Colocalized Delivery of Rapamycin and Paclitaxel to Tumors Enhances Synergistic Targeting of the PI3K/Akt/mTOR Pathway
Colocalized Delivery of Rapamycin and Paclitaxel to Tumors Enhances Synergistic Targeting of the PI3K/Akt/mTOR Pathway
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DOI：
10.1038/mt.2014.27
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发表时间：
2014-07-01
影响因子：
12.4
通讯作者：
Ferrari, Mauro
中科院分区：
文献类型：
--
作者：
Blanco, Elvin;Sangai, Takafumi;Ferrari, Mauro
正在进行的临床试验针对乳腺癌中异常的PI3K/Akt/哺乳动物雷帕霉素靶点(MTOR)途径，通过给予变构mTOR抑制剂雷帕霉素与紫杉醇联合使用。然而，由于不同药物的药代动力学参数不同，协同作用可能没有在临床上得到充分利用。这项研究探索了雷帕霉素和紫杉醇通过纳米颗粒掺入的位置特异性、共定位递送的协同潜力。准确控制纳米粒载药量，建立体外协同给药比例。在给小鼠注射纳米颗粒48小时后，肿瘤中精确的药物比例保持在比肝脏和脾高两倍的水平，与对照组相比，产生了更好的抗肿瘤活性。雷帕霉素和紫杉醇同时和优先体内给药对协同作用产生了机械性的见解，包括抑制反馈环Akt磷酸化及其下游靶点。研究结果表明，同一时间、同一地点、特定剂量的纳米粒递送联合化疗方法有可能成功地将体外协同结果转化为体内协同结果。体外预测模型可用于确定抗肿瘤疗效的最佳药物比例，而在临床前动物模型中纳米粒联合化疗可能导致对协同机制的更好理解，最终为个性化治疗开辟几条途径。
Ongoing clinical trials target the aberrant PI3K/Akt/mammalian target of rapamycin (mTOR) pathway in breast cancer through administration of rapamycin, an allosteric mTOR inhibitor, in combination with paclitaxel. However, synergy may not be fully exploited clinically because of distinct pharmacokinetic parameters of drugs. This study explores the synergistic potential of site-specific, colocalized delivery of rapamycin and paclitaxel through nanoparticle incorporation. Nanoparticle drug loading was accurately controlled, and synergistic drug ratios established in vitro. Precise drug ratios were maintained in tumors 48 hours after nanoparticle administration to mice, at levels twofold greater than liver and spleen, yielding superior antitumor activity compared to controls. Simultaneous and preferential in vivo delivery of rapamycin and paclitaxel to tumors yielded mechanistic insights into synergy involving suppression of feedback loop Akt phosphorylation and its downstream targets. Findings demonstrate that a same time, same place, and specific amount approach to combination chemotherapy by means of nanoparticle delivery has the potential to successfully translate in vitro synergistic findings in vivo. Predictive in vitro models can be used to determine optimum drug ratios for antitumor efficacy, while nanoparticle delivery of combination chemotherapies in preclinical animal models may lead to enhanced understanding of mechanisms of synergy, ultimately opening several avenues for personalized therapy.