Butt Adeel Masood, Mohd Amin Mohd Cairul Iqbal, Katas Haliza
Centre for Drug Delivery Research, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
Int J Nanomedicine. 2015 Feb 13;10:1321-34. doi: 10.2147/IJN.S78438. eCollection 2015.
Doxorubicin (DOX), an anthracycline anticancer antibiotic, is used for treating various types of cancers. However, its use is associated with toxicity to normal cells and development of resistance due to overexpression of drug efflux pumps. Poloxamer 407 (P407) and vitamin E TPGS (D-α-tocopheryl polyethylene glycol succinate, TPGS) are widely used polymers as drug delivery carriers and excipients for enhancing the drug retention times and stability. TPGS reduces multidrug resistance, induces apoptosis, and shows selective anticancer activity against tumor cells. Keeping in view the problems, we designed a mixed micelle system encapsulating DOX comprising TPGS for its selective anticancer activity and P407 conjugated with folic acid (FA) for folate-mediated receptor targeting to cancer cells.
FA-functionalized P407 was prepared by carbodiimide crosslinker chemistry. P407-TPGS/FA-P407-TPGS-mixed micelles were prepared by thin-film hydration method. Cytotoxicity of blank micelles, DOX, and DOX-loaded micelles was determined by alamarBlue(®) assay.
The size of micelles was less than 200 nm with encapsulation efficiency of 85% and 73% for P407-TPGS and FA-P407-TPGS micelles, respectively. Intracellular trafficking study using nile red-loaded micelles indicated improved drug uptake and perinuclear drug localization. The micelles show minimal toxicity to normal human cell line WRL-68, enhanced cellular uptake of DOX, reduced drug efflux, increased DOX-DNA binding in SKOV3 and DOX-resistant SKOV3 human ovarian carcinoma cell lines, and enhanced in vitro cytotoxicity as compared to free DOX.
FA-P407-TPGS-DOX micelles show potential as a targeted nano-drug delivery system for DOX due to their multiple synergistic factors of selective anticancer activity, inhibition of multidrug resistance, and folate-mediated selective uptake.
阿霉素（DOX）是一种蒽环类抗癌抗生素，用于治疗多种类型的癌症。然而，其使用与对正常细胞的毒性以及由于药物外排泵的过度表达而产生的耐药性有关。泊洛沙姆407（P407）和维生素E TPGS（D-α-生育酚聚乙二醇琥珀酸酯，TPGS）是广泛用作药物递送载体和辅料的聚合物，用于延长药物保留时间和提高稳定性。TPGS可降低多药耐药性、诱导细胞凋亡，并对肿瘤细胞表现出选择性抗癌活性。鉴于这些问题，我们设计了一种包封DOX的混合胶束系统，该系统包含具有选择性抗癌活性的TPGS和与叶酸（FA）共轭以实现叶酸介导的对癌细胞靶向的P407。
通过碳二亚胺交联剂化学方法制备FA功能化的P407。采用薄膜水化法制备P407-TPGS/FA-P407-TPGS混合胶束。通过alamarBlue（®）测定法测定空白胶束、DOX和载药胶束的细胞毒性。
胶束尺寸小于200nm，P407-TPGS和FA-P407-TPGS胶束的包封率分别为85%和73%。使用尼罗红负载胶束进行的细胞内转运研究表明，药物摄取和核周药物定位得到改善。与游离DOX相比，这些胶束对正常人细胞系WRL-68的毒性最小，增强了DOX的细胞摄取，减少了药物外排，增加了SKOV3和耐DOX的SKOV3人卵巢癌细胞系中DOX与DNA的结合，并增强了体外细胞毒性。
FA-P407-TPGS-DOX胶束由于其选择性抗癌活性、多药耐药性抑制和叶酸介导的选择性摄取等多种协同因素，显示出作为DOX靶向纳米药物递送系统的潜力。
