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Current Drug Delivery

Author(s): Hongshuai Lv, Weiping Jia, Peng Dong, Jiaojiao Liu, Si Wang, Xiaohai Li, Jinghua Hu, Ling Zhao and Yikang Shi*

DOI: 10.2174/1567201820666230622105503

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Improved Antitumor Efficacy of a Dextran-based Docetaxel-coupled Conjugate against Triple-Negative Breast Cancer

Page: [775 - 784] Pages: 10

  • * (Excluding Mailing and Handling)

Abstract

Background: Most chemotherapeutic agents are characterized by poor water solubility and non-specific distribution. Polymer-based conjugates are promising strategies for overcoming these limitations.

Objective: This study aims to fabricate a polysaccharide, dextran-based, dual-drug conjugate by covalently grafting docetaxel (DTX) and docosahexaenoic acid (DHA) onto the bifunctionalized dextran through a long linker, and to investigate the antitumor efficacy of this conjugate against breast cancer.

Methods: DTX was firstly coupled with DHA and covalently bounded with the bifunctionalized dextran (100 kDa) through a long linker to produce a conjugate dextran-DHA-DTX (termed C-DDD). Cytotoxicity and cellular uptake of this conjugate were measured in vitro. Drug biodistribution and pharmacokinetics were investigated through liquid chromatography/mass spectrometry analysis. The inhibitory effects on tumor growth were evaluated in MCF-7- and 4T1-tumor-bearing mice.

Results: The loading capacity of the C-DDD for DTX was 15.90 (weight/weight). The C-DDD possessed good water solubility and was able to self-assemble into nanoparticles measuring 76.8 ± 5.5 nm. The maximum plasma concentration and area under the curve (0-∞) for the released DTX and total DTX from the C-DDD were significantly enhanced compared with the conventional DTX formulation. The C-DDD selectively accumulated in the tumor, with limited distribution was observed in normal tissues. The C-DDD exhibited greater antitumor activity than the conventional DTX in the triplenegative breast cancer model. Furthermore, the C-DDD nearly eliminated all MCF-7 tumors in nude mice without leading to systemic adverse effects.

Conclusion: This dual-drug C-DDD has the potential to become a candidate for clinical application through the optimization of the linker.

Graphical Abstract

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