Study Of Curcumin-Loaded Mpeg-P(Cl-CO-PDO) Polymeric Micelles

Curcumin is a polyphenolic compound isolated from the rhizome of the perennial herb Curcuma longa. It possesses a wide range of pharmacological effects including anti-oxidant, anti-inflammatory, and anti-tumor activities. but it has low water solubility, poor stability, and low bioavailability. Considering the advantages of polymeric micelles in the aspects of increasing the solubility and stability of drug, we synthesized biodegradable polyesters and prepared cucurmin-loaded polymeric micelles. The physicochemical characteristics of curcumin-loaded micelles were investigated. Also, stability, in vitro release behavior, anti-tumor activity of the micelles and in vivo pharmacokinetics were evaluated.Methoxy poly(ethylene glycol)-b-poly(ε-caprolactone) (MPEG- PCL) and methoxy poly(ethylene glycol)-b-poly(ε-caprolactone-co-p- dioxanone) [MPEG-P(CL-co-PDO)] copolymers were synthesized and characterized by NMR and gel permeation chromatography (GPC). The influence of copolymer compositions on the crystallinity and water solubility of the copolymers was investigated. We found that MPEG-P(CL-co-PDO) showed lower crystallinity and higher water solubility compared to MPEG-PCL. Then we prepared the MPEG-PCL and MPEG-P(CL-co-PDO) micelles and investigated the degradation of copolymer micelles in PBS over a period of four months. The result showed that the degradation of MPEG-P(CL-co-PDO) micelles is obviously faster than MPEG-PCL.MPEG-P(CL-co-PDO) micelles were selected as the curcumin carrier for the following research. Curcumin was successfully loaded into the MPEG-P(CL-co-PDO) micelles by a solid dispersion method with a high encapsulation efficiency (> 95%). The curcumin-loaded micelles were monodisperse (PDI < 0.15) with small particle sizes (around 30 nm). Then the stability of lyophilization and the reconstituted micelles was investigated. We found that these prepared MPEG-P(CL-co-PDO) micelles without any lyoprotective agents showed good stability during the lyophilization process and easy to reconstitute in water by simply shaking. The size and PDI of the reconstituted curcumin-loaded MPEG-P(CL-co-PDO) micelles were similar with those of the micelles before lyophilization. The stability of the reconstituted curcumin-loaded micelles experiments revealed that the stability decreased with the increase of PDO/CL ratios in the copolymers and loading contents of curcumin. Considering the water insolubility and instability, we selected a suitable release medium and investigated the in vitro release of curcumin from micelles. The results indicate that both the curcumin-loaded MPEG-P(CL-co-PDO) micelles could slowly release curcumin without any burst effect. Then we investigated the pharmacokinetics of curcumin-loaded micelles in rats. The concentration of curcumin in plasma was 12.7μg/mL at 5min and then decreased rapidly to 727 ng/mL at 35 min.Finally, we evaluated the in vitro cytotoxicity of curcumin-loaded micelles, and found that curcumin-loaded micelles markedly inhibited the growth of PC-3 human prostate cancer cells in a dose-dependent manner. Furthermore, we investigated the influence of cucumin-loaded micelles on PC-3 cell cycle, and found that it induced PC-3 cell cycle arrest at the S and G2/M phase.