Intracellular delivery of doxorubicin with RGD-modified sterically stabilized liposomes for an improved antitumor efficacy:: In vitro and in vivo
Intracellular delivery of doxorubicin with RGD-modified sterically stabilized liposomes for an improved antitumor efficacy:: In vitro and in vivo
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DOI：
10.1002/jps.20397
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发表时间：
2005-08-01
影响因子：
3.8
通讯作者：
Zhang, Q
中科院分区：
文献类型：
--
作者：
Xiong, XB;Huang, Y;Zhang, Q
空间稳定脂质体（SSL）的被动靶向，一旦与有效的细胞内递送相结合，可能是一个非常有用的策略，以提高抗癌药物的抗肿瘤疗效。已知精氨酸-甘氨酸-天冬氨酸三肽（RGD）充当位于细胞表面上的几种不同整合素的识别基序。在这项研究中，将RGD三肽偶联到聚（乙二醇）包被的脂质体（RGD-SSL）的远端，旨在实现增加的肿瘤蓄积和增强的细胞内摄取。比较了DOX负载的RGD-SSL（RGD-SSLDOX）、DOX负载的SSL（SSL-DOX）和游离DOX在它们的体外摄取和细胞毒性以及它们在荷瘤小鼠中的体内生物分布和治疗功效。流式细胞术和共聚焦显微镜研究表明，RGD-SSL可以促进整合素介导的内吞DOX进入黑色素瘤细胞。RGD-SSL-DOX对黑色素瘤细胞的细胞毒性高于SSL-DOX。虽然RGD-SSL-DOX表现出与SSL-DOX一样的延长的循环时间和增加的肿瘤积聚，但其显示出比SSL-DOX显著更高的脾摄取。与接受相同剂量的SSL-DOX、游离DOX溶液或盐水的小鼠相比，接受RGD-SSL-DOX（5 mg DOX/kg）的小鼠显示出肿瘤生长的有效阻滞。这些结果表明，RGD修饰的SSL可能是一种可行的细胞内靶向载体，用于有效地将化疗药物递送到肿瘤细胞中。(c)2005 Wiley-Liss，Inc.
Passive targeting by sterically stabilized liposomes (SSL), once combined with efficient intracellular delivery, may be a very useful strategy to improve the antitumor efficacy for the anticancer agents. The arginine-glycine-aspartic acid tripeptide (RGD) is known to serve as a recognition motif for several different integrins located on cell surface. In this study, the RGD tripeptide was coupled to the distal end of the poly (ethylene glycol)-coated liposomes (RGD-SSL) aimed to achieve increased tumor accumulation and enhanced intracellular uptake.. DOX-loaded RGD-SSL (RGD-SSLDOX), DOX-loaded SSL (SSL-DOX), and free DOX were compared with respect to their in vitro uptake and cytotoxicity and their in vivo biodistribution and therapeutic efficacy in tumor-bearing mice. Flow cytometry and confocal microscopy studies revealed that RGD-SSL could facilitate the DOX uptake into melanoma cells by integrin-mediated endocytosis. RGD-SSL-DOX displayed higher cytotoxicity on melanoma cells than SSL-DOX. While RGD-SSL-DOX demonstrated prolonged circulation time and increased tumor accumulation as SSL-DOX did, it showed remarkably higher splenic uptake than SSL-DOX. Mice receiving RGD-SSL-DOX (5 mg DOX/kg) showed effective retardation in tumor growth compared with those receiving same dose of SSL-DOX, free DOX solution, or saline. These results suggest that RGD-modified SSL may be a feasible intracellular targeting carrier for efficient delivery of chemotherapeutic agents into tumor cells. (c) 2005 Wiley-Liss, Inc.