Synthesis and Selective Cytotoxicity of a Hyaluronic Acid−Antitumor Bioconjugate

TLDR

A cell‑targeted prodrug was developed for the anti‑cancer drug Taxol by using hyaluronic acid (HA) as the drug carrier. The authors synthesized HA–Taxol bioconjugates by linking Taxol to adipic dihydrazide‑modified HA via a succinate ester, producing variants with differing ADH levels and drug loadings, and created a fluorescent BODIPY–HA probe to visualize cell targeting and uptake by confocal microscopy. HA–Taxol conjugates selectively killed HA‑receptor–overexpressing breast, colon, and ovarian cancer cells while sparing mouse fibroblasts, and this selective cytotoxicity matched confocal microscopy showing BODIPY–HA uptake only in cancer cells; the HA carrier itself was nontoxic.

Abstract

A cell-targeted prodrug was developed for the anti-cancer drug Taxol, using hyaluronic acid (HA) as the drug carrier. HA−Taxol bioconjugates were synthesized by linking the Taxol 2'-OH via a succinate ester to adipic dihydrazide-modified HA (HA-ADH). The coupling of Taxol-NHS ester and HA-ADH provided several HA bioconjugates with different levels of ADH modification and different Taxol loadings. A fluorescent BODIPY−HA was also synthesized to illustrate cell targeting and uptake of chemically modified HA using confocal microscopy. HA−Taxol conjugates showed selective toxicity toward the human cancer cell lines (breast, colon, and ovarian) that are known to overexpress HA receptors, while no toxicity was observed toward a mouse fibroblast cell line at the same concentrations used with the cancer cells. The drug carrier HA-ADH was completely nontoxic. The selective cytotoxicity is consistent with the results from confocal microscopy, which demonstrated that BODIPY−HA only entered the cancer cell lines.