Nanohydrogel withN,N′-bis(acryloyl)cystine crosslinker for high drug loading
Substantially improved hydrogel particles based on poly(N-isopropylacrylamide) (pNIPA) have been obtained. First, as a result of replacing commercially available N,N′-bis(acryloyl)cystamine (BAC), the crosslinker, with acryloyl derivative of cystine containing a carboxylic group (BISS), the hydrogel particles acquired improved stability vs. ionic strength and allowed further chemical modification of the chains, including the attachment of drug molecules. Next, a redox-initiated aqueous precipitation polymerization via the semi-batch method was used. This led to substantially increased BISS content and diminished size of the nanoparticles that made them suitable to an endocytic process. In addition, the obtained nanogels revealed high loading capacity of anticancer drug vs. dry gel (circa 16%) and they exhibited much better stability and enhanced drug release under the typical conditions existing in cancer cells. Size of obtained nanogels was investigated by dynamic light scattering (DLS). It appeared that nanoparticle size was in the range from ca. 40 to 200 nm. In 0.01 M solution of glutathione (GSH) the -S-S- bonds were reduced and the nanogel particles were degraded. This could be seen in obtained SEM and TEM micrographs. The cytotoxicity investigation against the HeLa cells showed that DOX loaded nanogels were more cytotoxic (IC50 = 0.51 μM) than free DOX (IC50 = 0.83 μM), while unloaded nanogels did not inhibit proliferation of the cells. It was also found that the nanogels loaded with DOX reached a high intracellular concentration in HeLa cells just after 2 h while free DOX needed 6 h for that.