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.

Glycan-based scaffolds and nanoparticles as drug delivery system in cancer therapy

“…As drug delivery carriers, some DEX-based DOX encapsulated and chemically conjugated NPs have shown excellent antitumor activity (125-127). Peng et al synthesized a polysaccharide DEX-based conjugate for the selective delivery of DOX (128). In the field of oral cancer treatment, nanotechnology also has emerged as an innovative tool that has been shown to overcome the limitations of conventional drug therapies (129).…”

Marine biomaterials in biomedical nano/micro-systems

“…Additionally, it can hinder tumor invasion and metastasis by reducing tumor cell rolling, adhesion, and migration. Importantly, previous research has shown that DHA can increase the susceptibility of cancer cells to chemotherapeutic agents without amplifying the toxicity to healthy tissues [ 209 , 210 ]. Both of these factors have prompted researchers to incorporate marine-derived PUFAs into drug delivery systems as assemblers or drug loaders for the purpose of synthetically enhancing cancer treatment.…”