Houdaihed Loujin, Evans James Christopher, Allen Christine
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, M5S 3M2, Canada.
Cancers (Basel). 2019 May 29;11(6):752. doi: 10.3390/cancers11060752.
A synergistic combination of paclitaxel (PTX) and everolimus (EVER) can allow for lower drug doses, reducing the toxicities associated with PTX, while maintaining therapeutic efficacy. Polymeric nanoparticles (NPs) of high stability provide opportunities to modify the toxicity profile of the drugs by ensuring their delivery to tumor at the synergistic ratio while limiting systemic drug exposure and the toxicities that result. The current study goal is to study the in vivo fate of human epidermal factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) dual-targeted PTX+EVER-loaded NPs (Dual-NPs) in an MDA-MB-231-H2N BC tumor-bearing mouse model. The pharmacokinetic parameters, plasma area under the curve (AUC) and half-life (t), were found to be 20-fold and 3 to 4-fold higher, respectively, for the drugs when administered in the Dual-NPs in comparison to the free-drug combination (i.e., PTX+EVER) at an equivalent dose of PTX. While maintaining anti-tumor efficacy, the levels of body weight loss were significantly lower (p < 0.0001) and the overall degree of neurotoxicity was reduced with Dual-NP treatment in comparison to the free-drug combination when administered at an equivalent dose of PTX. This study suggests that Dual-NPs present a promising platform for the delivery of the PTX and EVER combination with the potential to reduce severe PTX-induced toxicities and in turn, improve quality of life for patients with BC.
紫杉醇（PTX）和依维莫司（EVER）的协同组合可以降低药物剂量，减少与PTX相关的毒性，同时保持治疗效果。高稳定性的聚合物纳米颗粒（NPs）通过确保药物以协同比例递送至肿瘤，同时限制全身药物暴露及其导致的毒性，为改变药物的毒性特征提供了机会。当前的研究目标是在携带MDA-MB-231-H2N乳腺癌肿瘤的小鼠模型中研究人表皮生长因子受体2（HER2）和表皮生长因子受体（EGFR）双靶向负载PTX+EVER的纳米颗粒（双纳米颗粒）的体内命运。与等剂量PTX的游离药物组合（即PTX+EVER）相比，当以双纳米颗粒给药时，药物的药代动力学参数、血浆曲线下面积（AUC）和半衰期（t）分别高出20倍和3至4倍。在保持抗肿瘤疗效的同时，与等剂量PTX的游离药物组合相比，双纳米颗粒治疗导致的体重减轻水平显著更低（p<0.0001），并且神经毒性的总体程度降低。这项研究表明，双纳米颗粒为PTX和EVER组合的递送提供了一个有前景的平台，有可能降低严重的PTX诱导的毒性，进而改善乳腺癌患者的生活质量。
