文献：Engineering of Bone- and CD44-Dual-Targeting Redox-Sensitive Liposomes for the Treatment of Orthotopic Osteosarcoma

文献链接：https://xueshu.baidu.com/usercenter/paper/show?paperid=12380rf0eg3h00n0y97j0vk07w259190&site=xueshu_se

作者：Shuaishuai Feng, Zi-Xin Wu, Ziyan Zhao, Jinhu Liu,Kaoxiang Sun, Chuanyou Guo, Hongbo Wang, and Zimei Wu

相关产品：DSPE-PEG2000-COOH 磷脂-聚乙二醇2000-羧基

原文摘要：This study aimed to develop an efficient step-by-step osteosarcoma (OS)-targeting liposome system functionalized with a redox-cleavable, bone- and cluster of differentiation 44 (CD44)-dual-targeting polymer. Furthermore, the effect of coadministration of a tumor-penetrating peptide, internalizing-RGD (iRGD), was investigated. First, a bone-targeting moiety, alendronate (ALN), was conjugated with hyaluronic acid (HA), a ligand for CD44. This ALN-HA conjugate was coupled with DSPE-PEG2000-COOH through a bioreducible disulfide linker (-SS-) to obtain a functionalized lipid, ALN-HA-SS-L, to be post-inserted into preformed liposomes loaded with doxorubicin (DOX). The roles of ALN, HA and the redox-sensitivity of the ALN-HA-SS-L

liposomes (ALN-HA-SS-L-L) in the anti-osteosarcoma effect were critically evaluated against various reference liposomal formulations (with only ALN, HA or redox sensitivity).

ALN-HASS-L-Ldisplayed a zeta potential of -26.07±0.32 mV and selectively disassembled in the presence of a reducing agent, 10 mM glutathione (GSH), which can be found in cancer cells. Compared to various reference liposomes, ALN-HA-SS-L-L/DOX had significantly higher cytotoxicity to human OS MG-63 cells alongside high and rapid cellular uptake. In the orthotopic OS nude mouse models, ALN-HA-SS-L-L/DOX showed remarkable tumor growth suppression and prolonged survival time. This result was further improved by the coadministration of iRGD. The antitumor effects of various liposomes were ranked in the same order as the degree of tumor biodistribution shown by in vivo/ex vivo imaging: ALN-HA-SS-L-L coadministered with iRGD > ALN-HA-SS-L-L > HA-SS-L-L > HA-L-L > PEG-L> free drug. ALN-HA-SS-L-L/DOX also reduced the cardiotoxicity of DOX and lung metastases. Overall, this study demonstrated that ALN-HA-SS-L-L/DOX, equipped with bone- and CD44-dual-targeting abilities and redox sensitivity,could be a promising OS-targeted therapy. The efficacy could also be augmented by coadministration of iRGD.

DSPE-PEG2000-COOH是由亲水性的聚乙二醇2000（PEG2000）连接疏水性的二棕榈酰磷脂酰乙醇胺（DSPE）和羧基（COOH）组成，这种结构使其兼具亲水性和疏水性，能在水中自组装形成脂质体等纳米结构.该产品的羧基可与含有氨基的蛋白、多肽、抗体等分子发生反应，实现生物分子的偶联，常用于制备靶向化合物递送系统、生物传感器等。基于此该文献旨在开发一种逐步（OS）靶向脂质体系统，该系统具有氧化还原可切割和分化簇44（CD44）双靶向聚合物。过程如下：

图：中间体产品的合成方案

ALN-HA-HA-SS-L的制备：

首先，将骨靶向部分阿仑膦酸盐（ALN）与透明质酸（CD44的配体）结合。该ALN-HA偶联物通过生物可还原二硫连接物（-SS-）与DSPE-PEG2000-COOH偶联，获得功能化脂质ALN-HA-HA-SS-L，将其插入到装载阿霉素（DOX）的预制脂质体中。ALN、HA和ALN-HA-SS-L脂质体（ALN-HA-HS-sS-L-L）的作用通过各种参考脂质体配方进行严格评估。

图：HA-L-L（A-C）和ALN-HA-SS-L-L（D-F）在DTT溶液中的TEM图像

结论：DSPE-PEG2000-COOH参与制备的ALN-HASS-L-L显示出-26.07±0.32 mV的zeta电位，并在还原剂10 mM谷胱甘肽（GSH）的存在下选择性分解，这可以在cancer细胞中发现。与各种参考脂质体相比，ALN-HA-SS-L-L/DOX对人OS MG-63细胞具有更高的细胞有害性，同时具有高而快速的细胞摄取。ALN-HA-SS-L-L/DOX表现出阻止tumor生长和延长生存时间。