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Tumor-Targeting Micelles Based on Linear–Dendritic PEG–PTX8 Conjugate for Triple Negative Breast Cancer Therapy
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2017-08-30 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00430
Yujie Zhang 1 , Yifei Lu 1 , Yu Zhang 1 , Xi He 1 , Qinjun Chen 1 , Lisha Liu 1 , Xinli Chen 1 , Chunhui Ruan 1 , Tao Sun 1 , Chen Jiang 1
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Most small molecular chemotherapeutics have poor water solubility and unexpected pharmacokinetics and toxicity to normal tissues. A series of nano drug delivery systems have been developed to solve the problems, among which a micelle based on linear–dendritic polymer–drug conjugates (LDPDCs) is a promising strategy to deliver hydrophobic chemotherapeutics due to its small size, fine stability in blood circulation, and high drug loading capacity. In this work we synthesized a novel amphiphilic linear–dendritic PEG–PTX8 conjugate which can also encapsulate extra free PTX and self-assemble into uniform ultrasmall micelles with a hydrated diameter of 25.50 ± 0.27 nm. To realize efficient drug delivery to tumor sites, a cyclic tumor homing and penetrating peptide iNGR was linked to the PEG–PTX8 conjugate. The biological evaluation was performed on a human triple negative breast cancer model. PTX accumulation in tumor at 24 h of the TNBC-bearing mice treated with iNGR–PEG–PTX8/PTX micelles was significantly enhanced (P < 0.001, two-way ANOVA) compared to that of Taxol and untargeted MeO–PEG–PTX8/PTX micelles. Furthermore, iNGR–PEG–PTX8/PTX micelles showed an obvious strong antitumor effect, and the median survival time of TNBC bearing mice treated with iNGR-modified micelles was significantly extended compared to Taxol. Therefore, this smart micelle system may be a favorable platform for effective TNBC therapy.

中文翻译:

基于线性-树突状PEG-PTX 8共轭的肿瘤靶向胶束用于三阴性乳腺癌治疗。

大多数小分子化学治疗剂的水溶性差,对正常组织的药代动力学和毒性也很差。为了解决这些问题,已经开发出了一系列的纳米药物递送系统,其中基于线性-树突状聚合物-药物偶联物(LDPDCs)的胶束由于其体积小,血液循环中的良好稳定性而成为提供疏水化学疗法的有前途的策略。 ,并且载药量高。在这项工作中,我们合成了一种新型的两亲性线性树突状PEG-PTX 8共轭物,该共轭物还可以包裹额外的游离PTX并自组装成水合直径为25.50±0.27 nm的均匀超小胶束。为了实现将药物高效递送至肿瘤部位,将循环肿瘤归巢和穿透肽iNGR与PEG–PTX 8连接共轭物。生物学评估是在人类三阴性乳腺癌模型上进行的。与紫杉醇和未靶向的MeO-PEG-PTX 8相比,用iNGR–PEG–PTX 8 / PTX胶束处理的TNBC荷瘤小鼠在24小时内肿瘤中PTX的积累显着增强(P <0.001,双向ANOVA)。/ PTX胶束。此外,iNGR–PEG–PTX 8 / PTX胶束具有明显的抗肿瘤作用,与紫杉醇相比,经iNGR修饰的胶束处理的TNBC荷瘤小鼠的中位生存时间显着延长。因此,该智能胶束系统可能是有效TNBC治疗的有利平台。
更新日期:2017-08-30
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