School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in University of Shandong , Yantai University , Yantai 264005 , PR China.
Qingdao Municipal Hospital , Qingdao 266071 Shandong Province , PR China.
ACS Appl Mater Interfaces. 2019 Feb 20;11(7):7357-7368. doi: 10.1021/acsami.8b18820. Epub 2019 Feb 7.
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-PEG-COOH through a bioreducible disulfide linker (-SS-) to obtain a functionalized lipid, ALN-HA-SS-L, to be postinserted 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-OS effect were critically evaluated against various reference liposomal formulations (with only ALN, HA, or redox sensitivity). ALN-HA-SS-L-L displayed a zeta potential of -26.07 ± 0.32 mV and selectively disassembled in the presence of a reducing agent, 10 mM glutathione, 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.
本研究旨在开发一种高效的、逐步的骨肉瘤（OS）靶向脂质体系统，该系统具有氧化还原裂解、骨和 CD44 双靶向聚合物。此外，还研究了共给药肿瘤穿透肽、内化 RGD（iRGD）的效果。首先，将骨靶向部分，阿仑膦酸钠（ALN）与透明质酸（HA）偶联，HA 是 CD44 的配体。通过生物还原二硫键（-SS-）将 ALN-HA 缀合物与 DSPE-PEG-COOH 偶联，得到功能化脂质 ALN-HA-SS-L，用于将阿霉素（DOX）加载到预形成的脂质体中。通过各种参考脂质体制剂（仅含有 ALN、HA 或氧化还原敏感性），对 ALN、HA 和 ALN-HA-SS-L 脂质体（ALN-HA-SS-L-L）的抗 OS 作用的作用进行了严格评估。ALN-HA-SS-L-L 具有-26.07±0.32 mV 的 ζ 电位，并在还原剂 10 mM 谷胱甘肽存在下选择性解组装，谷胱甘肽可在癌细胞中找到。与各种参考脂质体相比，ALN-HA-SS-L-L/DOX 对人骨肉瘤 MG-63 细胞具有更高的细胞毒性和更高的快速细胞摄取率。在原位骨肉瘤裸鼠模型中，ALN-HA-SS-L-L/DOX 显示出显著的肿瘤生长抑制和延长的生存时间。通过共给 iRGD，进一步改善了该结果。各种脂质体的抗肿瘤效果与体内/体外成像所示的肿瘤生物分布程度一致：共给药 iRGD 的 ALN-HA-SS-L-L 联合给药>ALN-HA-SS-L-L>HA-SS-L-L>HA-L-L>PEG-L>游离药物。ALN-HA-SS-L-L/DOX 还降低了 DOX 的心脏毒性和肺转移。总体而言，本研究表明，ALN-HA-SS-L-L/DOX 具有骨和 CD44 双重靶向能力和氧化还原敏感性，可能是一种有前途的骨肉瘤靶向治疗方法。通过共给 iRGD，还可以增强疗效。
