Journal
ACS APPLIED MATERIALS & INTERFACES
Volume 12, Issue 40, Pages 44407-44419Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsami.0c08473
Keywords
hypoxia; antiangiogenic therapy; immunotherapy; tumor-associated macrophage; hepatocellular carcinoma; MnO2
Funding
- Ministry of Science and Technology [MOST 108-3017-F-007-003, MOST 109-2634-F-007-023, MOST 105-2628-E-007-007-MY3, 108-2321-B-009-004, 109-2321-B-009-006, 109-2327-B-039 -002, 108-2221-E-007-104-MY5]
- Chang Gung Memorial Hospital-National Tsing Hua University Joint Research grant [108Q2508E1, CORPG3I0071]
- National Health Research Institutes [NHRI-EX109-10609BC]
- Frontier Research Center on Fundamental and Applied Sciences of Matters from the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) [109QR001I5]
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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.
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