叶酸靶向胆固醇基胶束载多西他赛的药代动力学、器官毒性及抗肿瘤活性

Pharmacokinetics, Organ Toxicity and Antitumor Activity of Docetaxel Loaded in Folate Targeted Cholesterol Based Micelles.

作者信息

Taymouri Somayeh, Varshosaz Jaleh, Hassanzadeh Farshid, Javanmard Shaghayegh H, Mahzouni Parvin

机构信息

Department of Pharmaceutics, Faculty of Pharmacy and Novel Drug Delivery Systems Research Centre, Isfahan University of Medical Sciences, Isfahan, PO Box 81745-359, Iran.

出版信息

Curr Drug Deliv. 2016;13(4):545-56. doi: 10.2174/1567201812666150416154552.

DOI:10.2174/1567201812666150416154552

PMID:25879868

Abstract

BACKGROUND

To overcome insufficient concentration of chemotherapeutic drugs at tumor site and severe side effects in non-targeted tissues which limit their use targeting their overexpressed receptors represent a promising approach for cancer therapy.

METHODS

The antitumor activity of docetaxel (DTX) loaded in folate targeted Synpronic F127- Cholesterol (FA-PF127-Chol) nanomicelles was evaluated in C57BL6 mice bearing melanoma and their survival was studied. The pharmacokinetic of DTX loaded FA-PF127-Chol micelles in comparison with Taxoter(®) was investigated in male Wistar rats. The tumor proliferation was detected by Ki67 assay. The systemic organ toxicity was evaluated in healthy bulb-c mice.

RESULTS

DTX loaded FA-PF127-Chol micelles significantly inhibited tumor growth and enhanced animal survival compared to Taxoter(®) and non-targeted micelles. FA-PF127-Chol micelles significantly enhanced mean residence time (MRT) and AUC0-∞ of DTX compared to Taxoter(®). The immunehistochemical study demonstrated that DTX loaded FA-PF127-Chol significantly inhibited intra-tumoral cell proliferation in comparison with other treated groups. Safety evaluation showed no toxicity of DTX loaded targeted micelles on blood cells. Histopathology analysis of major organs of mice treated with DTX loaded FA-PF127-Chol micelles showed less tissue damages compared to Taxoter(®) and non-targeted ones.

DISCUSSION

The results of this contribution showed the potential of DTX loaded FA-PF127-Chol in treatment of melanoma.

摘要

背景

为克服化疗药物在肿瘤部位浓度不足以及非靶向组织中严重的副作用，而这些副作用限制了它们的使用，靶向肿瘤细胞中过表达的受体是一种很有前景的癌症治疗方法。

方法

在携带黑色素瘤的C57BL6小鼠中评估负载多西他赛（DTX）的叶酸靶向泊洛沙姆F127-胆固醇（FA-PF127-Chol）纳米胶束的抗肿瘤活性，并研究其生存期。在雄性Wistar大鼠中研究负载DTX的FA-PF127-Chol胶束与泰索帝（Taxoter®）相比的药代动力学。通过Ki67检测法检测肿瘤增殖情况。在健康的球c小鼠中评估全身器官毒性。

结果

与泰索帝（Taxoter®）和非靶向胶束相比，负载DTX的FA-PF127-Chol胶束显著抑制肿瘤生长并提高动物生存期。与泰索帝（Taxoter®）相比，FA-PF127-Chol胶束显著提高了DTX的平均驻留时间（MRT）和AUC0-∞。免疫组织化学研究表明，与其他治疗组相比，负载DTX的FA-PF127-Chol显著抑制肿瘤内细胞增殖。安全性评估显示，负载DTX的靶向胶束对血细胞无毒性。与泰索帝（Taxoter®）和非靶向胶束相比，用负载DTX的FA-PF127-Chol胶束治疗的小鼠主要器官的组织病理学分析显示组织损伤较少。