Abstract
A series of well-defined methoxy-poly(ethylene glycol)-block-polylactic acid (mPEG-b-PLA) diblock copolymers were successfully synthesized, characterized and used for the construction of anticancer nanoparticle delivery system. Nanoparticles (NPs) based on these polymers were prepared by employing the nanoprecipitation method, and they were non-covalently loaded with curcumin, curcumin-bortezomib model or curcumin-bortezomib complex (curc-BTZ). Both curcumin and bortezomib are rather hydrophobic and poorly water-soluble potent anticancer drugs with synergic effects forming together a pH-sensitive complex, stable at pH of blood plasma, yet hydrolytically labile at mildly acidic milieu typical for endosomes and interstitial space in solid tumors. PEG-Curcumin-loaded and curc-BTZ-loaded NPs with 100–150nm size showed the maximum cellular uptake by HeLa, MCF-7 and MDA-MB 231 cells after 3h. The NPs were located in the cytoplasm of the cells but not inside the nucleus. Bare NPs did not induce any cytotoxicity in the same cell lines in in vitro experiments, even at very high concentrations (up to 800µg/mL). NPs containing curcumin were cytotoxic with an IC50 of 25µg/mL, which corresponds to 2.5µg/mL of loaded curcumin. These results show that the efficacy of curcumin is significantly enhanced when using the NPs as carriers. The efficiency was further augmented through the complexation of BTZ with curcumin. When using free curc-BTZ-complex, MCF-7 cells were more sensitive to the free complex 18.8nM (IC50) than MDA-MB-231 cells 122.4nM (IC50). Nanoparticle formulations with these drugs caused significant cytotoxicity with 7.5nM (IC50) and 59.2nM (IC50) after 24h of the treatment.
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