A pH‐responsive carboxymethyl dextran‐based conjugate as a carrier of docetaxel for cancer therapy

Abstract

Although docetaxel is available for the treatment of various cancers, its clinical applications are limited by its poor water solubility and toxicity to normal cells, resulting in severe adverse effects. In this study, we synthesized a polymeric conjugate with an acid-labile ester linkage, consisting of carboxymethyl dextran (CMD) and docetaxel (DTX), as a potential anticancer drug delivery system. The conjugate exhibited sustained release of DTX in physiological buffer (pH 7.4), whereas its release rate increased remarkably under mildly acidic conditions (pH < 6.5), mimicking the intracellular environment. Cytotoxicity tests conducted in vitro demonstrated that the conjugate exhibited much higher toxicity to cancer cells under mildly acidic conditions than at physiological buffer (pH 7.4). These results implied that the ester linkage in the conjugate allowed for selective release of biologically active DTX under mildly acidic conditions. The in vivo biodistribution of a Cy5.5-labeled conjugate was observed using the noninvasive optical imaging technique after its systemic administration into tumor-bearing mice. The conjugate was effectively accumulated into the tumor site, which may have been because of an enhanced permeability and retention effect. In addition, in vivo antitumor efficacy of the conjugate was significantly higher than that of free DTX. Overall, the CMD-based conjugate might have promising potential as a carrier of DTX for cancer therapy.

The enhanced antitumor activity of the polymeric conjugate covalently coupled with docetaxel and docosahexaenoic acid

“…14 A CMD-pH-DTX conjugate was synthesized with carboxymethyl dextran (CMD) and DTX through an acid-labile ester linkage, which dramatically inhibited tumor growth than parent DTX. 15 Carboxymethyl dextran covalently coupled with paclitaxel via a gly-gly-phe-gly linker (AZ10992) exhibited excellent antitumor effects than parent paclitaxel. 16 DTX was encapsulated either in the bilayer of dextran-PLGA or in folate-conjugated dextran-PLGA nanoparticles and the antitumor potency of these DTX-loaded nanoparticles outperformed parent DTX in mice.…”

Self-assembled nanoparticles based on chondroitin sulfate-deoxycholic acid conjugates for docetaxel delivery: Effect of degree of substitution of deoxycholic acid

“…To address this problem, DTX has been successfully encapsulated to various nanocarriers such as carboxymethyl chitosan-poly(ethyleneglycol)-NGR peptide conjugated nanoparticles [26] and carboxymethyl dextran based conjugates [24]. These DTX-loaded nanoformulations showed improved drug solubility, enhanced cell internalization and therapeutic efficacy compared to free DTX.…”

“…However, the poor solubility in aqueous media and non-ignorable toxicity to normal tissues limit its clinical application [24,25]. To address this problem, DTX has been successfully encapsulated to various nanocarriers such as carboxymethyl chitosan-poly(ethyleneglycol)-NGR peptide conjugated nanoparticles [26] and carboxymethyl dextran based conjugates [24].…”

Recent Progress and Advances in Stimuli-Responsive Polymers for Cancer Therapy

“…These results indicated that the hydrazone linkages could be stable at physiological pH 7.4 but degrade effectively at the lower pH of endosomes and lysosomes (pH 5–6) to release the drug. In another recent report, Seung Han et al reported CMD and docetaxel (DTX) with ester linkers (Seung Han et al, 2015 ). The polymer conjugate exhibited sustained release of DTX in pH 7.4, and its release rate increased remarkably under mildly acidic conditions resembling the intracellular environment.…”