Targeted delivery of Doxorubicin by folic acid-decorated dual functional nanocarrier.
Targeted delivery of Doxorubicin by folic acid-decorated dual functional nanocarrier.
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DOI：
10.1021/mp500389v
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发表时间：
2014-11-03
影响因子：
4.9
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Lu J;Zhao W;Huang Y;Liu H;Marquez R;Gibbs RB;Li J;Venkataramanan R;Xu L;Li S;Li S
多柔比星（DOX）是最常用的抗肿瘤药物之一，但其临床应用经常伴随严重的副作用。通过纳米药物载体选择性地将DOX递送至肿瘤代表了解决该问题的有吸引力的方法。以前，我们开发了一种双功能纳米胶束载体，PEG 5 K-EB 2（PEG 5 K-EB 2），它能够选择性地将紫杉醇（PTX）递送到肿瘤并实现增强的治疗效果。在本研究中，我们检查了PEG 5 K-EB 2将DOX递送至肿瘤的效用。此外，叶酸（FA）耦合到PEG 5 K-EB 2胶束（FA-PEG 5 K-EB 2）的表面，以进一步提高系统的选择性靶向能力。DOX负载的PEG 5 K-EB 2胶束是直径约20 nm的均匀球形颗粒。FA的掺入对颗粒的尺寸影响最小。PEG 5 K-EB 2和FA-PEG 5 K-EB 2的DOX负载效率分别高达91.7%和93.5%。与游离DOX相比，在PEG 5 K-EB 2胶束（具有或不具有FA修饰）中配制的DOX显示出DOX释放的持续动力学。FA-PEG 5 K-EB 2在乳腺癌细胞4T1.2和耐药细胞NCI/ADR-RES中显著促进DOX的细胞内摄取，而在游离DOX和PEG化脂质体DOX（Doxil）中不显著。P-gp ATP酶测定显示PEG 5 K-EB 2显著抑制P-gp外排泵的功能。DOX负载的PEG 5 K-EB 2胶束在小鼠中的最大耐受剂量为15 mg/kg，这是游离DOX的1.5倍。药代动力学（PK）和生物分布研究表明，两种类型的DOX载药胶束，特别是FA-PEG 5 K-EB 2，能够显著延长DOX的血液循环时间，并促进其在肿瘤组织中的优先蓄积。最后，DOX/PEG 5 K-EB 2混合胶束的抑瘤作用明显增强，且毒性最小，叶酸修饰后抑瘤活性进一步增强。我们的数据表明FA-PEG 5 K-EB 2胶束代表了一种有前途的DOX递送系统，值得在未来进行更多的研究。
Doxorubicin (DOX) is one of the most commonly used antineoplastic agents, but its clinical application is oftentimes coupled with severe side effects. Selective delivery of DOX to tumors via nanosized drug carrier represents an attractive approach to this problem. Previously, we developed a dual functional nanomicellar carrier, PEG5K-embelin2 (PEG5K-EB2), which was able to deliver paclitaxel (PTX) selectively to tumors and to achieve an enhanced therapeutic effect. In the present study, we examined the utility of PEG5K-EB2 to deliver DOX to tumors. In addition, folic acid (FA) was coupled to the surface of the PEG5K-EB2 micelles (FA-PEG5K-EB2) to further improve the selective targetability of the system. DOX-loaded PEG5K-EB2 micelles were uniformly spherical particles with a diameter of approximately 20 nm. Incorporation of FA had minimal effect on the size of the particles. The DOX loading efficiency was as high as 91.7% and 93.5% for PEG5K-EB2 and FA-PEG5K-EB2, respectively. DOX formulated in PEG5K-EB2 micelles (with or without FA decoration) demonstrated sustained kinetics of DOX release compared to free DOX. FA-PEG5K-EB2 significantly facilitated the intracellular uptake of DOX over free DOX and PEGylated liposomal DOX (Doxil) in breast cancer cells, 4T1.2, and drug resistant cells, NCI/ADR-RES. P-gp ATPase assay showed that PEG5K-EB2 significantly inhibited the function of the P-gp efflux pump. The maximum tolerated dose of DOX-loaded PEG5K-EB2 micelles was 15 mg/kg in mice, which was 1.5-fold greater than that for free DOX. Pharmacokinetics (PK) and biodistribution studies showed that both types of DOX-loaded micelles, especially FA-PEG5K-EB2, were able to significantly prolong the blood circulation time of DOX and facilitate its preferential accumulation at the tumor tissue. Finally, DOX/PEG5K-EB2 mixed micelles demonstrated significantly enhanced tumor growth inhibitory effect with minimal toxicity in comparison to free DOX and Doxil and the antitumor activity was further enhanced after the decoration by folic acid. Our data suggest that FA-PEG5K-EB2 micelles represent a promising DOX delivery system that warrants more study in the future.
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影响因子：
4.9
作者：
Collnot, Eva-Maria;Baldes, Christiane;Lehr, Claus-Michael
通讯作者：
Lehr, Claus-Michael
影响因子：
4.9
作者：
Laechelt, Ulrich;Wittmann, Valentin;Wagner, Ernst
通讯作者：
Wagner, Ernst
影响因子：
4.9
作者：
Loo, Tip W.;Bartlett, M. Claire;Clarke, David M.
通讯作者：
Clarke, David M.
影响因子：
14
作者：
Lu, Jianqin;Huang, Yixian;Zhao, Wenchen;Marquez, Rebecca T.;Meng, Xiaojie;Li, Jiang;Gao, Xiang;Venkataramanan, Raman;Wang, Zhou;Li, Song
通讯作者：
Li, Song
DOI：
10.1016/j.jconrel.2010.02.027
发表时间：
2010-06-15
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Li Y;Xiao K;Luo J;Lee J;Pan S;Lam KS
通讯作者：
Lam KS