamic therapy (PDT) to clinical transformation. Different from traditional O2 delivery approaches, here we describe an innovative binary photodynamic O2-economizer (PDOE) tactic to reverse hypoxia-driven resistance by designing a superoxide radical (O2•-) generator targeting mitochondria respiration, termed SORgenTAM. This PDOE system is able to block intracellular O2 consumption and down-regulate HIF-1α expression, which successfully rescues cancer cells from becoming hypoxic and relieves the intrinsic hypoxia burden of tumors in vivo, thereby sparing sufficient endogenous O2 for the PDT process. Photosensitization mechanism studies demonstrate that SORgenTAM has an ideal intersystem crossing rate and triplet excited state lifetime for generating O2•- through type-I photochemistry, and the generated O2•- can further trigger a biocascade to reduce the PDT's demand for O2 in an O2-recycble manner. Furthermore, SORgenTAM also serves to activate the AMPK metabolism signaling pathway to inhibit cell repair and promote cell death. Consequently, using this two-step O2-economical strategy, under relatively low light dose irradiation, excellent therapeutic responses toward hypoxic tumors are achieved. This study offers a conceptual while practical paradigm for overcoming the pitfalls of phototherapeutics.

• Authors: Mingle Li, Yujie Shao, Ji Hyeon Kim, Zhongji Pu, Xueze Zhao, Haiqiao Huang, Tao Xiong, Yao Kang, Guangzhe Li, Kun Shao, Jiangli Fan, James W Foley, Jong Seung Kim, Xiaojun Peng
• Journal: Journal of the American Chemical Society (J Am Chem Soc) Vol. 142 Issue 11 Pg. 5380-5388 (03 18 2020) ISSN: 1520-5126 [Electronic] United States
• PMID: 32105455 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Phenothiazines
• Photosensitizing Agents
• Superoxides

Topics

• Animals
• Cell Respiration (drug effects)
• Female
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Light
• MCF-7 Cells
• Mice, Inbred BALB C
• Mitochondria (drug effects)
• Neoplasms (drug therapy)
• Phenothiazines (chemical synthesis, radiation effects, therapeutic use)
• Photochemotherapy
• Photosensitizing Agents (chemical synthesis, radiation effects, therapeutic use)
• Superoxides (metabolism)
• Tumor Hypoxia (drug effects)