An improved D-α-tocopherol-based nanocarrier for targeted delivery of doxorubicin with reversal of multidrug resistance.
An improved D-α-tocopherol-based nanocarrier for targeted delivery of doxorubicin with reversal of multidrug resistance.
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DOI：
10.1016/j.jconrel.2014.10.016
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发表时间：
2014-12-28
期刊：
影响因子：
--
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Lu J;Zhao W;Liu H;Marquez R;Huang Y;Zhang Y;Li J;Xie W;Venkataramanan R;Xu L;Li S
纳米载体最近已经成为用于递送各种类型的治疗剂（包括抗癌剂）的有吸引力的平台。以前，我们开发了一种改进的TPGS递送系统（PEG 5 K-VE 2），其表现出改进的胶体稳定性和更大的体内抗肿瘤活性。然而，该系统的应用仍然受到相对较低的载药量（DLC）的限制。在这项研究中，我们报告说，芴甲氧羰基（Fmoc）基序在PEG 5 K-VE 2的界面区域的掺入导致显着改善的系统通过引入一个额外的药物/载体相互作用的机制。阿霉素（DOX）可以以39.9%的DLC有效地装载到PEG 5 K-Fmoc-VE 2胶束中，这与大多数报道的DOX纳米制剂相比是有利的。此外，PEG 5 K-Fmoc-VE 2/DOX混合胶束与不含Fmoc基序的对应物相比显示出更好的DOX缓释。MTT法显示PEG 5 K-Fmoc-VE 2/DOX对PC-3和4T1.2细胞的杀伤作用明显高于DOX、Doxil和PEG 5 K-VE 2/DOX。NCI/ADR-RES耐药细胞株的细胞毒性实验表明，PEG 5 K-Fmoc-VE 2对P-gp ATP酶的抑制作用支持了其逆转耐药的作用。药代动力学（PK）和生物分布研究显示，对于在PEG 5 K-Fmoc-VE 2胶束中配制的DOX，血液循环中的半衰期增加，并且肿瘤蓄积更有效。更重要的是，载有DOX的PEG 5 K-Fmoc-VE 2胶束显示出优异的安全性特征，MTD（~30 mg DOX/kg）是游离DOX的约3倍。最后，与DOX、Doxil和PEG 5 K-VE 2/DOX相比，PEG 5 K-Fmoc-VE 2/DOX在药物敏感性（4T1.2和PC-3）和耐药性（KB 8-5）肿瘤模型中均表现出上级抗肿瘤活性。
Nanocarriers have recently emerged as an attractive platform for delivery of various types of therapeutics including anticancer agents. Previously, we developed an improved TPGS delivery system (PEG5K-VE2) which demonstrated improved colloidal stability and greater in vivo antitumor activity. Nevertheless, the application of this system is still limited by a relatively low drug loading capacity (DLC). In this study we report that incorporation of a fluorenylmethyloxycarbonyl (Fmoc) motif at the interfacial region of PEG5K-VE2 led to significant improvement of the system through the introduction of an additional mechanism of drug/carrier interaction. Doxorubicin (DOX) could be effectively loaded into PEG5K-Fmoc-VE2 micelles at a DLC of 39.9%, which compares favorably to most reported DOX nanoformulations. In addition, PEG5K-Fmoc-VE2/DOX mixed micelles showed more sustained release of DOX in comparison to the counterpart without Fmoc motif. MTT assay showed that PEG5K-Fmoc-VE2/DOX exerted significantly higher levels of cytotoxicity over DOX, Doxil as well as PEG5K-VE2/DOX in PC-3 and 4T1.2 cells. Cytotoxicity assay with NCI/ADR-RES, a drug resistant cell line, suggested that PEG5K-Fmoc-VE2 may have a potential to reverse the multidrug resistance, which was supported by its inhibition on P-gp ATPase. Pharmacokinetics (PK) and biodistribution studies showed an increased half-life in blood circulation and more effective tumor accumulation for DOX formulated in PEG5K-Fmoc-VE2 micelles. More importantly, DOX-loaded PEG5K-Fmoc-VE2 micelles showed an excellent safety profile with a MTD (~30 mg DOX/kg) that is about 3 times as much as that for free DOX. Finally, superior antitumor activity was demonstrated for PEG5K-Fmoc-VE2/DOX in both drug-sensitive (4T1.2 and PC-3) and drug-resistant (KB 8-5) tumor models compared to DOX, Doxil, and PEG5K-VE2/DOX.
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影响因子：
14
作者：
Cao, Na;Feng, Si-Shen
通讯作者：
Feng, Si-Shen
影响因子：
14
作者：
Maeng, Jin Hee;Lee, Don-Haeng;Hong, Soon-Sun
通讯作者：
Hong, Soon-Sun
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
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
影响因子：
29.4
作者：
Jayawarna, V;Ali, M;Ulijn, RV
通讯作者：
Ulijn, RV