title: Vanadium(V) and -(IV) complexes of anionic polysaccharides: Controlled release pharmaceutical formulations and models of vanadium biotransformation products.
abstract: Uncontrolled reactions in biological media are a main obstacle for clinical translation of V-based anti-diabetic or anti-cancer pro-drugs. We investigated the use of controlled-release pharmaceutical formulations to ameliorate this issue with a series of V(V) and (IV) complexes of anionic polysaccharides. Carboxymethyl cellulose, xanthan gum, or alginic acid formulations were prepared by the reactions of [VO4](3-) with one or two molar equivalents of biological reductants, L-ascorbic acid (AA) or L-cysteine (Cys), in the presence of excess polysaccharide at pH~7 or pH~4. XANES studies with the use of a previously developed library of model V(V), V(IV) and V(III) complexes showed that reactions in the presence of AA led mostly to the mixtures of five- and six-coordinate V(IV) species, while the reactions in the presence of Cys led predominantly to the mixtures of five- and six-coordinate V(V) species. The XANES spectra of some of these samples closely matched those reported previously for [VO4](3-) biotransformation products in isolated blood plasma, red blood cells, or cultured adipocytes, which supports the hypothesis that modified polysaccharides are major binders of V(V) and V(IV) in biological systems. Studies by EPR spectroscopy suggested predominant V(IV)-carboxylato binding in complexes with polysaccharides. One of the isolated products (a V(IV)-alginato complex) showed selective release of low-molecular-mass V species at pH~8, but not at pH~2, which makes it a promising lead for the development of V-containing formulations for oral administration that are stable in the stomach, but release the active ingredient in the intestines.
authors.affiliation: School of Chemistry The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Kremer
authors.affiliation: School of Chemistry The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Andrew I
authors.initials: AI
authors.lastname: McLeod
authors.affiliation: School of Chemistry The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Jade B
authors.initials: JB
authors.lastname: Aitken
authors.affiliation: School of Chemistry The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Aviva
authors.initials: A
authors.lastname: Levina
authors.affiliation: School of Chemistry The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: peter.lay@sydney.edu.au.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Lay
mesh_terms: D000464:Alginates / Q000737:chemistry*; D001205:Ascorbic Acid / Q000737:chemistry; D002266:Carboxymethylcellulose Sodium / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003545:Cysteine / Q000737:chemistry; D004339:Drug Compounding / Q000295:instrumentation; D065546:Drug Liberation; D005750:Gastric Juice / Q000737:chemistry; D020723:Glucuronic Acid / Q000737:chemistry; D006603:Hexuronic Acids / Q000737:chemistry; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry*; D011135:Polysaccharides, Bacterial / Q000737:chemistry*; D014638:Vanadates / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: D000464:Alginates; D006603:Hexuronic Acids; D007004:Hypoglycemic Agents; D011135:Polysaccharides, Bacterial; D014638:Vanadates; D020723:Glucuronic Acid; D002266:Carboxymethylcellulose Sodium; D003545:Cysteine; D001205:Ascorbic Acid; C002563:xanthan gum
keywords: EPR; Oral V anti-diabetic drugs; Pharmaceutical formulations with anionic polysaccharides; XANES speciation