Nanoparticle Delivery of MnO2 and Antiangiogenic Therapy to Overcome Hypoxia-Driven Tumor Escape and Suppress Hepatocellular Carcinoma
| Autor: | Jane Wang, Fu Nien Wang, Yunching Chen, Yi-An Lee, Chih-Chun Chang, Trinh Kieu Dinh, Yi-Da Huang, Dehui Wan, Yu-Chuan Shih, Tsai-Te Lu, Yun-Chieh Sung, Pei-Lun Yu, Shao-Chieh Chiu, Cheng-Yun Wu |
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| Rok vydání: | 2020 |
| Předmět: |
Sorafenib
Tumor microenvironment Materials science medicine.medical_treatment Macrophage polarization 02 engineering and technology Immunotherapy Tumor-associated macrophage 021001 nanoscience & nanotechnology medicine.disease Primary tumor Metastasis 03 medical and health sciences 0302 clinical medicine 030220 oncology & carcinogenesis medicine Cancer research General Materials Science Cancer vaccine 0210 nano-technology medicine.drug |
| Zdroj: | ACS Applied Materials & Interfaces. 12:44407-44419 |
| ISSN: | 1944-8252 1944-8244 |
| DOI: | 10.1021/acsami.0c08473 |
| Popis: | Antiangiogenic therapy is widely administered in many cancers, and the antiangiogenic drug sorafenib offers moderate benefits in advanced hepatocellular carcinoma (HCC). However, antiangiogenic therapy can also lead to hypoxia-driven angiogenesis and immunosuppression in the tumor microenvironment (TME) and metastasis. Here, we report the synthesis and evaluation of NanoMnSor, a tumor-targeted, nanoparticle drug carrier that efficiently codelivers oxygen-generating MnO2 and sorafenib into HCC. We found that MnO2 not only alleviates hypoxia by catalyzing the decomposition of H2O2 to oxygen but also enhances pH/redox-responsive T1-weighted magnetic resonance imaging and drug-release properties upon decomposition into Mn2+ ions in the TME. Moreover, macrophages exposed to MnO2 displayed increased mRNA associated with the immunostimulatory M1 phenotype. We further show that NanoMnSor treatment leads to sorafenib-induced decrease in tumor vascularization and significantly suppresses primary tumor growth and distal metastasis, resulting in improved overall survival in a mouse orthotopic HCC model. Furthermore, NanoMnSor reprograms the immunosuppressive TME by reducing the hypoxia-induced tumor infiltration of tumor-associated macrophages, promoting macrophage polarization toward the immunostimulatory M1 phenotype, and increasing the number of CD8+ cytotoxic T cells in tumors, thereby augmenting the efficacy of anti-PD-1 antibody and whole-cell cancer vaccine immunotherapies. Our study demonstrates the potential of oxygen-generating nanoparticles to deliver antiangiogenic agents, efficiently modulate the hypoxic TME, and overcome hypoxia-driven drug resistance, thereby providing therapeutic benefit in cancer. |
| Databáze: | OpenAIRE |
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