Nanoemulsion formulations for anti-cancer agent piplartine--Characterization, toxicological, pharmacokinetics and efficacy studies.
Nanoemulsion formulations for anti-cancer agent piplartine--Characterization, toxicological, pharmacokinetics and efficacy studies.
复制标题
抗癌药皮的纳米乳剂制剂 - 特征，毒理学，药代动力学和功效研究。
DOI：
10.1016/j.ijpharm.2015.11.045
复制
发表时间：
2016-02-10
影响因子：
5.8
通讯作者：
Srivastava SK
中科院分区：
文献类型：
--
作者：
Fofaria NM;Qhattal HS;Liu X;Srivastava SK
Piplartine （PL）是一种在黑胡椒中发现的生物碱，以其抗癌活性而闻名，然而，由于溶解度差和缺乏适当的配方，其用于口服给药是一个挑战。本研究的目的是将聚乳酸制成纳米乳给药系统，用于口服给药，并对其毒性、药代动力学和治疗效果进行评价。采用自乳化和均质-超声法制备了优化的纳米乳液。两种纳米乳剂提高了聚乳酸的溶解度，具有低的多分散指数和高的稳定性。与纯聚乳酸相比，两种负载聚乳酸的纳米乳都表现出增强的溶解性、细胞渗透性和细胞毒性作用。将聚乳酸配制成纳米乳不会阻碍其在癌细胞中的细胞摄取。空白或负载PL的纳米乳剂在小鼠中每日口服60天没有表现出毒性。静脉给药后的药代动力学遵循双室模型。与游离聚乳酸相比，负载聚乳酸纳米乳的口服生物利用度增加了1.5倍。最后，负载聚乳酸纳米乳在黑色素瘤荷瘤小鼠中显示出10 mg/kg剂量的显著抗肿瘤活性。综上所述，我们首次开发了一种稳定的口服给药的纳米乳给药系统，提高了其溶解度、口服生物利用度和抗肿瘤功效。
Piplartine (PL) is an alkaloid found in black-pepper and known for its anticancer activity, however, due to poor solubility and lack of proper formulation, its use for oral administration is a challenge. The objective of this study was to formulate PL into nanoemulsion drug delivery system for oral delivery and thereafter evaluate toxicity, pharmacokinetics and therapeutic efficacy. Optimized nanoemulsions were formulated by self-emulsification as well as by homogenization-sonication method. Two nanoemulsions enhanced the solubility of PL with low polydispersity index and high stability. Both PL loaded nanoemulsions exhibited enhanced dissolution, cellular permeability and cytotoxic effects as compared to pure PL. Formulation of PL into nanoemulsions did not obstruct its cellular uptake in cancer cells. Blank or PL loaded nanoemulsions did not exhibited toxicity in mice upon daily oral administration for 60 days. Pharmacokinetics of PL followed a two-compartment model after intravenous administration. PL loaded nanoemulsions showed 1.5-fold increase in oral bioavailability as compared to free PL. Finally, PL loaded nanoemulsions showed marked anti-tumor activity at a dose of 10 mg/kg in melanoma tumor bearing mice. In conclusion, for the first time we have developed a stable nanoemulsion delivery system for oral administration of PL, which enhanced its solubility, oral bioavailability and anti-tumor efficacy.