Preparation And Evaluation Of A Novel Curcumin-loaded MPEG-PCL-Phe(Boc) Micelles

Curcumin, a polyphenolic natural extract of curcuma longa, exhibits a wide range of pharmacological effects including anti-oxidant, anti-inflammatory, and anti-tumor activities in various preclinical models, In addition, curcumin is nontoxic to human body. However, curcumin’s low systemic bioavailability also became apparent, which has been mainly attributed to its water insolubility and severe liver first pass effect. In the present study, N-t-butoxycarbonyl-phenylalanine (Boc-Phe) terminated monomethoxyl poly(ethylene glycol)-b-poly(ε-caprolactone) block copolymer (mPEG-PCL-Phe(Boc)) was synthesized and characterized by’H-NMR and GPC. The curcumin-loaded mPEG-PCL-Phe(Boc) micelles were prepared by a solid dispersion method, and showed great capsulation ability for curcumin (encapsulation efficiency was up to94.45±0.25%with loading capacity of4.84±0.13%). Besides, this formulation was also able to improve bioavailability of curcumin and showed controlled release-behavior over a few days and showed specific inhibiting effect to human pancreatic SW1990cell lines with a dose dependent manner. The pharmacokinetics and biodistribution results in Sprague-Dawley (SD) rats indicated that intravenously (i.v.) administration of mPEG-PCL-Phe(Boc) micelles stably retained curcumin in the plasma with a6.8-fold larger of the area under the time-concentration curve (AUC),4.33-fold longer of the half-life of elimination (tl/2z), and4.06-fold higher of the maximum concentration in the plasma, as compared with solvent solubilized curcumin, while the apparent volume of distribution (Vz) and total body clearance (CLz) were significantly decreased, hi xenograft models of human refractory multiple myeloma (RPMI8226) established in nude mice, administration of curcumin micelles significantly inhibited primary tumor growth. The combination of parenteral curcumin micelle with doxorubicin resulted in enhanced rumor growth inhibition compared with either single agent. Furthermore, a simultaneous decrease in doxorubicin-induced systemic toxicity and lessened MDR effect by curcumin-loaded micelles has also been observed. Overall, the presently described micellar system was expected to find future use for delivering curcumin in combination with cytotoxic agents for synergistically increasing the antitumor efficacy and decreasing toxicity in traditional chemotherapy.