Drug-interactive mPEG-b-PLA-Phe(Boc) micelles enhance the tolerance and anti-tumor efficacy of docetaxel
Drug-interactive mPEG-b-PLA-Phe(Boc) micelles enhance the tolerance and anti-tumor efficacy of docetaxel
复制标题
药物相互作用的 mPEG-b-PLA-Phe(Boc) 胶束增强多西紫杉醇的耐受性和抗肿瘤功效
DOI：
10.1080/10717544.2020.1718245
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发表时间：
2020-01-01
期刊：
影响因子：
6
通讯作者：
Cui, Zhong-Kai
中科院分区：
文献类型：
--
作者：
Gong, Feirong;Wang, Rongrong;Cui, Zhong-Kai
多西他赛（DTX）是治疗多种实体瘤最有前途的化疗药物之一。然而，市售制剂Taxotere（R）的临床功效由于其水溶性差、乳化剂引起的副作用和低选择性DTX体内分布而受到限制。本文制备了一种简单、定义明确且易于放大的载有DTX的N-（叔丁氧羰基）-（L）-苯丙氨酸封端的甲氧基-聚（乙二醇）-嵌段-聚（（D，L）-丙交酯）（mPEG-b-PLA-Phe（Boc））胶束（DTX-PM），以努力开发毒性更低且更有效的多西他赛制剂。与市售的DTX制剂泰索帝（R）相比，评价了其物理化学性质、药代动力学、生物分布和体内抗肿瘤功效。DTX成功地包封在疏水胶束核心中，具有高包封率（> 95%）和高载药量（4.81 +/-0.08%）。由于末端氨基酸残基与多西他赛之间的强相互作用，DTX-PM在水环境中表现出突出的稳定性。在Sprague-Dawley大鼠中的药代动力学研究显示，由于胶束制剂的稳定性提高，DTX-PM治疗组的全血和血浆中的DTX浓度高于Taxotere治疗组。在人非小细胞肺癌（A549）荷瘤Balb/c裸鼠中，DTX-PM显著改善了肿瘤中的DTX蓄积，并使肿瘤中的DTX消除停滞。此外，仅用DTX剂量的一半，我们的DTX/mPEG-b-PLA-Phe（Boc）胶束就可以达到与Taxotere（R）相似的治疗效果。总的来说，DTX-PM作为一种简单有效的癌症化疗药物输送系统具有很大的前景。
Docetaxel (DTX) is one of the most promising chemotherapeutic agents for a variety of solid tumors. However, the clinical efficacy of the marketed formulation, Taxotere (R), is limited due to its poor aqueous solubility, side effects caused by the emulsifier, and low selective DTX distribution in vivo. Here a facile, well-defined, and easy-to-scale up DTX-loaded N-(tert-butoxycarbonyl)-(L)-phenylalanine end-capped methoxy-poly(ethylene glycol)-block-poly((D,L)-lactide) (mPEG-b-PLA-Phe(Boc)) micelles (DTX-PMs) were prepared in an effort to develop a less toxic and more efficacious docetaxel formulation. The physicochemical properties, pharmacokinetics, biodistribution, and in vivo anti-tumor efficacy were evaluated in comparison to the marketed DTX formulation Taxotere (R). DTX was successfully encapsulated in the hydrophobic micellar core with a high encapsulation efficiency (> 95%) and a high drug loading capacity (4.81 +/- 0.08%). DTX-PMs exhibited outstanding stability in the aqueous environment due to the strong interactions between the terminal amino acid residues and docetaxel. The pharmacokinetic study in Sprague-Dawley rats revealed higher DTX concentrations in both whole blood and plasma for the group treated with DTX-PMs than that treated with Taxotere (R) due to the improved stability of the micellar formulation. In human non-small cell lung cancer (A549) tumor-bearing Balb/c nude mice, DTX-PMs significantly improved DTX accumulation and stalled DTX elimination in tumors than in bone marrow. Furthermore, only by half of the DTX dosage, our DTX/mPEG-b-PLA-Phe(Boc) micelles can achieve similar therapeutic effects as Taxotere (R). Altogether, DTX-PMs hold great promise as a simple and effective drug delivery system for cancer chemotherapy.