Blanco Elvin, Sangai Takafumi, Wu Suhong, Hsiao Angela, Ruiz-Esparza Guillermo U, Gonzalez-Delgado Carlos A, Cara Francisca E, Granados-Principal Sergio, Evans Kurt W, Akcakanat Argun, Wang Ying, Do Kim-Anh, Meric-Bernstam Funda, Ferrari Mauro
Department of Nanomedicine, The Houston Methodist Research Institute, Houston, Texas, USA.
Department of Surgical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Mol Ther. 2014 Jul;22(7):1310-1319. doi: 10.1038/mt.2014.27. Epub 2014 Feb 26.
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.
正在进行的临床试验旨在通过给予雷帕霉素（一种变构mTOR抑制剂）与紫杉醇联合使用，来靶向乳腺癌中异常的PI3K/Akt/雷帕霉素哺乳动物靶蛋白（mTOR）信号通路。然而，由于药物不同的药代动力学参数，协同作用在临床上可能无法得到充分利用。本研究通过纳米颗粒包载探索雷帕霉素和紫杉醇在特定部位共定位递送的协同潜力。精确控制纳米颗粒的载药量，并在体外确定协同药物比例。纳米颗粒给药小鼠48小时后，肿瘤中维持了精确的药物比例，其水平比肝脏和脾脏高两倍，与对照组相比产生了更强的抗肿瘤活性。雷帕霉素和紫杉醇同时且优先在体内递送至肿瘤，对协同作用的机制有了深入了解，包括对反馈环Akt磷酸化及其下游靶点的抑制。研究结果表明，通过纳米颗粒递送进行联合化疗的同时、同地和特定量方法有可能在体内成功转化体外协同研究结果。预测性体外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进行联合化疗的纳米颗粒递送可能会增强对协同作用机制的理解，最终为个性化治疗开辟多条途径。
