| Curcumin (Cur), bis(4-hydroxy-3-methoxyphenyl)-1,6-diene-3,5-dione (Fig.1), is a the traditional Chinese medicine, and is the polyphenol compound derived from the rhizome of plant Curcuma longa. Recently, it has been reported that Cur has a wide range of pharmacologic activities such as anti-inflammation, anti-human immuno-deficiency virus, anti-microbial, anti-oxidant, anti-parasitic, anti-mutagenic and anti-cancer with low or no intrinsic toxicity. Among these pharmacologic activities, the anti-cancer activity has almost attracted the highest attention from researchers. Cur can prevent and inhibit the generation, vegetation and metastasis of many kinds of tumor cells, such as breast cancer, cervical cancer, colon carcinoma, stomach cancer, liver cancer, epithelial cell carcinoma, pancreatic cancer and so on. Despite of the excellent anti-cancer properties, the application of Cur in clinic has been limited because of its low solubility in aqueous solution and rapid degradation in physiological conditions. Therefore, it will be needed to improve the stability, solubility and bioactivity of Cur.Recently, studies show that polymeric micelle is one of the most attractive alternatives for hydrophobic drugs to improve their bioavailability. Amphiphilic block copolymers can form nano-sized aggregates with core-shell structure which can solubilize poorly water soluble drugs. Compared with other delivery systems, the polymeric micelle has many advantages as followed:(ⅰ) To entrap considerable hydrophobic drugs to improve the apparent dissolvability of drugs and protect drugs that are sensitive to the surrounding environment because of the hydrophobic inner core;(ii) To reduce the nonspecific uptake by the reticuloendothelial system (RES), and thus to prolong the circulation time in the blood due to its flexible or hydrophilic outer core;(iii) To achieve the possible targeting delivery through surface modification by leading in targeting molecules.Folate receptor is highly expressed in several human tumor cells including cancers of the breast, liver, uterus, testis, brain, colon and lung. Folate and folate conjugates can bind to the folate receptor with high affinity and enter cells by receptor-mediated endocytosis, so the folate-drug delivery carriers can transfer the therapeutical agent to rumour cells which highly express folate receptor. Since the folate receptor-mediated endocytosis was discovered, folate based candidates have been widely used for targeted drug delivery. In the present study, poly(ethylene glycol)-poly(lactic acid)(PEG-PLA), which is one of biocompatible and biodegradable materials, was used as a delivery carrier to improve the solubility of Cur in aqueous solution. Aiming at strengthening the drug’s antiangiogenic efficacy and improving the antitumor efficacy, a folate targeting amphiphilic copolymer, FA-PEG-PLA, was synthesized and a folate conjugated polymeric micelle for Cur (Cur-FPP) was prepared.The main objective of this study was to evaluate the potential of a folate-modified curcumin (Cur) loaded micelle (Cur-FPP) as a cancer-targeted drug delivery system. In this study, the targeting material, Folate-PEG3ooo-PLA2ooo, was synthesized by the amide bond formation reaction. And the Cur loaded micelles were prepared by thin-film hydration method with mPEG2ooo-PLA2ooo (Cur-PP) or mPEG2ooo-PLA2ooo and Folate-PEG3000-PLA2000(Cur-FPP) as carrier. A central composite design (CCD) was used to optimize the formulation, and the optimized Cur-RPP was prepared with the ratio of Folate-PEG3ooo-PLA2ooo and mPEG2ooo-PLA2ooo at1:9. The average size of the mixed micelles was70nm, the encapsulating efficiency and drug-loading were80.7±2.3%and4.8±1.9%, respectively. Compared with the Cur propylene glycol solution, the in vitro release of Cur from Cur-FPP showed the sustained-release property. The in vitro cytotoxicity and cellular uptake assay presented that the Cur-FPPs could increase the cytotoxicity and cellular uptake of Cur on MCF-7and HepG2cells. The pharmacokinetic studies in rats showed that Cur loaded micelle formulations increased the half-life of Cur3-fold that of the solubilized Cur. All the results demonstrated that folate-modified Cur mixed micelles might serve as a potential nanocarrier to improve the solubility and anti-cancer activity of Cur. |
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