Tumor Cell-Targeting and Tumor Microenvironment–Responsive Nanoplatforms for the Multimodal Imaging-Guided Photodynamic/Photothermal/Chemodynamic Treatment of Cervical Cancer

Abstract

Ying Wang,1,* Yiyan Xu,2,* Jiayu Song,1 Xueting Liu,1 Sijia Liu,1 Nan Yang,1 Le Wang,1 Yujie Liu,1 Yiwei Zhao,1 Wenhu Zhou,3,4 Yunyan Zhang1 1Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150081, People’s Republic of China; 2Department of Vascular Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, People’s Republic of China; 3Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410013, People’s Republic of China; 4Hunan Key Laboratory of The Research and Development of Novel Pharmaceutical Preparations, School of Pharmaceutical Science, Changsha Medical University, Changsha, 410219, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yunyan Zhang, Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, Heilongjiang Province, 150081, People’s Republic of China, Tel [phone], Fax [phone], Email [email protected] Wenhu Zhou, Xiangya School of Pharmaceutical Sciences, Central South University, 172 Tongzipo Road, Changsha, Hunan, 410013, People’s Republic of China, Tel [phone], Fax [phone], Email [email protected]: Phototherapy, known for its high selectivity, few side effects, strong controllability, and synergistic enhancement of combined treatments, is widely used in treating diseases like cervical cancer.Methods: In this study, hollow mesoporous manganese dioxide was used as a carrier to construct positively charged, poly(allylamine hydrochloride)–modified nanoparticles (NPs). The NP was efficiently loaded with the photosensitizer indocyanine green (ICG) via the addition of hydrogen phosphate ions to produce a counterion aggregation effect. HeLa cell membrane encapsulation was performed to achieve the final M-HMnO2@ICG NP. In this structure, the HMnO2 carrier responsively degrades to release ICG in the tumor microenvironment, self-generates O2 for sensitization to ICG-mediated photodynamic therapy (PDT), and consumes GSH to expand the oxidative stress therapeutic effect [chemodynamic therapy (CDT) + PDT]. The ICG accumulated in tumor tissues exerts a synergistic PDT/photothermal therapy (PTT) effect through single laser irradiation, improving efficiency and reducing side effects. The cell membrane encapsulation increases nanomedicine accumulation in tumor tissues and confers an immune evasion ability. In addition, high local temperatures induced by PTT can enhance CDT. These properties of the NP enable full achievement of PTT/PDT/CDT and targeted effects.Results: Mn2+ can serve as a magnetic resonance imaging agent to guide therapy, and ICG can be used for photothermal and fluorescence imaging. After its intravenous injection, M-HMnO2@ICG accumulated effectively at mouse tumor sites; the optimal timing of in-vivo laser treatment could be verified by near-infrared fluorescence, magnetic resonance, and photothermal imaging. The M-HMnO2@ICG NPs had the best antitumor effects among treatment groups under near-infrared light conditions, and showed good biocompatibility.Conclusion: In this study, we designed a nano-biomimetic delivery system that improves hypoxia, responds to the tumor microenvironment, and efficiently loads ICG. It provides a new economical and convenient strategy for synergistic phototherapy and CDT for cervical cancer.Keywords: phototherapy, reactive oxygen species, hypoxia relief, collaborative therapy

Keywords

• phototherapy
• reactive oxygen species
• hypoxia relief
• collaborative therapy