PH-Sensitive Prodrug Micellar Nanoparticles As A Novel Platform For Cancer Chemotherapy

A kind of pH sensitive curcumin prodrug micellar nanoparticles were chemically prepared in this review. D,L-lactide was ring-opening polymerized with mPEG2000 which act as an initiator to generate polyethylene glycol monomethyl ether-polylactic acid. Succinic anhydride and ethyleneoxy ethanol was used to modify m PEG-PLA and introduce an acetal bond between single-ended curcumin and mPEG-PLA. Thus,the synthetic mPEG-PLA-acetal-cur showed pH sensitive ability. By contrast,mPEG-PLA-cur was synthesized. Both of the two prodrug polymers would self-assemble into spherical micelles after dissolved in water.The structure of mPEG-PLA-acetal-cur and mPEG-PLA-cur have been characterized by 1H-NMR. Appearance of peak at σ 4.70 proved successful synthesis of acetal bond, and the curcumin grafting rate was 71% and 63% respectively. Using fluorescent chromatography to determine critical micelle concentration and the CMC value of the two polymers were 7.2 ± 0.8 μg/mL and 5.1 ± 1.2 μg/mL, which certified good stabilities of the two kind of curcumin prodrug micelles. Dynamic light scattering method and transmission electron microscopy was applied to characterize size distribution and morphology of polymer micelles. Both two micelles have better dispersion, and the particle size was about 90 nm, and 100 nm separately. TEM results show that the spherical polymeric micelles were uniformly distributed on the copper network. The drug loading efficiency was measured by UV method. The drug loading of mPEG-PLA-acetal-cur and mPEG-PLA-cur were 7.87% ± 2.39% and 6.63% ±0.04%.Selecting phosphate-citrate buffer of pH 5.0, pH 6.0 and pH 7.4 as release medium to conduct the drug release experiment of mPEG-PLA-acetal-cur. The results showed that the cumulative release rate of curcumin was 45.6%, 36.4% and 19.6%respectively in three pH conditions. In addition, curcumin release in acidic medium(pH 5.0 and pH 6.0) was significantly faster than neutral release medium(pH 7.4).Thus, pH sensitive nature of m PEG-PLA-acetal-cur was confirmed. The drug cumulative release rate of mPEG-PLA-cur in acid medium was significantly lower than mPEG-PLA-acetal-cur, which further proved the superiority of the synthesized curcumin prodrug micellar nanoparticles.The cytotoxicity and cellular uptake of the different samples were investigatedon HepG2 cell. the cytotoxicity result showed that acetal-linked curcumin prodrug polymer had stronger cytotoxicity than ester-linked curcumin prodrug polymer. Drugs were mainly distributed in the cytoplasm and cell membrane when uptaked into HepG2 cell, and almost no drug appear in nucleus.