Engineering of Bone- and CD44-Dual-Targeting Redox-Sensitive Liposomes for the Treatment of Orthotopic Osteosarcoma
| Autor: | Hongbo Wang, Shuaishuai Feng, Jinhu Liu, Zi-Xin Wu, Chuanyou Guo, Ziyan Zhao, Zimei Wu, Kaoxiang Sun |
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| Rok vydání: | 2019 |
| Předmět: |
Biodistribution
Materials science Cell Survival Mice Nude Bone Neoplasms 02 engineering and technology 010402 general chemistry 01 natural sciences Nude mouse In vivo Cell Line Tumor medicine Animals Humans General Materials Science Doxorubicin Cytotoxicity Mice Inbred BALB C Osteosarcoma Liposome Alendronate biology 021001 nanoscience & nanotechnology biology.organism_classification Xenograft Model Antitumor Assays Neoplasm Proteins 0104 chemical sciences Hyaluronan Receptors Liposomes Cancer cell Cancer research Female 0210 nano-technology Ex vivo medicine.drug |
| Zdroj: | ACS Applied Materials & Interfaces. 11:7357-7368 |
| ISSN: | 1944-8252 1944-8244 |
| DOI: | 10.1021/acsami.8b18820 |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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