Amphiphilic multiarm star block copolymer-based multifunctional unimolecular micelles for cancer targeted drug delivery and MR imaging
Amphiphilic multiarm star block copolymer-based multifunctional unimolecular micelles for cancer targeted drug delivery and MR imaging
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基于两亲性多臂星形嵌段共聚物的多功能单分子胶束，用于癌症靶向药物输送和磁共振成像
DOI：
10.1016/j.biomaterials.2011.05.049
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发表时间：
2011-09-01
期刊：
影响因子：
14
通讯作者：
Liu, Shiyong
中科院分区：
文献类型：
--
作者：
Li, Xiaojie;Qian, Yinfeng;Liu, Shiyong
我们报告的制造多功能聚合物单分子胶束作为一个综合平台，癌症靶向药物输送和磁共振成像（MRI）对比度增强在体外和体内条件下。以第四代超支化聚酯Boltorn H40为原料，通过在H40外围开环聚合己内酯（CL），再与2-溴异丁酰溴进行端基酯化反应，合成了基于星星共聚物的原子转移自由基聚合（ATRP）大分子引发剂H40-PCL-Br。以低聚乙二醇单甲醚甲基丙烯酸酯（OEGMA）和甲基丙烯酸叠氮丙酯（AzPMA）为原料，通过原子转移自由基聚合（ATRP）合成了结构规整的多臂星星型嵌段共聚物H40-PCL-b-P（OEGMA-co-AzPMA）。随后是H40-PCL-b-P（OEGMA-co-AzPMA）与炔基官能化的癌细胞靶向部分、炔基叶酸和T（1）型MRI造影剂、炔基-DOTA-Gd（DOTA是1，4，7，10-四氮杂环十二烷-1，4，7，10-四乙酸）的点击反应，得到H40-PCL-b-P（OEGMA-Gd-FA）。在水溶液中，两亲性多臂星星嵌段共聚物以结构稳定的单分子胶束形式存在，该胶束具有超支化聚酯核、疏水性PCL内层和亲水性P（OEGMA-Gd-FA）外冠。H40-PCL-b-P（OEGMA-Gd-FA）单分子胶束能够包封紫杉醇（一种众所周知的疏水性抗癌药物），其负载含量为6.67 w/w%，并且在类似于120 h的时间段内表现出高达80%负载药物的受控释放。体外MRI实验表明，单分子胶束的T（1）弛豫率显着增强（18.14 s（-1）mM（-1）），而小分子对应物炔基-DOTA-Gd的T（1）弛豫率为3.12 s（-1）mM（-1）。进一步的大鼠体内MR成像实验显示，单分子胶束在大鼠肝脏和肾脏内有良好的积聚，显着的阳性对比增强，以及相对较长的血液循环持续时间。所报道的基于单分子胶束的结构稳定的纳米载体与癌症靶向药物递送和控制释放以及MR成像功能协同整合，预示着它们作为治疗诊断系统的潜在应用。(C)2011爱思唯尔有限公司保留所有权利。
We report on the fabrication of multifunctional polymeric unimolecular micelles as an integrated platform for cancer targeted drug delivery and magnetic resonance imaging (MRI) contrast enhancement under in vitro and in vivo conditions. Starting from a fractionated fourth-generation hyperbranched polyester (Boltorn H40), the ring-opening polymerization of e-caprolactone (CL) from the periphery of H40 and subsequent terminal group esterification with 2-bromoisobutyryl bromide afforded star copolymer-based atom transfer radical polymerization (ATRP) macroinitiator, H40-PCL-Br. Well-defined multiarm star block copolymers, H40-PCL-b-P(OEGMA-co-AzPMA), were then synthesized by the ATRP of oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) and 3-azidopropyl methacrylate (AzPMA). This was followed by the click reaction of H40-PCL-b-P(OEGMA-co-AzPMA) with alkynyl-functionalized cancer cell-targeting moieties, alkynyl-folate, and T(1)-type MRI contrast agents, alkynyl-DOTA-Gd (DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakisacetic acid), affording H40-PCL-b-P(OEGMA-Gd-FA). In aqueous solution, the amphiphilic multiarm star block copolymer exists as structurally stable unimolecular micelles possessing a hyperbranched polyester core, a hydrophobic PCL inner layer, and a hydrophilic P(OEGMA-Gd-FA) outer corona. H40-PCL-b-P(OEGMA-Gd-FA) unimolecular micelles are capable of encapsulating paclitaxel, a well-known hydrophobic anticancer drug, with a loading content of 6.67 w/w% and exhibiting controlled release of up to 80% loaded drug over a time period of similar to 120 h. In vitro MRI experiments demonstrated considerably enhanced T(1) relaxivity (18.14 s(-1) mM(-1)) for unimolecular micelles compared to 3.12 s(-1) mM(-1) for that of the small molecule counterpart, alkynyl-DOTA-Gd. Further experiments of in vivo MR imaging in rats revealed good accumulation of unimolecular micelles within rat liver and kidney, prominent positive contrast enhancement, and relatively long duration of blood circulation. The reported unimolecular micelles-based structurally stable nanocarriers synergistically integrated with cancer targeted drug delivery and controlled release and MR imaging functions augur well for their potential applications as theranostic systems. (C) 2011 Elsevier Ltd. All rights reserved.