Bolu Burcu Sumer, Golba Bianka, Boke Nazli, Sanyal Amitav, Sanyal Rana
Department of Chemistry and ‡Center for Life Sciences and Technologies, Bogazici University , Istanbul, 34342, Turkey.
Bioconjug Chem. 2017 Dec 20;28(12):2962-2975. doi: 10.1021/acs.bioconjchem.7b00595. Epub 2017 Dec 6.
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 αβ/αβ 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 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 EC values of drug loaded micellar sets were in the range of 10 M whereas EC value of free docetaxel was around 10 M. For MDA-MB-231 cell line EC value of free docetaxel was 6 × 10 M similar to EC of nontargeted AB type docetaxel doped micellar constructs whereas the EC value of its targeted counterpart decreased to 5.5 × 10 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.
聚合物胶束系统正成为一类非常重要的纳米药物，因为它们能够改善化疗药物的药代动力学和生物分布，并降低相关的全身毒性。虽然这些纳米尺寸的递送系统通过增强渗透和滞留效应固有地受益于被动靶向，从而导致在肿瘤中积累增加，但通过用针对肿瘤细胞过表达受体的靶向基团对胶束进行表面修饰，可以实现额外的主动靶向。在本项目中，使用两种类型的树枝状聚合物共轭物生成了无毒、可生物降解且可模块化调节的胶束递送系统。具有2K PEG的AB型树枝状聚合物构建体或具有6K PEG基中间嵌段的ABA型树枝状聚合物-树枝状共轭物用作主要构建体；同时使用含有cRGDfK靶向基团的AB型树枝状聚合物来主动靶向过表达αβ/αβ整合素的癌细胞。制备了一组包封多西他赛（一种广泛使用的化疗药物）的胶束，其主要构建体和含有靶向基团的二级构建体的进料比不同。所有胶束系统的临界胶束浓度在10 M范围内。动态光散射测量表明流体动力学尺寸分布在170至200 nm之间变化。观察到所有胶束在酸性pH下多西他赛释放增加。MDA-MB-231人乳腺癌细胞对尼罗红掺杂胶束的细胞内化增强表明，靶向胶束的摄取效率最高。对MDA-MB-231乳腺癌和A549肺癌细胞系的体外细胞毒性实验表明，含RGD的胶束毒性有所改善。对于A549细胞系，载药胶束组的EC值在10 M范围内，而游离多西他赛的EC值约为10 M。对于MDA-MB-231细胞系，游离多西他赛的EC值为6×10 M，与非靶向AB型多西他赛掺杂胶束构建体的EC值相似，而其靶向对应物的EC值降至5.5×10 M。总体而言，在这项比较研究中，由基于2 kDa PEG的二嵌段树枝状聚合物共轭物制备的含靶向基团的胶束构建体由于合成简便、胶束稳定性高和靶向效率高而成为一种有吸引力的药物递送载体。
