基于两亲性多臂星型嵌段共聚物的多功能单分子胶束用于癌症靶向药物递送和磁共振成像。
Amphiphilic multiarm star block copolymer-based multifunctional unimolecular micelles for cancer targeted drug delivery and MR imaging.
机构信息
CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230026, China.
出版信息
Biomaterials. 2011 Sep;32(27):6595-605. doi: 10.1016/j.biomaterials.2011.05.049. Epub 2011 Jun 12.
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 ɛ-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 ∼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.
我们报告了多功能聚合物单分子胶束的制备，作为在体外和体内条件下用于癌症靶向药物输送和磁共振成像（MRI）对比增强的集成平台。从分段的第四代超支化聚酯（Boltorn H40）开始，通过 H40 外围的 ε-己内酯（CL）的开环聚合和随后与 2-溴异丁酰溴的末端基团酯化反应，得到基于星形共聚原子转移自由基聚合（ATRP）的大分子引发剂 H40-PCL-Br。然后，通过 ATRP 合成了具有明确结构的多臂星型嵌段共聚物 H40-PCL-b-P（OEGMA-co-AzPMA），其单体为聚乙二醇单甲醚甲基丙烯酸酯（OEGMA）和 3-叠氮丙基甲基丙烯酸酯（AzPMA）。随后，通过点击反应将 H40-PCL-b-P（OEGMA-co-AzPMA）与炔基功能化的癌细胞靶向部分、炔基叶酸和 T1 型 MRI 对比剂炔基-DOTA-Gd（DOTA 是 1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸）偶联，得到 H40-PCL-b-P（OEGMA-Gd-FA）。在水溶液中，两亲性多臂星型嵌段共聚物作为结构稳定的单分子胶束存在，其具有超支化聚酯核、疏水性 PCL 内层和亲水性 P（OEGMA-Gd-FA）外层冠。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，载药量为 6.67 w/w%，并在约 120 h 的时间内释放高达 80%的载药。体外 MRI 实验表明，与小分子对应物炔基-DOTA-Gd 的 3.12 s(-1) mM(-1)相比，单分子胶束的 T1 弛豫率（18.14 s(-1) mM(-1)）有了显著提高。在大鼠体内磁共振成像实验中，进一步研究表明，单分子胶束在大鼠肝和肾中的积累良好，具有显著的阳性对比增强作用，并且血液循环时间相对较长。报道的基于单分子胶束的结构稳定纳米载体与癌症靶向药物输送和控制释放以及 MRI 成像功能协同集成，为其作为治疗诊断系统的潜在应用提供了良好的前景。
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