Bioconjugated Manganese Dioxide Nanoparticles Enhance Chemotherapy Response by Priming Tumor-Associated Macrophages toward M1-like Phenotype and Attenuating Tumor Hypoxia

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• 作者：Manli Song ; Ting Liu ; Changrong Shi ; Xiangzhong Zhang ; Xiaoyuan Chen
• 刊名：ACS Nano
• 出版年：2016
• 出版时间：January 26, 2016
• 年：2016
• 卷：10
• 期：1
• 页码：633-647
• 全文大小：1119K
• ISSN：1936-086X

文摘

Hypoxia promotes not only the invasiveness of tumor cells, but also chemoresistance in cancer. Tumor associated macrophages (TAMs) residing at the site of hypoxic region of tumors have been known to cooperate with tumor cells, and promote proliferation and chemoresistance. Therefore, there is an urgent need for new strategies to alleviate tumor hypoxia and enhance chemotherapy response in solid tumors. Herein, we have taken advantage of high accumulation of TAMs in hypoxic regions of tumor and high reactivity of manganese dioxide nanoparticles (MnO₂ NPs) toward hydrogen peroxide (H₂O₂) for the simultaneous production of O₂ and regulation of pH to effectively alleviate tumor hypoxia by targeted delivery of MnO₂ NPs to the hypoxic area. Furthermore, we also utilized the ability of hyaluronic acid (HA) modification in reprogramming anti-inflammatory, pro-tumoral M2 TAMs to pro-inflammatory, antitumor M1 macrophages to further enhance the ability of MnO₂ NPs to lessen tumor hypoxia and modulate chemoresistance. The HA-coated, mannan-conjugated MnO₂ particle (Man-HA-MnO₂) treatment significantly increased tumor oxygenation and down-regulated hypoxia-inducible factor-1 α (HIF-1α) and vascular endothelial growth factor (VEGF) in the tumor. Combination treatment of the tumors with Man-HA-MnO₂ NPs and doxorubicin significantly increased apparent diffusion coefficient (ADC) values of breast tumor, inhibited tumor growth and tumor cell proliferation as compared with chemotherapy alone. In addition, the reaction of Man-HA-MnO₂ NPs toward endogenous H₂O₂ highly enhanced T₁- and T₂-MRI performance for tumor imaging and detection.