A new hyaluronic acid pH sensitive derivative obtained by ATRP for potential oral administration of proteins

Abstract

Atom transfer radical polymerization (ATRP) has been successfully employed to obtain a new derivative of hyaluronic acid (HA) able to change its solubility as a function of external pH and then to be potentially useful for intestinal release of bioactive molecules, included enzymes and proteins.In particular, a macroinitiator has been prepared by linking 2-bromo-2-methypropionic acid (BMP) to the amino groups of ethylenediamino derivative of tetrabutyl ammonium salt of HA (HA-TBA-EDA). This macroinititor, named HA-TBA-EDA-BMP has been used for the ATRP of sodium methacrylate (MANa) using a complex of Cu(I) and 2,2 ′ -bipyridyl (Byp) as a catalyst.The resulting copolymer, named HA-EDA-BMP-MANa, has been characterized by 1 H NMR and size exclusion chromatography (SEC) analyses. A turbidimetric analysis has showed its pH sensitive behavior, being insoluble in simulated gastric fluid but soluble when pH increases more than 2.5. To confirm the ability of HA-EDA-BMP-MANa in protecting peptides or proteins from denaturation in acidic medium, ␣-chymotrypsin has been chosen as a model of protein molecule and its activity has been evaluated after entrapment into HA-EDA-BMP-MANa chains and treatment under simulated gastric conditions. Finally, cell compatibility has been evaluated by performing a MTS assay on murine dermal fibroblasts cultured with HA-EDA-BMP-MANa solutions.

A polycarboxylic/amino functionalized hyaluronic acid derivative for the production of pH sensible hydrogels in the prevention of bacterial adhesion on biomedical surfaces

“…In particular, the HA-EDA-BMP macroinitiator produced had a functionalization in BMP equal to 37 AE 9 mol% and an amount of unreacted EDA groups equal to 30 AE 5 mol% as calculated via 1 H NMR and colorimetric assay (NTSB). The HA-TBA-EDA-BMP has been employed as a macroinitiator for the polymerization of the MANa monomer (Fiorica et al, 2013). The obtained product, named HA-EDA-BMP-MANa, showed a derivatization degree in MANa equal to 76 AE 2 mol%.…”

“…Synthesis of HA-EDA-2-bromo-2-methylpropionic-methacrylate sodium salt (HA-EDA-BMP-MANa) copolymer through ATRP HA-EDA-BMP-MANa copolymer was synthesized according to a procedure reported in our previous work (Fiorica et al, 2013), by modifying some reaction parameters. In particular 50 mg of HA-TBA-EDA-BMP were dissolved in 10 ml of twice distilled water, then the MANa monomer was added in order to obtain a molar ratio between vinyl monomer and BMP equal to 100.…”

“…The development of a biomatrix that not only could be able to modulate the release of antibiotic, but also could have per se anti-biofilm activity, would have great interest. Recently our research group proposed a polycarboxylic and amino functionalized, pH sensible HA derivative, obtained via atom transfer radical polymerization (ATRP) (HA-EDA-BMP-MANa) (Fiorica et al, 2013). In this study the pH sensibility of the polymer HA-EDA-BMP-MANa has been exploited to prepare vancomycin releasing hydrogels.…”

pH-Responsive carriers for oral drug delivery: challenges and opportunities of current platforms

“…HA, an anionic glycosaminoglycan, is also commonly used in drug delivery formulations. The presence of one carboxylic group per repeat unit imparts a pH-responsiveness, (Bell & Peppas, 1996;Lowman et al, 1999;Ichikawa & Peppas, 2003 (Huang et al, 2000), hemoglobin (George & Abraham, 2006), melatonin (Chen et al, 2004a), vaccines (Chen et al, 2004b;Kulkarni et al, 2001), peptides (Edelman et al, 2000), probiotic yeast (Rasmussen et al, 2003), cedroxil (Peppas & Huang, 2004) Hyaluronic acid-based Natural Small intestine Insulin (Hurteaux et al, 2005), thrombin (Kim et al, 2002), a-chymotrypsin (Fiorica et al, 2013) Cationic Chitosan-based Natural Small intestine Insulin (Li et al, 2016), BSA (Patel & Amiji, 1996;Kamei et al, 2009 Small intestine and colon Dexamethasone (Das & Subuddhi, 2015) which is enhanced in crosslinked hydrogel network (Fiorica et al, 2013). The pH-responsive behavior of photocrosslinked HA hydrogels for the release of thrombin was evaluated by Pitarresi et al (2004).…”

Hyaluronic Acid Bioconjugates for the Delivery of Bioactive Molecules

“…Nanoparticles for intestinal release to proteins were produced by exploiting the HA pH sensitivity in aqueous environment and with a specific crosslinking [87]. An ethylenediamine derivative of HA was synthesized as a macroinitiator for the atom transfer radical polymerization of sodium methacrylate monomer.…”