Preparation of novel ferrocene-based shell cross-linked thermoresponsive hybrid micelles with antitumor efficacy

The shell cross-linked (SCL) thermoresponsive hybrid poly(N-isopropylacrylamide-co-aminoethyl methacrylate)-b-polymethyl methacrylate (P(NIPAAm-co-AMA)-b-PMMA) micelle consisting of a cross-linked thermoresponsive hybrid shell and a hydrophobic core domain was fabricated via a two-step process: micellization of P(NIPAAm-co-AMA)-b-PMMA in aqueous solution followed by cross-linking of the hydrophilic shell layer via the amidation reaction between the amine groups of AMA units and the carboxylic acid functions of 1,1'-ferrocenedicarboxylic acid. The SCL micelle showed reversible dispersion/aggregation in response to the temperature cycles through the lower critical solution temperature (LCST) of the thermoresponsive hybrid shell at around 36 degrees C, observed by turbidity measurements and dynamic light scattering (DLS). Besides the usage as an inorganic difunctional cross-linker, the inorganic ferrocene segment further endowed the SCL hybrid micelle with the antitumor efficacy, namely, the resulting SCL micelle exhibited a remarkable cytotoxic effect for HeLa cells with a very low IC50. The results showed that the SCL hybrid micelle developed in this study could be potentially used as an antitumor agent, which is unique compared to the conventional tumor therapy by using the antitumor drug loaded in the micellar core.