Wang Yingzhe, Fan Wei, Dai Xin, Katragadda Usha, Mckinley DeAngelo, Teng Quincy, Tan Chalet
Cancer Nanomedicine Laboratory, Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University , Atlanta, Georgia 30341, United States.
Mol Pharm. 2014 Apr 7;11(4):1140-50. doi: 10.1021/mp4005904. Epub 2014 Mar 10.
Gemcitabine is a potent anticancer drug approved for the treatment of pancreatic, non-small-cell lung, breast, and ovarian cancers. The major deficiencies of current gemcitabine therapy, however, are its rapid metabolic inactivation and narrow therapeutic window. Herein, we employed polyethylene glycol-b-distearoylphosphatidylethanolamine (PEG-DSPE)/tocopheryl polyethylene glycol 1000 succinate (TPGS) mixed micelles as a delivery system, to improve the pharmacokinetic characteristics of gemcitabine and enhance its antitumor efficacy. By conjugating stearic acid to gemcitabine and subsequently encapsulating stearoyl gemcitabine (GemC18) within PEG-DSPE/TPGS mixed micelles, the deamination of gemcitabine was delayed in vitro and in vivo. Importantly, compared to free gemcitabine, GemC18-loaded micelles pronouncedly prolonged the circulation time of gemcitabine and elevated its concentration in the tumor by 3-fold, resulting in superior antitumor efficacy in mice bearing human pancreatic cancer BxPC-3 xenografts. Our findings demonstrate the promise of PEG-DSPE/TPGS mixed micelles as a nanocarrier system for the delivery of gemcitabine to achieve safer and more efficacious therapeutic outcomes.
吉西他滨是一种经批准用于治疗胰腺癌、非小细胞肺癌、乳腺癌和卵巢癌的强效抗癌药物。然而，当前吉西他滨治疗的主要缺陷是其快速的代谢失活和狭窄的治疗窗口。在此，我们采用聚乙二醇-b-二硬脂酰磷脂酰乙醇胺（PEG-DSPE）/生育酚聚乙二醇1000琥珀酸酯（TPGS）混合胶束作为递送系统，以改善吉西他滨的药代动力学特性并增强其抗肿瘤疗效。通过将硬脂酸与吉西他滨缀合，随后将硬脂酰吉西他滨（GemC18）包裹在PEG-DSPE/TPGS混合胶束中，吉西他滨的脱氨基作用在体外和体内均被延迟。重要的是，与游离吉西他滨相比，负载GemC18的胶束显著延长了吉西他滨的循环时间，并使其在肿瘤中的浓度提高了3倍，从而在携带人胰腺癌BxPC-3异种移植瘤的小鼠中产生了优异的抗肿瘤疗效。我们的研究结果证明了PEG-DSPE/TPGS混合胶束作为一种纳米载体系统用于递送吉西他滨以实现更安全、更有效的治疗效果的前景。
