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 effective in-vivo concentrations. The short half-life (about 5 minutes) of sodium butyrate results in rapid metabolism and excretion. To increase the availability of sodium butyrate over a longer period of time, we co-valently linked it to hyaluronic acid (a component of the extracellular matrix). Its major advantages as a drug carrier consist in its high biocompatibility and its ability to bind CD44, a specific membrane receptor frequently over-expressed 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 derivatives 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 up to d.s.=0.20; thereafter, the anti-proliferative effect of the ester derivatives decreased. Fluorescence microscopy showed that after 2 hr of treatment fluorescein-labelled compounds appeared to be almost completely internalized into MCF7 cells, expressing CD44 standard and variant isoforms. These findings indicate that hyaluronic acid could offer an important advantage in drug delivery, in addition to its biocompatibility: the ability to bind to CD44, which are known to be frequently over-expressed on the tumor-cell surface.
Coradini
D
D
Oncologia Sperimentale C, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy. coradini@istitutotumori.mi.it
Pellizzaro
C
C
Miglierini
G
G
Daidone
M G
MG
Perbellini
A
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002087:Butyrates / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis / Q000378:metabolism; D006820:Hyaluronic Acid / Q000493:pharmacokinetics / Q000494:pharmacology*; D008970:Molecular Weight; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002087:Butyrates; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid