Abstract
Particulate carriers such as polymeric micelles (PMs) and liposomes have been investigated to increase drug accumulation in tumors and reduce distribution to healthy tissues. In this study, we prepared PM and hybrid nanoparticles (HNPs) with poly(ethylene oxide)-block-poly(methacrylic acid) (PEO-b-PMAA) for loading cisplatin, and evaluated cisplatin release, cytotoxicity, and biodistribution in mice. PM composed of PEO-b-PMAA and HNPs composed of egg phosphatidylcholine (EPC)/PEO-b-PMAA at molar ratios of 50/2.8 (HNP-P5) and 50/50 (HNP-P50), respectively, were prepared by a nanoprecipitation method. The sizes of PM, HNP-P5, and HNP-P50 after inclusion of cisplatin were approximately 200, 100, and 55 nm, respectively, and their entrapment efficiencies were approximately 44% - 66%. In the drug-release study, HNP-P5 and HNP-P50 showed reduced release of cisplatin compared with PM. Regarding the cytotoxic assay, HNP-P5 exhibited lower cytotoxicity for mouse Lewis lung carcinoma (LLC) and mouse colon carcinoma Colon 26 cells than PM and HNP-P50. In terms of biodistribution, PM could significantly improve blood circulation and tumor accumulation after intravenous injection into Colon 26 tumor-bearing mice compared with free cisplatin, but HNP-P5 and HNP-P50 did not. EPC in HNPs might be destabilized in the circulation, although it could reduce release of cisplatin in in vitro experiments. This study suggested that polymeric micelles composed of PEO-b-PMAA are a better carrier for cisplatin than hybrid nanoparticles composed of PEO-b-PMAA and EPC.
Highlights
Cisplatin is a platinum (Pt) complex classified as an alkylating agent that has been widely used as monochemotherapy for cancers including lung, testicular, ovarian, bladder, head, neck, and esophageal cancer, or in combination with other drugs such as taxanes, gemcitabines, befuximab, bleomycin, etoposide, and vinca alkaloids [1]-[3]
polymeric micelles (PMs) consisted of 100% Poly(ethylene oxide) (PEO)-bPMAA, and hybrid nanoparticles (HNPs)-P5 and HNP-P50 contained at 5.3 and 50 mol% PEO-b-poly(methacrylic acid) (PMAA) with egg phosphatidylcholine (EPC), respectively
These lipophilic chains are expected to associate with the hydrophobic segment of PEO-b-PMAA to form an additional protective layer of the micelle and avoid micelle breakage during the excessive dilution in body fluids
Summary
Cisplatin is a platinum (Pt) complex classified as an alkylating agent that has been widely used as monochemotherapy for cancers including lung, testicular, ovarian, bladder, head, neck, and esophageal cancer, or in combination with other drugs such as taxanes, gemcitabines, befuximab, bleomycin, etoposide, and vinca alkaloids [1]-[3]. To overcome the problems of toxicities caused by cisplatin, particulate carriers such as polymeric micelles (PMs) and liposomes have been investigated to obtain high drug accumulation in tumors and reduce distribution to healthy tissues. Liposomal cisplatin, such as PEGylated liposomes e.g. Lipoplatin TM and SPI-077 [9] [10], or pH-sensitive PEGylated liposomes [11], could have high efficacy for the treatment of cancer and reduce the toxicity of cisplatin. Cisplatin can interact with carboxylic acid in an aqueous environment [13] It can be loaded into PMs composed of a biodegradable block ionomers containing carboxylic acid such as poly(ethylene oxide)block-poly(methacrylic acid) (PEO-b-PMAA). An excess dilution upon systemic administration often causes the disintegration of PMs [16]
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