Polymeric micellar systems are emerging as a very important class of nanopharmaceuticals due to their ability to improve pharmacokinetics and biodistribution of chemotherapy drugs, as well as to reduce related systemic toxicities. While these nanosized delivery systems inherently benefit from passive targeting through the enhanced permeation and retention effect leading to increased accumulation in the tumor, additional active targeting can be achieved through surface modification of micelles with targeting groups specific for overexpressed receptors of tumor cells. In this project, nontoxic, biodegradable, and modularly tunable micellar delivery systems were generated using two types of dendron–polymer conjugates. Either an AB type dendron–polymer construct with 2K PEG or an ABA type dendron–polymer–dendron conjugate with 6K PEG based middle block was used as primary construct; along with an AB type dendron–polymer containing a cRGDfK targeting group to actively target cancer cells overexpressing α_υβ₃/α_υβ₅ integrins. A set of micelles encapsulating docetaxel, a widely employed chemotherapy drug, were prepared with varying feed ratios of primary construct and targeting group containing secondary construct. Critical micelle concentrations of all micellar systems were in the range of 10^–6 M. DLS measurements indicated hydrodynamic size distributions varying between 170 to 200 nm. An increase in docetaxel release at acidic pH was observed for all micelles. Enhanced cellular internalization of Nile red doped micelles by MDA-MB-231 human breast cancer cells suggested that the most efficient uptake was observed with targeted micelles. In vitro cytotoxicity experiments on MDA-MB-231 breast cancer and A549 lung carcinoma cell lines showed improved toxicity for RGD containing micelles. For A549 cell line EC₅₀ values of drug loaded micellar sets were in the range of 10^–9 M whereas EC₅₀ value of free docetaxel was around 10^–10 M. For MDA-MB-231 cell line EC₅₀ value of free docetaxel was 6 × 10^–8 M similar to EC₅₀ of nontargeted AB type docetaxel doped micellar constructs whereas the EC₅₀ value of its targeted counterpart decreased to 5.5 × 10^–9 M. Overall, in this comparative study, the targeting group containing micellar construct fabricated with a 2 kDa PEG based diblock dendron–polymer conjugate emerges as an attractive drug delivery vehicle due to the ease of synthesis, high stability of the micelles, and efficient targeting.

中文翻译：

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设计具有“混搭”模块的基于Dendron-聚合物共轭物的靶向药物递送平台

高分子胶束系统由于具有改善化疗药物的药代动力学和生物分布以及降低相关全身毒性的能力而成为一类非常重要的纳米药物。尽管这些纳米级递送系统固有地受益于通过增强的渗透和保留效应导致的在肿瘤中积累的增加的被动靶向，但是可以通过用对肿瘤细胞的过表达受体具有特异性的靶向基团对胶束进行表面修饰来实现额外的主动靶向。在该项目中，使用两种类型的树突-聚合物共轭物生成了无毒，可生物降解和模块化可调的胶束输送系统。带有2K PEG的AB型树突-聚合物构建体或带有基于6K PEG中间嵌段的ABA型树突-聚合物-树突共轭物被用作主要构建体。连同含有cRGDfK靶向基团的AB型树突状聚合物一起，主动靶向过度表达α的癌细胞_υ β ₃ /α _υ β ₅整联。以不同的一级构建体和含有靶向构建体的靶向基团的进料比例，制备了一组封装了多西他赛（一种广泛使用的化疗药物）的胶束。所有胶束体系的临界胶束浓度在10〜^-6 M. DLS测量表明流体动力学尺寸分布纳米170 200之间不同。对于所有胶束，观察到多西他赛在酸性pH下的释放增加。MDA-MB-231人乳腺癌细胞对尼罗红掺杂胶束的增强的细胞内在化作用表明，靶向胶束的吸收效率最高。体外对MDA-MB-231乳腺癌和A549肺癌细胞系的细胞毒性实验表明，对含RGD的胶束具有改善的毒性。对于A549细胞系，载药胶束组的EC ₅₀值在^10–9 M范围内，而游离多西紫杉醇的EC ₅₀值在^10–10 M左右。对于MDA-MB-231细胞系，游离多西紫杉醇的EC ₅₀值在^10–10 M左右。6×10 ^-8中号类似于EC ₅₀非靶向AB型多烯紫杉醇的胶束掺杂构建体而EC ₅₀的目标对应的值降低到5.5×10 ^-9 M.总体而言，在这项比较研究中，由于合成容易，胶束的高稳定性和有效的靶向作用，含有2 kDa PEG基二嵌段树突-聚合物共轭物制成的含有胶束构建体的靶向组成为有吸引力的药物递送载体。 。