Title:Improved Antitumor Efficacy of a Dextran-based Docetaxel-coupled
Conjugate against Triple-Negative Breast Cancer
Volume: 21
Issue: 5
Author(s): Hongshuai Lv, Weiping Jia, Peng Dong, Jiaojiao Liu, Si Wang, Xiaohai Li, Jinghua Hu, Ling Zhao and Yikang Shi*
Affiliation:
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology,
NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate Based Medicine, Shandong University,
Qingdao, Shandong 266237, China
Keywords:
Docetaxel, dextran, docosahexaenoic acid, conjugate, triple-negative breast cancer, nanomedicine.
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.
