Lysosomal delivery of a lipophilic gemcitabine prodrug using novel acid-sensitive micelles improved its antitumor activity.
Lysosomal delivery of a lipophilic gemcitabine prodrug using novel acid-sensitive micelles improved its antitumor activity.
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DOI：
10.1021/bc2005945
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发表时间：
2012-05-16
影响因子：
4.7
通讯作者：
Cui Z
中科院分区：
文献类型：
--
作者：
Zhu S;Lansakara-P DS;Li X;Cui Z
刺激敏感型胶束是一类很有吸引力的抗癌药物传递系统。本文报道了一种利用亲水性聚乙二醇（PEG）与疏水性硬脂酸衍生物（C18）通过酸敏感性腙键（PHC）直接缀合而合成的两亲性材料来构建酸敏感性胶束的新策略。还合成了酸不敏感的PEG-酰胺-C18（PAC）化合物作为对照。将核苷类似物吉西他滨的前药4-（N）-硬脂酰吉西他滨（GemC 18）装载到胶束中，并且发现它们对肿瘤细胞的细胞毒性比GemC 18溶液显著更强，这可能是由于胶束对GemC 18的溶酶体递送。此外，GemC 18在酸敏感的PHC胶束中比在酸不敏感的PAC胶束中更具有细胞毒性，这可能归因于GemC 18在溶酶体中从PHC胶束中的酸敏感释放。在荷B16-F10黑色素瘤小鼠中，GemC 18负载的PHC或PAC胶束显示出比GemC 18或吉西他滨溶液更强的抗肿瘤活性，这可能是因为胶束延长的循环时间和增加的GemC 18的肿瘤蓄积。重要的是，在体内的抗肿瘤活性的GemC 18加载的PHC胶束是显着强于PAC胶束，证明了潜在的新型酸敏感胶束作为抗癌药物输送系统。
Stimulus-sensitive micelles are attractive anticancer drug delivery systems. Herein we reported a novel strategy to engineer acid-sensitive micelles using a amphiphilic material synthesized by directly conjugating the hydrophilic polyethylene glycol (PEG) with a hydrophobic stearic acid derivative (C18) using an acid-sensitive hydrazone bond (PHC). An acid-insensitive PEG-amide-C18 (PAC) compound was also synthesized as a control. 4-(N)-stearoyl gemcitabine (GemC18), a prodrug of the nucleoside analog gemcitabine, was loaded into the micelles, and they were found to be significantly more cytotoxic to tumor cells than GemC18 solution, likely due to the lysosomal delivery of GemC18 by micelles. Moreover, GemC18 in the acid-sensitive PHC micelles was more cytotoxic than in the acid-insensitive PAC micelles, which may be attributed to the acid-sensitive release of GemC18 from the PHC micelles in lysosomes. In B16-F10 melanoma-bearing mice, GemC18-loaded PHC or PAC micelles showed a stronger antitumor activity than GemC18 or gemcitabine solution, likely because of the prolonged circulation time and increased tumor accumulation of the GemC18 by the micelles. Importantly, the in vivo antitumor activity of GemC18-loaded PHC micelles was significantly stronger than that of the PAC micelles, demonstrating the potential of the novel acid-sensitive micelles as an anticancer drug delivery system.
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第一阶段的试验结合了晚期皮肤和紫veal黑色素瘤患者中的吉西他滨和treosulfan。
影响因子：
8.8
作者：
Corrie, PG;Shaw, J;Spanswick, VJ;Sehmbi, R;Jonson, A;Mayer, A;Bulusu, R;Hartley, JA;Cree, IA
通讯作者：
Cree, IA
影响因子：
3.6
作者：
Guo, ZW;Gallo, JM
通讯作者：
Gallo, JM
影响因子：
16.6
作者：
Haag, R
通讯作者：
Haag, R
影响因子：
4.8
作者：
Baldwin, SA;Yao, SYM;Young, JD
通讯作者：
Young, JD
DOI：
10.1021/la900310k
发表时间：
2009-07-07
期刊：
Langmuir : the ACS journal of surfaces and colloids
影响因子：
--
作者：
Kastantin M;Ananthanarayanan B;Karmali P;Ruoslahti E;Tirrell M
通讯作者：
Tirrell M