Dual targeting folate-conjugated hyaluronic acid polymeric micelles for paclitaxel delivery
Dual targeting folate-conjugated hyaluronic acid polymeric micelles for paclitaxel delivery
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DOI：
10.1016/j.ijpharm.2011.09.006
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发表时间：
2011-12-12
影响因子：
5.8
通讯作者：
He, Zhonggui
中科院分区：
文献类型：
--
作者：
Liu, Yanhua;Sun, Jin;He, Zhonggui
合成了一系列新型的自组装透明质酸衍生物（HA-C-18），并将其与疏水性十八烷基基团接枝，进而将其与叶酸偶联（FA-HA-C-18）。随着十八烷基取代度从12.7%增加到19.3%，HA-C-18共聚物的临界胶束浓度从37.3 μ g/mL降低到10.0 μ g/mL。紫杉醇（PTX）成功地包封在HA-C-18和FA-HA-C-18胶束的疏水核中，包封率高达97.3%。用DES、TEM和DSC对聚合物胶束的物理化学性质进行了表征。采用透析袋法考察了PTX的体外释放行为，发现PTX从胶束中以近零级缓释方式释放。体外抗肿瘤活性测试表明，在较低PTX浓度下，与紫杉醇相比，PTX负载的HA-C-18和FA-HA-C-18胶束对MCF-7和A549细胞表现出显著更高的细胞毒活性。通过定量测定PTX细胞蓄积和共聚焦激光扫描显微镜成像香豆素-6标记的HA-C-18和FA-HA-C-18胶束在叶酸受体过表达的MCF-7细胞中进行细胞摄取实验。通过荧光显微镜成像进行的叶酸和CD 44受体竞争性抑制研究表明，HA-C-18和FA-HA-C-18胶束的细胞内递送通过CD 44受体介导的内吞作用被有效摄取。与HA-C-18胶束相比，叶酸受体介导的内吞作用进一步增强了MCF-7细胞中FA-HA-C-18胶束的内化量。载PTX的HA-C-18和FA-HA-C-18胶束的内化途径可能包括网格蛋白介导的内吞、小窝介导的内吞和巨胞饮。因此，本研究表明，HA-C-18和FA-HA-C-18共聚物作为生物可降解的，生物相容性和细胞特异性靶向纳米结构载体，是有前途的细胞内和细胞内靶向递送疏水性抗癌药物的纳米系统。皇冠版权所有（C）201 1由Elsevier B. V.出版。保留所有权利。
A series of novel self-assembled hyaluronic acid derivatives (HA-C-18) grafted with hydrophobic octadecyl moiety and further dual targeting folic acid-conjugated HA-C-18 (FA-HA-C-18) were synthesized. With the increase in the degree of substitution of octadecyl group from 12.7% to 19.3%, the critical micellar concentration of HA-C-18 copolymers decreased from 37.3 to 10.0 mu g/mL. Paclitaxel (PTX) was successfully encapsulated into the hydrophobic cores of the HA-C-18 and FA-HA-C-18 micelles, with encapsulation efficiency as high as 97.3%. The physicochemical properties of the polymeric micelles were measured by DES, TEM and DSC. Moreover, in vitro release behavior of PTX was investigated by dialysis bag method and PTX was released from micelles in a near zero-order sustained manner. In vitro antitumor activity tests suggested PTX-loaded HA-C-18 and FA-HA-C-18 micelles exhibited significantly higher cytotoxic activity against MCF-7 and A549 cells compared to Taxol at a lower PTX concentration. The cellular uptake experiments were conducted by quantitative assay of PTX cellular accumulation and confocal laser scanning microscopy imaging of coumarin-6 labeled HA-C-18 and FA-HA-C-18 micelles in folate receptor overexpressing MCF-7 cells. Folate and CD44 receptor competitive inhibition studies performed by fluorescence microscopy imaging suggested intracellular delivery of HA-C-18 and FA-HA-C-18 micelles were efficiently taken up via CD44 receptor-mediated endocytosis. The folate receptor-mediated endocytosis further enhanced internalized amounts of FA-HA-C-18 micelles in MCF-7 cells, as compared with HA-C-18 micelles. The internalization pathways of PTX-loaded HA-C-18 and FA-HA-C-18 micelles might include clathrin-mediated endocytosis, caveolae-mediated endocytosis and macropinocytosis. Therefore, the present study suggested that HA-C-18 and FA-HA-C-18 copolymers as biodegradable, biocompatible and cell-specific targetable nanostructure carriers, are promising nanosystems for cellular and intracellular targeting delivery of hydrophobic anticancer drugs. Crown Copyright (C) 201 1 Published by Elsevier B.V. All rights reserved.