Hydrotropic polymers: Synthesis and characterization of polymers containing picolylnicotinamide moieties

Our previous studies on low molecular weight hydrotropes showed that nicotinamide derivatives increased the aqueous solubility of paclitaxel by several orders of magnitude. We were interested in knowing whether the polymeric forms of those low molecular weight hydrotropes could maintain hydrotropic properties. N-Picolylnicotinamide (PNA) was one of the best hydrotropes identified for paclitaxel, and polymers based on PNA were synthesized and tested for their hydrotropic properties. The pendent hydrotropic PNA moieties were attached to the polymer backbone through either an oligo(ethylene glycol) or a phenyl group as a spacer. The PNA moiety was bound to the polymer backbone either at the 2-position or at the 6-position of the pyridine ring of nicotinamide to result in poly(2-(4-vinylbenzyloxy)-N-picolylnicotinamide) (P(2-VBOPNA)) or poly(6-(4-vinylbenzyloxy)-N-picolylnicotinamide) (P(6-VBOPNA)), respectively. The ability of PNA-containing polymers to increase the aqueous solubility of paclitaxel was examined by measuring the concentration of dissolved paclitaxel in various polymer concentrations. The PNA-containing polymers increased the water solubility of paclitaxel by more than 3 orders of magnitude, and the hydrotropic property of the polymers was pronounced even at low polymer concentrations. P(2-VBOPNA) showed a higher hydrotropic property than P(6-VBOPNA). At the polymer concentration of 40 mg/mL, the water solubility of paclitaxel was enhanced up to 700-fold, depending on the type of polymer used. On the other hand, PNA displayed an efficient solubilizing ability at above 100 mg/mL. Fluorescence study indicated that the hydrotropic polymers formed noncovalent molecular assemblies through the self-association of pendent hydrotropic PNA moieties at much lower concentration range ((2.1-4.6) x 10(-2) mg/mL) than PNA (22 mg/mL). This observation supports the high solubilization abilities of hydrotropic polymers for paclitaxel. These results suggest a hydrotropic property of the PNA-based polymers operates under the same mechanism as PNA itself. The cross-linked networks of PNA-based hydrotropic polymers (i.e., hydrotropic hydrogels) were as effective as water-soluble polymers in solubilizing paclitaxel. This study shows that hydrotropic polymers and hydrogels that are prepared based on low molecular weight hydrotropic agent are as effective as the low molecular weight counterpart.