Synthesis and Characterization of Amphiphilic Cyclotriphosphazenes and Polymeric Platinum Anticancer Drugs

Abstract

Amphiphilic cyclotriphosphazenes bearing hydrophilic poly(ethylene glycol) and a variety of lipophilic oligopeptide esters as side groups were synthesized and characterized by elemental analysis, 1H and 31P-NMR. These trimeric phosphazenes were found to exhibit a lower critical solution temperature (LCST) around and higher than the body temperature and to form micelles by self-assembly in aqueous solution. Therefore, these cyclotriphosphazenes were evaluated for their applications as new delivery systems for anticancer drugs. In order to afford selective delivery of platinum anticancer drugs, new polymeric drug carriers were designed and synthesized by grafting cyclic phosphazene trimers with equimolar hydrophilic poly(ethylene glycol) and hydrophobic oligopeptide. These amphiphilic phosphazene trimers were hydrolyzed using potassium hydroxide or barium hydroxide in methanol and then reacted with (diamine)platinum(II) nitrate or sulfate in organic solvent to obtain hydrophobic phosphazene trimer-platinum(II) conjugates. After characterization by means of multinuclear NMR spectroscopy, DLS and elemental analysis, the conjugates were subjected to in vitro bioassay. These conjugates were found to form stable nanoparticles with a mean diameter of approximately 90 to 200 nm depending on the hydrophobicity of the conjugated (diamine)platinum moieties.These nanoparticulate platinum(II) conjgates have shown outstanding tumor selectivity with high tumor/tissue ratios of 22.3 at 2 hr and 83.0 at 24 hr post injection and comparable cytotoxicity against selected human tumor cells. The present conjugates are promising candidates for selective local delivery of platinum anticancer drugs for the treatments of various solid tumors.