Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310006, China.
Int J Mol Sci. 2020 Mar 9;21(5):1856. doi: 10.3390/ijms21051856.
On account of their excellent capacity to significantly improve the bioavailability and solubility of chemotherapy drugs, amphiphilic block copolymer-based micelles have been widely utilized for chemotherapy drug delivery. In order to further improve the antitumor ability and to also reduce undesired side effects of drugs, cell-penetrating peptides have been used to functionalize the surface of polymer micelles endowed with the ability to target tumor tissues. Herein, we first synthesized functional polyethylene glycol-polylactic acid (PEG-PLA) tethered with maleimide at the PEG section of the block polymer, which was further conjugated with a specific peptide, the transactivating transcriptional activator (TAT), with an approved capacity of aiding translocation across the plasma membrane. Then, TAT-conjugated, paclitaxel-loaded nanoparticles were self-assembled into stable nanoparticles with a favorable size of 20 nm, and displayed a significantly increased cytotoxicity, due to their enhanced accumulation via peptide-mediated cellular association in human breast cancer cells (MCF-7) . But when further used , TAT-NP-PTX showed an acceleration of the drug's plasma clearance rate compared with NP-PTX, and therefore weakened its antitumor activities in the mice model, because of its positive charge, its elimination by the endoplasmic reticulum system more quickly, and its targeting effect on normal cells leading towards being more toxic. So further modification of TAT-NP-PTX to shield TAT peptide's positive charges may be a hot topic to overcome the present dilemma.
由于两亲嵌段共聚物胶束具有显著提高化疗药物生物利用度和溶解度的能力，因此被广泛用于化疗药物传递。为了进一步提高抗肿瘤能力，同时降低药物的不良副作用，细胞穿透肽被用于功能化具有靶向肿瘤组织能力的聚合物胶束表面。在此，我们首先合成了功能化的聚乙二醇-聚乳酸（PEG-PLA），其在嵌段聚合物的 PEG 部分带有马来酰亚胺，然后进一步与一种特定的肽（转导转录激活因子（TAT））结合，TAT 具有促进跨膜转位的能力。然后，TAT 修饰的、载紫杉醇的纳米颗粒自组装成稳定的纳米颗粒，其尺寸为 20nm，由于通过肽介导的细胞相互作用在人乳腺癌细胞（MCF-7）中的增强积累，表现出显著增加的细胞毒性。但是，当进一步使用时，TAT-NP-PTX 与 NP-PTX 相比，显示出药物血浆清除率的加速，因此在小鼠模型中减弱了其抗肿瘤活性，这是由于其正电荷，使其更快地被内质网系统清除，并且其对正常细胞的靶向作用导致毒性更大。因此，进一步修饰 TAT-NP-PTX 以屏蔽 TAT 肽的正电荷可能是克服当前困境的热门话题。
