Amino acid coordination complex mediates cisplatin entrapment within PEGylated liposome: An implication in colorectal cancer therapy

Abstract

Cis-Diaminedichloroplatinum (cisplatin, CDDP) remained among the most widely used anti-cancer agents; however, management of the dose-limiting side effects is still a great hurdle to its therapeutic potential. In the framework of this investigation, novel approach was developed for CDDP encasement within liposome based on the formation of a coordination bond between the platinum (II) atom and a carboxylic group in aspartic acid (AA) and glutamic acid (GA). We have also compared two methods of preparation based on equilibration and conventional lipid film hydration. For this, first FTIR spectra of the conjugates confirmed coordination bond between Pt and the carboxylate moieties. The PEGylated liposomes composed of HSPC, cholesterol and DPPG had a size of 134 to 197 nm and negative zeta potential (−14.20 to −20.90 mv). Cytotoxicity study revealed IC50 values of <7 µg/ml for liposomes. In vivo plasma retention following iv administration indicated the potential of liposome in maintaining cisplatin levels within the circulation, while free cisplatin and cisplatin conjugates were promptly eliminated. Anti-tumor efficacy studies following iv injections at 3 mg/kg cisplatin weekly for three weeks in C26 tumor bearing BALB/c mice demonstrated the potential of the cisplatin liposomes in tumor growth inhibition. Pt-complexes were not as effective as liposomal formulations showing the crucial role of liposomes in maintaining cisplatin levels within blood circulation. Overall, the developed cisplatin liposome seems to be a promising therapeutic approach for targeting solid tumors.