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Drug-interactive mPEG-b-PLA-Phe(Boc) micelles enhance the tolerance and anti-tumor efficacy of docetaxel.
Drug Delivery ( IF 6.5 ) Pub Date : 2020-01-31 , DOI: 10.1080/10717544.2020.1718245
Feirong Gong 1 , Rongrong Wang 1 , Zhengquan Zhu 1 , Jiayao Duan 1 , Xin Teng 1 , Zhong-Kai Cui 2, 3, 4
Affiliation  

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®, 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®. 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® 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®. Altogether, DTX-PMs hold great promise as a simple and effective drug delivery system for cancer chemotherapy.

中文翻译:

药物相互作用mPEG-b-PLA-Phe(Boc)胶束增强了多西紫杉醇的耐受性和抗肿瘤功效。

多西他赛(DTX)是用于多种实体瘤的最有前途的化学治疗剂之一。然而,由于其水溶性差,乳化剂引起的副作用以及体内低选择性DTX分布,市售制剂Taxotere®的临床疗效受到限制。这是一种简便,定义明确且易于按比例放大的DTX负载的N-(叔丁氧基羰基)-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-PMs)的制备旨在开发毒性更小,更有效的多西他赛制剂。与市售DTX制剂比较,评估了其理化性质,药代动力学,生物分布和体内抗肿瘤功效。DTX以高的包封率(> 95%)和高的载药量(4.81±0.08%)成功地包封在疏水性胶束芯中。由于末端氨基酸残基和多西他赛之间的强相互作用,DTX-PM在水性环境中表现出出色的稳定性。在Sprague-Dawley大鼠中进行的药代动力学研究表明,由于胶束制剂的稳定性提高,DTX-PMs治疗组的全血和血浆DTX浓度均高于Taxotere®治疗组。在人类非小细胞肺癌(A549)荷瘤Balb / c裸鼠中,与骨髓相比,DTX-PMs显着改善了肿瘤中DTX的积累并阻止了DTX的消除。此外,仅DTX剂量的一半,我们的DTX / mPEG-b-PLA-Phe(Boc)胶束可达到与Taxotere®类似的治疗效果。总而言之,DTX-PM作为癌症化疗的简单有效的药物递送系统具有广阔的前景。
更新日期:2020-04-20
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