Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 240, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114567
Keywords
Paclitaxel; Dextran; Docosahexaenoic acid; Nanoparticle; Dextran-DHA-paclitaxel conjugate
Categories
Funding
- Shandong Province Major Science and Technology Innovation Project [2018CXGC1402]
- Shandong Post- doctoral Science Foundation [202002049]
- Natural Science Foundation of Shandong Province [ZR2019MH134]
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A novel dual drug delivery system based on carboxymethyl dextran (CMD) was developed in this study, which successfully delivered two water-insoluble drugs to tumor sites and exhibited excellent anticancer activities. The system showed high drug loading contents and improved water solubility, and could self-assemble into nanoparticles. The released drugs continuously in plasma and cancer cells, and showed higher distribution in tumor sites compared to traditional drug formulations. The system demonstrated superior antitumor efficacy without causing any weight loss in the mice model.
In this study, a novel carboxymethyl dextran (CMD)-based dual drug delivery system that delivering two water insoluble drugs to tumor sites was developed and evaluated for anticancer activities. Paclitaxel (PTX) and docosahexaenoic acid (DHA) were covalently coupled with CMD to generate CMD-DHA-PTX conjugate S and conjugate L with different linkers containing amino acids Gly-Gly or Lys-Gly-Gly, respectively. Both conjugates possessed high PTX loading contents and enhanced water solubility, as well as the ability of being self-assembled into nanoparticles with the nanoparticle size ranged from 88.7 nm to 94.7 nm. These two conjugates released free PTX continuously in plasma and cancer cells. The conjugate S exhibited improved pharmacokinetic parameters and higher distribution extent in tumor sites than the parent PTX, Abraxane and the conjugate L. The antitumor efficacy of these two conjugates outperformed parent PTX formulation and Abraxane in nude mice bearing breast cancer cells MCF-7. More importantly, the conjugate S treatment eliminated all the xenograft tumors without causing any mice body weight loss in mice model. This study revealed that the dextran-based dual drug conjugates may represent an effective and innovative way to deliver anticancer agents to a variety of tumors.
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