| In rencent years, the stimuli-sensitive polymeric micelles have received extensive attention in biomedical application in the past several decades due to their sense to the external physical or chemical stimuli such as temperature, pH, ionic strength, light, and biomolecules. Among the stimuli-sensitive polymeric micelles, temperature and pH-responsive polymeric micelles were the most widely studied in drug delivery applications. Temperature-sensitive micelles which undergo a volume phase-transition at a critical temperature, namely, lower critical solution temperature (LCST) has practical advantages both in vitro and in vivo. Temperature-sensitive polymers exhibit a hydrophilic-to-hydrophobic transition with increasing temperature and have been widely studied for drug delivery. To date, Most thermo-responsive (co)polymers are synthesized from poly(N-isopropylacrylamide) P(NIPAm), whose LCST (32?C) is close to physiological temperature, 37?C. However, the P(NIPAm) block as the temperature-responsive micelles outer shell is easy becomes hydrophobic at physiological temperature, which could result in the copolymer precipitation and reduce their biocompatibility in the circulation. In our study, for NIPAm, we examined its copolymerization with AA with varying composition. For P(NIPAm-co-AA), their temperature-induced transition over broad and useful compositional an pH ranges was obtained. Different types micelles comprised P(NIPAm-co-AA) as the Thermo- and pH-sensitive hydrophilic shell were prepared. Their drug delivery property on folic acid under different conditions was also investigated.Firstly, the thermo- and amphiphilic ABC triblock copolymers of poly(ethylene glycol)-b-poly(N-isoproylacrylamide-co-acrylic acid)-b-poly(methyl methacrylate) (PEG-b-P(NIPAm-a-AA)-b-PMMA) were synthesized by reversible addition fragmentation chain transfer (RAFT) radical polymerization using a novel PEG-based trithiocarbonate as the RAFT agent. The triblock polymers were characterized by FTIR, 1H NMR and GPC, respectively. The copolymers were capable of undergoing supramolecular self-assembly to thermo-response nanosized micelles in aqueous media. The results determined by transmission electron microscopy (TEM) and dynamic light scattering instrument (DLS) were shown that the micelles were regularly spherical in shape with an average hydrodynamic diameter around 120 nm. The folic acid (FA)-loaded micelles were prepared and the controlled release of folic acid under different conditions was also studied for their application. The in vitro release behavior showed a dramatic thermo-responsive fast/slow switching presumably associated with the temperature-responsive structural changes of a micellar shell structure.Secondly, a series of thermoresponsive random copolymers, P(NIPAm-co-AA and their diblock copolymers with 2-(dimethylamino) ethyl methacrylate (DMAEMA) or AA were synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization. In aqueous media, this pair of oppositely-charged diblock copolymers could self-assemble into stable polyion complex micelles (PICMs). The effects of pH, temperature and ionicstrength (Ic) on the structure of the PICMs were studied by transmission electron micrographs (TEM) and dynamic light scattering (DLS), respectively. The results indicated that the hydrodynamic diameters of the micelles increased with increasing ionic strength (from 0 M to 1.1 M) of the aqueous solution. The high ionic strength (> 1.1 M) could lead to dissociation of the micelles. When the ionic strength was regulated to 0.15 M, the phenomenon was also observed with decreasing the pH of the aqueous solution. The dissociation of the micelles was accelerated at a low pH (< 5.0) and the higher temperature (> LCST). The FA-loading PICMs was also investigated for FA release behavior at different experimental conditions. The results suggest that novel thermo- and pH-responsive PIC micelles have great potential in drug delivery systems. |
