Hyaluronic acid as drug delivery for sodium butyrate: Improvement of the anti-proliferative activity on a breast-cancer cell line

The potential clinical utility of sodium butyrate, a natural compound known to inhibit tumor-cell growth, is hampered by the difficulty of achieving e ffective in-vivo concentrations. The short half-life (about 5 minutes) of s odium butyrate results in rapid metabolism and excretion. To increase the a vailability of sodium butyrate over a longer period of time, we co-valently linked it to hyaluronic acid (a component of the extracellular matrix). It s major advantages as a drug carrier consist in its high biocompatibility a nd its ability to bind CD44, a specific membrane receptor frequently overex pressed on the tumor-cell surface. The degree of substitution of hyaluronic acid with butyrate residues ranged from d.s. = 0.10 to d.s. = 2.24 (1.8-28 .4% w/w), The biological activity of hyaluronic-acid-butyric-ester derivati ves was evaluated in terms of the inhibition of the growth of the MCF7 cell line and compared with that of sodium butyrate, After 6 days of treatment, we observed a progressive improvement of the anti-proliferative activity u p to d.s. = 0.20; thereafter, the anti-proliferative effect of the ester de rivatives decreased. Fluorescence microscopy showed that after 2 hr of trea tment fluorescein labelled compounds appeared to be almost completely inter nalized into MCF7 cells, expressing CD44 standard and variant isoforms, The se findings indicate that hyaluronic acid could offer an important advantag e in drug delivery, in addition to its biocompatibility: the ability to bin d to CD44, which are known to be frequently over-expressed on the tumor-cel l surface. (C) 1999 Wiley-Liss, Inc.