ИСТИНА

Microgels based on N-isopropylacrylamide (NIPAM) can undergo reversible volume phase transition upon changes in the environment such as temperature, pH or ionic strength. In this work, this interesting feature was exploited to create a temperature-sensitive complex consisting of microgel and liposomes. The latter are being investigated as containers for drug delivery and several liposomal formulations have already been approved for use in medicine. Complexes have several advantages over conventional liposomes: 1) sensitivity to temperature; 2) possibility to deliver two or more different drugs with one carrier; 3) simultaneous infiltration of many liposomes into one cell. Microgels were synthesized by precipitation polymerization as previously described [1]. To make the microgel positively charged, 10 mol% of 3-(N,N-dimethylamino)propylmethacrylamide (DMAPMA) were added during the synthesis. This comonomer contains a pH-sensitive group which is fully protonated at pH less than 5 and carries no charge at pH higher than 9. Different amounts of cross-linker N,N-methylenebis-(acrylamide) were used to obtain a series of NIPAM-based microgels: 2, 4, 8 mol% (further refered to as 2, 4, 8, respectively). To obtain microgel-liposome complexes and to further discuss their properties one should begin with thorough investigation of the behavior of microgels in water media. In the first part of this work, we explored stability of microgel solutions, temperature-induced collapse of microgels, its reversibility and dependence on pH and ionic strength. Potentiometric titration was employed to determine that the amount of titratable groups is close to quantity of DMAPMA used in the synthesis. It was shown that at pH 7, when considerable part of DMAPMA groups are protonated, microgels 2 and 4 undergo reversible collapse in the range of temperatures 37-51°C; decrease in the effective diameter is more pronounced for less cross-linked microgel. Microgel 8, however, does not deswell. At pH 9, when DMAPMA groups are fully deprotonated, temperature-induced collapse is observed for all samples. Noteworthy, at these conditions, all studied samples aggregate at temperatures higher than 49°C, which is most likely due to the fact that microgel’s surface charge is not large enough to prevent aggregation. These observations lead to the conclusion that the possibility of volume phase transition and the ratio of diameters in swollen and deswollen states are determined by cross-linker content and charge density of microgel particles. The second part of this work was devoted to formation of microgel-liposome complexes. The maximum amount of liposomes that can be adsorbed onto microgel was estimated. No release of contents of liposomes was observed for at least 2 hours after the formation of complexes. Increase of temperature induces release from liposomes adsorbed onto microgel particles. Thereby this work demonstrates the possibility of formation of temperature-sensitive multiliposomal system based on microgel. This work was supported by Russian Science Foundation (14-13-00255).