Nanoparticle tumor localization, disruption of autophagosomal trafficking, and prolonged drug delivery improve survival in peritoneal mesothelioma.
Nanoparticle tumor localization, disruption of autophagosomal trafficking, and prolonged drug delivery improve survival in peritoneal mesothelioma.
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DOI：
10.1016/j.biomaterials.2016.06.031
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发表时间：
2016-09
期刊：
影响因子：
14
通讯作者：
Colson YL
中科院分区：
文献类型：
--
作者：
Liu R;Colby AH;Gilmore D;Schulz M;Zeng J;Padera RF;Shirihai O;Grinstaff MW;Colson YL
恶性腹膜间皮瘤的治疗结果很差，并且由于药物传递不佳而导致高并发症。因此，对新的方法的需求尚未得到满足，这些方法可以在肿瘤处长期集中药物，从而产生增强的抗肿瘤效果和改善治疗成功的指标。描述了一种紫杉醇pH响应型可膨胀纳米粒(PTX-ENP)系统，该系统可解决两个独特的挑战，以改善腹膜间皮瘤的预后。首先，在腹膜腔给药后，ENPs迅速和特异地定位于肿瘤。肿瘤摄取ENP的速度比非恶性细胞摄取的速度快一个数量级；随后自噬体内的积聚和自噬小体运输的中断导致ENP在细胞内的滞留时间延长。这些联合机制的净效果表现为注射后4小时内迅速定位于腹膜内肿瘤，并在肿瘤内持续滞留14天。其次，PTX-ENPs的高度肿瘤特异性导致在肿瘤中的药物浓度比单独使用PTX高100倍以上，而且这种情况在给药后至少保持7天。结果，当动物接受多剂量PTX-ENPs治疗时，与同等剂量的PTX或无反应的PTX负载纳米粒治疗相比，患有间皮瘤的动物的总存活率增加了一倍以上。
The treatment outcomes for malignant peritoneal mesothelioma are poor and associated with high co-morbidities due to suboptimal drug delivery. Thus, there is an unmet need for new approaches that concentrate drug at the tumor for a prolonged period of time yielding enhanced antitumor efficacy and improved metrics of treatment success. A paclitaxel-loaded pH-responsive expansile nanoparticle (PTX-eNP) system is described that addresses two unique challenges to improve the outcomes for peritoneal mesothelioma. First, following intraperitoneal administration, eNPs rapidly and specifically localize to tumors. The rate of eNP uptake by tumors is an order of magnitude faster than the rate of uptake in non-malignant cells; and, subsequent accumulation in autophagosomes and disruption of autophagosomal trafficking leads to prolonged intracellular retention of eNPs. The net effect of these combined mechanisms manifests as rapid localization to intraperitoneal tumors within 4 hrs of injection and persistent intratumoral retention for > 14 days. Second, the high tumor-specificity of PTX-eNPs leads to delivery of greater than 100 times higher concentrations of drug in tumors compared to PTX alone and this is maintained for at least seven days following administration. As a result, overall survival of animals with established mesothelioma more than doubled when animals were treated with multiple doses of PTX-eNPs compared to equivalent dosing with PTX or non-responsive PTX-loaded nanoparticles.