AUTHOR=Chen Zhenzhen , Liu Zhihong , Zhang Qian , Huang Sheng , Zhang Zaizhong , Feng Xianquan , Zeng Lingjun , Lin Ding , Wang Lie , Song Hongtao 

TITLE=Hypoxia-ameliorated photothermal manganese dioxide nanoplatform for reversing doxorubicin resistance

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1133011

DOI=10.3389/fphar.2023.1133011

ISSN=1663-9812

ABSTRACT=<p>Drug resistance is a huge hurdle in tumor therapy. Tumor hypoxia contributes to chemotherapy resistance by inducing the hypoxia-inducible factor-1α (HIF-1α) pathway. To reduce tumor hypoxia, novel approaches have been devised, providing significant importance to reverse therapeutic resistance and improve the effectiveness of antitumor therapies. Herein, the nanosystem of bovine serum albumin (BSA)-templated manganese dioxide (MnO<sub>2</sub>) nanoparticles (BSA/MnO<sub>2</sub> NPs) loaded with doxorubicin (DOX) (DOX-BSA/MnO<sub>2</sub> NPs) developed in our previous report was further explored for their physicochemical properties and capacity to reverse DOX resistance because of their excellent photothermal and tumor microenvironment (TME) response effects. The DOX-BSA/MnO<sub>2</sub> NPs showed good biocompatibility and hemocompatibility. Meanwhile, DOX-BSA/MnO<sub>2</sub> NPs could greatly affect DOX pharmacokinetic properties, with prolonged circulation time and reduced cardiotoxicity, besides enhancing accumulation at tumor sites. DOX-BSA/MnO<sub>2</sub> NPs can interact with H<sub>2</sub>O<sub>2</sub> and H<sup>+</sup> in TME to form oxygen and exhibit excellent photothermal effect to further alleviate hypoxia due to MnO<sub>2</sub>, reversing DOX resistance by down-regulating HIF-1α expression and significantly improving the antitumor efficiency in DOX-resistant human breast carcinoma cell line (MCF-7/ADR) tumor model. The hypoxia-ameliorated photothermal MnO<sub>2</sub> platform is a promising strategy for revering DOX resistance.</p>