Hybrid Manganese Dioxide Nanoparticles Potentiate Radiation Therapy by Modulating Tumor Hypoxia
Hybrid Manganese Dioxide Nanoparticles Potentiate Radiation Therapy by Modulating Tumor Hypoxia
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DOI：
10.1158/0008-5472.can-15-3475
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发表时间：
2016-11-15
期刊：
影响因子：
11.2
通讯作者：
Wu, Xiao Yu
中科院分区：
文献类型：
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作者：
Abbasi, Azhar Z.;Gordijo, Claudia R.;Wu, Xiao Yu
肿瘤微环境（TME）中的缺氧会介导对放疗的抵抗，并导致接受放疗的患者预后不良。在此，我们报告了临床上合适的混合二氧化锰 (MnO2) 纳米颗粒 (MDNP) 配方的设计，该配方使用生物相容性材料通过与内源性 H2O2 反应来对 TME 进行再氧合。含有亲水性三元共聚物-蛋白质-MnO2 或疏水性聚合物-脂质-MnO2 的MDNP 在与不同临床环境相关的TME 中提供不同的氧气生成速率。在高度缺氧的小鼠或人类异种移植乳腺肿瘤模型中，我们发现在放疗前施用 MDNP 制剂可调节肿瘤缺氧并提高放疗疗效，从而减少肿瘤生长、VEGF 表达和血管密度。 MDNP 治疗还增加了细胞凋亡和 DNA 双链断裂，使宿主中位存活率增加了 3 至 5 倍。值得注意的是，在小鼠模型中，大约 40% 的荷瘤小鼠在使用 MDNP 进行单次治疗后，加上放射治疗，其剂量比不用 MDNP 实现相同治疗所需的剂量低 2.5 倍。总体而言，我们的研究结果为使用 MDNP 制剂作为有效的放射治疗佐剂提供了临床前概念证明。
Hypoxia in the tumor microenvironment (TME) mediates resistance to radiotherapy and contributes to poor prognosis in patients receiving radiotherapy. Here we report the design of clinically suitable formulations of hybrid manganese dioxide (MnO2) nanoparticles (MDNP) using biocompatible materials to reoxygenate the TME by reacting with endogenous H2O2. MDNP containing hydrophilic terpolymer-protein-MnO2 or hydrophobic polymer-lipid-MnO2 provided different oxygen generation rates in the TME relevant to different clinical settings. In highly hypoxic murine or human xenograft breast tumor models, we found that administering either MDNP formulation before radiotherapy modulated tumor hypoxia and increased radiotherapy efficacy, acting to reduce tumor growth, VEGF expression, and vascular density. MDNP treatment also increased apoptosis and DNA double strand breaks, increasing median host survival 3- to 5-fold. Notably, in the murine model, approximately 40% of tumor-bearing mice were tumor-free after a single treatment with MDNPs plus radiotherapy at a 2.5-fold lower dose than required to achieve the same curative treatment without MDNPs. Overall, our findings offer a preclinical proof of concept for the use of MDNP formulations as effective radiotherapy adjuvants.