An arsenic trioxide nanoparticle prodrug (ATONP) potentiates a therapeutic effect on an aggressive hepatocellular carcinoma model via enhancement of intratumoral arsenic accumulation and disturbance of the tumor microenvironment
An arsenic trioxide nanoparticle prodrug (ATONP) potentiates a therapeutic effect on an aggressive hepatocellular carcinoma model via enhancement of intratumoral arsenic accumulation and disturbance of the tumor microenvironment
复制标题
三氧化二砷纳米颗粒前药 (ATONP) 通过增强瘤内砷积累和扰乱肿瘤微环境来增强侵袭性肝细胞癌模型的治疗效果
DOI：
10.1039/c9tb00349e
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发表时间：
2019-05-21
影响因子：
7
通讯作者：
Tang, Qun
中科院分区：
文献类型：
--
作者：
Fu, Xin;Liang, Qing-rong;Tang, Qun
在过去的几十年里，纳米医学发展迅速，但纳米抗癌剂的治疗效果仍然很差，尽管有些已经进入临床“床边”。纳米组装作为一种多功能和多阶段的平台，不仅有助于更高的抗癌药物递送，而且还提供协同效应（例如，整合疗法、治疗诊断学等）。我们已经设计了一种基于胶体亚砷酸钆纳米颗粒的“PI激活”三氧化二砷（ATO）前药（ATONP），并且现在提供了在转基因肝细胞癌模型上化疗疗效的证据。在温和条件下合成了胶体前药。在施用ATO纳米颗粒前药后，发现砷在肿瘤内的积累达到5%，这比施用纯ATO高十倍。此外，在体外和体内的一系列测试中显示，间质无机磷酸盐减少，并且相应的pH升高。我们使用临床相关的Tet-Off MYC诱导的转基因肝癌模型来评估治疗效果。在第一个队列中，多次给药后肿瘤体积减小超过50%。在第二个队列中，与对照治疗组（ATO、索拉非尼和生理盐水）相比，ATONP显著延长了小鼠生存期。此外，ATONP的毒性是可逆的。这些结果表明，ATONP是一种潜在的治疗肝癌的药物。
The past decades have seen rapid developments in nanomedicine, but the therapeutic efficacy of nanosized anti-cancer agents remains marginal, although some have reached the clinic "bedside". Nano-assembly, as a versatile and multi-stage platform, not only contributes to a higher anticancer drug delivery, but also provides synergistic effects (e.g., integrative therapy, theranostics, etc.). We have designed a "Pi-activated" arsenic trioxide (ATO) pro-drug (ATONP) based on colloidal gadolinium arsenite nanoparticles and now present evidence for chemotherapeutic efficacy on a transgenic hepatocellular carcinoma model. The colloidal prodrug was synthesized under mild conditions. After administration of the ATO nanoparticle prodrug, arsenic accumulation within tumors was found to reach as much as 5%, which is ten times higher than following administration of pure ATO. Moreover, the interstitial inorganic phosphate decreased, and the corresponding pH was elevated, as shown in a series of tests in vitro and in vivo. We used a clinically relevant Tet-Off MYC inducible transgenic liver cancer model to evaluate the therapeutic effect. In the first cohort, the tumor volume decreased more than 50% after multiple doses. In the second cohort, ATONP significantly prolonged mouse survival compared with control treatment groups (ATO, sorafenib and saline). Furthermore, the toxicity of the ATONP is reversible. These results suggest that ATONP is a potential drug for the treatment of liver cancer.