Enhanced tumor delivery of gemcitabine via PEG-DSPE/TPGS mixed micelles.
Enhanced tumor delivery of gemcitabine via PEG-DSPE/TPGS mixed micelles.
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DOI：
10.1021/mp4005904
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发表时间：
2014-04-07
影响因子：
4.9
通讯作者：
Tan C
中科院分区：
文献类型：
--
作者：
Wang Y;Fan W;Dai X;Katragadda U;Mckinley D;Teng Q;Tan C
吉西他滨是一种有效的抗癌药物，被批准用于治疗胰腺癌、非小细胞肺癌、乳腺癌和卵巢癌。然而，目前吉西他滨治疗的主要缺陷是其快速代谢失活和狭窄的治疗窗。本文采用聚乙二醇-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）混合胶束作为给药系统，改善吉西他滨的药代动力学特征，提高其抗肿瘤疗效。通过将硬脂酸与吉西他滨缀合，随后将硬脂酰吉西他滨（GemC 18）包封在PEG-DSPE/TPGS混合胶束中，在体外和体内延迟吉西他滨的脱氨基。重要的是，与游离吉西他滨相比，GemC 18负载的胶束显著延长了吉西他滨的循环时间，并将其在肿瘤中的浓度提高了3倍，从而在携带人胰腺癌BxPC-3异种移植物的小鼠中产生了上级抗肿瘤功效。我们的研究结果表明，PEG-DSPE/TPGS混合胶束作为纳米载体系统的吉西他滨，以实现更安全，更有效的治疗结果的承诺。
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.
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