Improved oral absorption and anti-lung cancer activity of paclitaxel-loaded mixed micelles

Drug Delivery

Zhong-Cheng Ke¹  E. Sun¹  Jing Wang¹  Xiao-Bin Tan¹  Zhen-Hai Zhang¹  Li Cui¹  Xiao-Bin Jia²  Jian Hou²  Lei Yang²  Huixia Lv³ 

[1] Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China;Key Laboratory of New Drug Delivery System of Chinese Meteria Medica, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing Jiangsu, China;Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China;Key Laboratory of New Drug Delivery System of Chinese Meteria Medica, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing Jiangsu, China;College of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, China, an;College of Pharmacy, China Pharmaceutical University, Nanjing Jiangsu, Chin;

关键词: Paclitaxel;    vitamin E-TPGS;    Plasdone®S-630 Copovidone;    micelles;    oral bioavailability;    Caco-2 monolayer;    anti-tumor;    gastrointestinal safety assay;   

DOI  :  10.1080/10717544.2016.1245370

来源: Taylor & Francis

【 摘 要 】

The aim of this study was to establish a paclitaxel (PTX)-loaded mixed micelle delivery system (PTX-TP-M) with vitamin E-TPGS (TPGS) and Plasdone®S-630 Copovidone (PVPS630) as carriers to improve the solubility, oral absorption, and anti-tumor activity of PTX against lung cancer. In this study, PTX-TP-M was prepared using the ethanol thin-film dispersion method followed by characterization of the binary mixed micelles system. The average size of the PTX-TP-M was 83.5 ± 1.8 nm with a polydispersity index of 0.265 ± 0.007 and the drug loading (DL%) and entrapment efficiency (EE%) were 3.09 ± 0.09% and 95.67 ± 2.84%, respectively, which contributed to a high solubility of PTX about 24947-fold increase in water (4.78 ± 0.14 mg/mL). In addition, TEM analysis showed that the PTX-TP-M appeared spherical in structure and was well dispersed without aggregation and adhesion. In vitro release studies showed that the PTX-TP-M displayed a sustained release compared to free PTX in the dialysis bag. The efflux ratio of PTX reduced from 44.83 to 3.52 when formulated as PTX-TP-M; a 92.15% reduction, studied using the Caco-2 monolayer model. The oral bioavailability of PTX also improved by 4.35-fold, suggesting that PTX-TP-M can markedly promote the absorption in the gastrointestinal tract. Using in vitro MTT assays, it was observed that cytotoxicity was markedly increased, and IC50 values of PTX-TP-M (3.14 ± 0.85 and 8.28 ± 1.02 μg/mL) were lower than those of PTX solution (5.21 ± 0.93 and 14.53 ± 1.96 μg/mL) in A549 and Lewis cell, respectively. In vivo anti-tumor studies showed that PTX-TP-M achieved higher anti-tumor efficacy compared with PTX in Lewis bared C57BL/6 mice. Furthermore, a gastrointestinal safety assay also proved the safety of PTX-TP-M. All results demonstrated that the PTX-TP-M exhibited great potential for delivering PTX with increased solubility, oral bioavailability, and anti-cancer activity and this binary mixed micelles drug delivery system has potential to be used clinically.

【 授权许可】

CC BY