Institute of Materia Medica, School of Pharmacy, Henan University, Jinming Road, Kaifeng, 475004, Henan, China.
National & Local Joint Engineering Research Center for Applied Technology of Hybrid Nanomaterials, Henan University, Jinming Road, Kaifeng, 475004, Henan, China.
Curr Cancer Drug Targets. 2019;19(4):338-347. doi: 10.2174/1568009618666180629150927.
Improving poorly soluble drugs into druggability was a major problem faced by pharmaceutists. Nanosuspension can improve the druggability of insoluble drugs by improving the solubility, chemical stability and reducing the use of additives, which provided a new approach for the development and application of the insoluble drugs formulation. Paclitaxel (PTX) is a well-known BCS class IV drug with poor solubility and permeability. Also, many studies have proved that paclitaxel is a substrate of the membrane-bound drug efflux pump P-glycoprotein (P-gp), therefore it often shows limited efficacy against the resistant tumors and oral absorption or uptake.
To manufacture an enhanced-penetration PTX nanosuspension (PTX-Nanos), and evaluate the physicochemical property, pharmacokinetics and tissue distribution in vivo and cytotoxic effect in vitro.
PTX-Nanos were prepared by microprecipitation-high pressure homogenization, with a good biocompatibility amphiphilic block copolymer poly(L-phenylalanine)-b-poly(L-aspartic acid) (PPA-PAA) as stabilizer.
The PTX-Nanos had a sustained-dissolution manner and could effectively reduce plasma peak concentration and extend plasma circulating time as compared to PTX injection, markedly passively targeting the MPS-related organs, such as liver and spleen. This unique property might enhance treatment of cancer in these tissues and reduce the side effects in other normal tissues. Moreover, the hybrid stabilizers could enhance penetration of PTX in PTX-Nanos to multidrug resistance cells.
To sum up, our results showed that the optimal formula could improve the solubility of PTX and the stability of the product. The PTX-Nanos developed in this research would be a promising delivery platform in cancer treatment.
提高难溶性药物的可药性是药剂师面临的主要问题。纳米混悬剂可以通过提高溶解度、化学稳定性和减少添加剂的使用来改善难溶性药物的可药性，为难溶性药物制剂的开发和应用提供了新途径。紫杉醇（PTX）是一种众所周知的 BCS 分类 IV 类药物，溶解度和渗透性差。此外，许多研究已经证明紫杉醇是膜结合药物外排泵 P-糖蛋白（P-gp）的底物，因此它常常对耐药肿瘤表现出有限的疗效和口服吸收或摄取。
制备增强渗透紫杉醇纳米混悬剂（PTX-Nanos），并评价其理化性质、药代动力学和体内组织分布以及体外细胞毒性。
采用复乳-高压匀质法制备 PTX-Nanos，以良好生物相容性的两亲性嵌段共聚物聚（L-苯丙氨酸）-b-聚（L-天冬氨酸）（PPA-PAA）为稳定剂。
PTX-Nanos 具有持续释放的特点，与 PTX 注射液相比，能有效降低血浆峰浓度，延长血浆循环时间，明显被动靶向 MPS 相关器官，如肝脏和脾脏。这种独特的特性可能会增强这些组织中癌症的治疗效果，并减少其他正常组织的副作用。此外，混合稳定剂可以增强 PTX-Nanos 中 PTX 向多药耐药细胞的渗透。
综上所述，我们的结果表明，最佳配方可以提高 PTX 的溶解度和产品的稳定性。本研究中开发的 PTX-Nanos 将成为癌症治疗有前途的给药平台。
