Polysaccharide dextran-based conjugate for selective co-delivery of two synergistic drugs docetaxel and docosahexaenoic acid to tumor cells

Abstract

Most chemotherapeutic agents are nonspecific distribution and cause systemic toxicities. Polysaccharide-based conjugates are promising strategies to overcome these drawbacks. To this end, two synergistic drugs docetaxel (DTX) and docosahexaenoic acid (DHA) were independently covalently bonded through individual linkers to dextran (100 kDa) to produce a novel dual-drug conjugate dextran–DHA–DTX. The single-drug conjugates dextran–DHA and dextran–DTX were also prepared for comparison. Fluorescent dye Cy7.5-based conjugates dextran–Cy7.5 and dextran–DHA–Cy7.5 were synthesized for cellular uptake study. The dual-drug conjugate dextran–DHA–DTX self-assembled into nanoparticles with the diameter of 102.3 ± 8.3 nm and demonstrated enhanced water solubility and improved pharmacokinetic profiles. Cellular uptake results showed that the dual-drug conjugate entered cells more than the parent DTX by determining the intracellular DTX contents via HPLC/MS analysis and by determining the fluorescent intensity of dextran-Cy7.5 and dextran–DHA–Cy7.5. Importantly, the dual-drug conjugate dextran–DHA–DTX significantly accumulated in tumor tissues and dramatically reduced the DTX concentrations in normal tissues. The dual-drug conjugate completely eradicated all the MCF-7 xenograft tumors without obvious side effects and showed more superior antitumor activity than parent DTX and single-drug conjugate dextran–DTX and dextran–DHA. Both in vitro and in vivo studies showed that DHA enhanced the antitumor activity of dextran–DTX. The polysaccharide dextran-based dual-drug conjugates may represent an effective way to improve the chemotherapeutic agents.

Keywords:

• Docetaxel
• dextran
• docosahexaenoic acid
• conjugate
• nanomedicine
• combined therapy

Disclosure statement

The authors report there are no competing interests to declare.

Ethical approval statement

All animal experiments were carried out and approved by the laboratory animal ethical and welfare committee of Shandong University Cheeloo College Medicine (No. 21069). All mice were housed in a specific pathogen-free environment at a constant temperature and humidity with free access to standard food and water. Mice were acclimatized for at least a week before experiments. At the end of the experiment, mice were euthanized in a carbon dioxide chamber.

Additional information

Funding

This work was supported by Shandong Province Major Science and Technology Innovation Project under grant No. 2018CXGC1402.