Ionic liquid-doped and p-NIPAAm-based copolymer (p-NIBIm): extraordinary drug-entrapping and -releasing behaviors at 38–42 °C

Abstract

Ionic liquid (IL)-doping of the temperature responsive p-NIPAAm was achieved by radical copolymerization of N-isopropyl acryl amide (NIPAAm; 90 mol%) and 1-butyl-3-vinylimidazolium bromide ([BVIm]Br; 10 mol%) to give a new temperature responsive copolymer (p-NIBIm). The as-prepared p-NIBIm copolymer showed a highly increased zeta potential value and optimal LCST (lower critical solution temperatures) value, respectively, +9.8 mV at pH = 7 and 38.2 °C, compared to those (+0.3 mV at pH = 7 and 32.1 °C) of p-NIPAAm. The temperature-dependent size change of the p-NIBIm micelles was determined in the range from 25 to 45 °C by SEM under dry conditions and by a zeta sizer under wet conditions, showing a certain size contraction from 253 ± 12.1 to 90.5 ± 7.8 nm in diameter (about 95.4% of volume contraction). The thermo-sensitive behavior to entrap BSA protein at body temperature (37 °C) and to release the protein between 38–42 °C (near the LCST) were also tested by sizing of the complexes of p-NIBIm/BSA using a zeta sizer and also by a colorimetric assay (Bio-Rad DC Protein Assay), resulting in a maximum entrapment of 1.02 mg BSA for 1.0 mg of the polymer at body temperature (37 °C) and in a maximum release of 0.73 mg BSA for 1.0 mg of the polymer (about 73% release of the entrapped amount) in the temperature range of 38–42 °C. Toxicity of the p-NIBIm micelles (in the range of <0.125 mg mL⁻¹) without drug for human embryonic kidney (HEK 293) cells was minimal in vitro. These results revealed that the IL-doped and temperature responsive co-polymeric systems have a very high applicability as a novel delivery system for charged (or polar) molecules as a natural (or synthetic) drug and DNA.