Abstract
The triblock copolymer is composed of two identical hydrophilic segments Monomethoxy poly(ethylene glycol) (mPEG) and one hydrophobic segment poly(ε-caprolactone) (PCL); which is synthesized by coupling of mPEG-PCL-OH and mPEG-COOH in a mild condition using dicyclohexylcarbodiimide and 4-dimethylamino pyridine. The amphiphilic block copolymer can self-assemble into nanoscopic micelles to accommodate doxorubixin (DOX) in the hydrophobic core. The physicochemical properties and in vitro tests, including cytotoxicity of the micelles, have been characterized in our previous study. In this study, DOX was encapsulated into micelles with a drug loading content of 8.5%. Confocal microscopy indicated that DOX was internalized into the cytoplasm via endocystosis. A dose-finding scheme of the polymeric micelle (placebo) showed a safe dose of PEG-PCL-PEG micelles was 71.4 mg/kg in mice. Importantly, the circulation time of DOX-loaded micelles in the plasma significantly increased compared to that of free DOX in rats. A biodistribution study displayed that plasma extravasation of DOX in liver and spleen occurred in the first four hours. Lastly, the tumor growth of human breast cancer cells in nude mice was suppressed by multiple injections (5 mg/kg, three times daily on day 0, 7 and 14) of DOX-loaded micelles as compared to multiple administrations of free DOX.
Highlights
Doxorubicin (DOX), an anthracycline drug has proven very effective for the treatment of breast, ovarian, prostate, brain, cervix and lung cancers [1,2,3,4]
We evaluated the safety of prepared poly(ethylene glycol) (PEG)-PCL-PEG micelle as an intravenous drug delivery system in a series of tests including cytotoxicity tests, in vitro nitric oxide production and hemolytic tests and in vivo acute toxicity tests in ICR mice
The triblock copolymer was characterized by proton nuclear magnetic resonance (1H NMR), gel permeation chromatography (GPC), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) and differential scanning calorimetry (DSC)
Summary
Doxorubicin (DOX), an anthracycline drug has proven very effective for the treatment of breast, ovarian, prostate, brain, cervix and lung cancers [1,2,3,4]. Some tumor cells showed multidrug resistance (MDR), which has been attributed to the P-glycoprotein (P-gp) efflux pump on the plasma membrane [5,6] To overcome these obstacles, strategies such as encapsulating DOX into the core of polymeric nanoparticles by chemical conjugation or physical entrapment have been attempted [7,8,9,10,11]. We evaluated the safety of prepared PEG-PCL-PEG micelle as an intravenous drug delivery system in a series of tests including cytotoxicity tests, in vitro nitric oxide production and hemolytic tests and in vivo acute toxicity tests in ICR mice. The therapeutic potential of single and multiple administrations of DOX-loaded micelle were investigated using the nude mice xenograft model
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