Razzaq Sobia, Rauf Aisha, Raza Abida, Akhtar Sohail, Tabish Tanveer A, Sandhu Mansur Abdullah, Zaman Muhammad, Ibrahim Ibrahim M, Shahnaz Gul, Rahdar Abbas, Díez-Pascual Ana M
Department of Pharmacy, Quaid-i-Azam University, Islamabad 45320, Pakistan.
NILOP Nanomedicine Research Laboratories, National Institute of Lasers and Optronics College, PIEAS, Islamabad 45650, Pakistan.
Nanomaterials (Basel). 2021 Oct 26;11(11):2858. doi: 10.3390/nano11112858.
P-glycoprotein (P-gP) efflux-mediated multidrug resistance is a fundamental aspect of chemotherapeutic failure in oncology. The current study aims to deliver paclitaxel (PTX) specifically at the target site with improved in vivo efficacy of poorly permeable PTX against solid tumors. Multifunctional polymeric micelles as targeted delivery have been devised for loading and release of PTX. Mucoadhesion, permeation enhancement, oral pharmacokinetics, biodistribution, and toxicological studies were carried out to fully elucidate the therapeutic outcomes of the polymeric micelles. Ex vivo permeation studies indicated a 7.89-fold enhancement in the permeation of PTX with mucopermeating papain functionalized thiolated redox micelles (PT-R-Ms) compared to the pure PTX. Moreover, PT-R-Ms exhibited a higher percentage of apoptotic cells (42.9 ± 0.07%) compared to pure PTX. Biodistribution studies revealed that fluorotagged PT-RMs accumulated in excised tumors and organs. The higher fluorescence intensity indicated the mucopermeation of micelles across the intestine. The orally administered PT-R-Ms efficiently overcome intestinal barriers and inhibit the P-gP efflux pump, resulting in increased bioavailability of PTX (up to 8-fold) in comparison to pure PTX. The enhanced anti-tumor efficacy and reduced toxic effects are key aspects of efficient cancer therapy. This study demonstrates that the use of mucopermeating PT-R-Ms is an encouraging approach to overwhelm the permeation barrier in cancer treatment.
P-糖蛋白（P-gP）外排介导的多药耐药是肿瘤化疗失败的一个基本因素。当前研究旨在将紫杉醇（PTX）特异性递送至靶位点，以提高渗透性差的PTX对实体瘤的体内疗效。已设计出多功能聚合物胶束用于PTX的装载和释放。进行了粘膜粘附、渗透增强、口服药代动力学、生物分布和毒理学研究，以充分阐明聚合物胶束的治疗效果。体外渗透研究表明，与纯PTX相比，含木瓜蛋白酶功能化硫醇化氧化还原胶束（PT-R-Ms）的PTX渗透增强了7.89倍。此外，与纯PTX相比，PT-R-Ms表现出更高比例的凋亡细胞（42.9±0.07%）。生物分布研究表明，荧光标记的PT-RMs在切除的肿瘤和器官中蓄积。较高的荧光强度表明胶束可透过肠道粘膜。口服PT-R-Ms可有效克服肠道屏障并抑制P-gP外排泵，与纯PTX相比，PTX的生物利用度提高（高达8倍）。增强的抗肿瘤疗效和降低的毒性作用是有效癌症治疗的关键方面。本研究表明，使用可透过粘膜的PT-R-Ms是克服癌症治疗中渗透屏障的一种令人鼓舞的方法。
