| Curcumin(CUR) is a low molecular weight, natural polyphenolic compound that is isolated from the rhizome of turmeric(Curcuma longa). It has a low intrinsic toxicity with a wide range of pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial, anti amyloid, and antitumor properties. Preclinical studies of CUR have shown its ability to inhibit a variety of cancer cell lines. The ability of CUR to induce apoptosis in cancer cells without cytotoxic effects on healthy cells makes it a potential compound against cancer. However, its water insolubility, instability, quick metabolism, and poor bioavailability limit its development in clinic.PEG-PCL2 copolymer is a amphiphilic diblock copolymer that has distinct lipophilic and hydrophilous fragments, which can self-assemble to form micelle with an internal lipophilic core and external hydrophilous shell in aqueous medium. The diblock copolymer has been used to encapsulate lipid drugs under hydrophobic interactions to enhance drug’s solubility or activity. Recent study revealed that biotin receptors were over expressed on numerous tumors. For this reason, copolymers modified with biotin would like to selectively deliver anticancer drug to tumor tissues or organs for improving their chemotherapeutic efficacy with less side-effects.In this study, the novel Biotin-PEG-PCL2 copolymer was synthesized through O-alkylation, alkaline ring-opening, radical addition, ring-opening polymerization and acylation reaction with monoallyloxy poly(ethylene glycol) ether as raw material. The structure of the biotin-conjugated copolymer was confirmed by 1H-NMR, GPC. Then preparation and quantitative analysis of CUR-loaded micelle were studied, and diblock copolymer CMC, particle diameter distribution of drug-loaded micelle, Zeta potential,microphology,X-ray diffraction, infrared spectroscopy and hemolytic test were also determined. The CUR-loaded micelle in vitro release behavior and anticance activities were also studied. CUR’s extraction from plama in rat and HPLC quantitative methodology were constructed, and in vivo pharmacokinetics were researched.Micelles were prepared by thin-film hydration, and the results demonstrated that mean entrapment effiency, mean drug-loading rate, mean particle parameter and Zeta potential of CUR-loaded biotin-PEG-PCL2 micelle were 93.83±0.26%, 11.94±0.13%, 49.28±1.46 nm and 4.62 m V, respectively. The shape of CUR-loaded biotin-PEG–PCL2 micelles was discontinuously globular in the TEM photograph. The solubility of CUR in aqueous medium was increased to 1.823 mg/m L, which was 1.704×105 times higher than that of free CUR. FT-IR analysis proved the existence of drug in micellar curcumin formulation. XRD study demonstrated that CUR in micelles was in disordered phase. The hemolysis study showed that the micelle hemolysis rate was less than 5% when biotin-PEG–PCL2 was given by the route of injection.The in vitro release showed CUR’s controlled release and biotin-unconjugated micelles provided a faster curcumin release than biotin-conjugated micelles in the whole period of release experiment. In vitro cellular uptake and cytotoxicity tests indicated that biotin could promote the uptake of curcumin-loaded micelles compared with biotin-unconjugated micelles, showing better anticancer activity for a long incubation time. |
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