Synthesis and Applications of Cyclotriphosphazenes as Novel Drug Carriers for Anticancer Agents

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 particular, amphiphilic and thermosensitive cyclotriphosphazenes bearing hydrophilic poly(ethylene glycol) and hydrophobic oligopeptide ethyl esters were found to efficiently solubilize Taxol by micellar encapsulation of Taxol, which was found to be more cytotoxic than free Taxol. The Taxol loading capacity in aqueous solution of the phosphazene trimer has been determined to be approximately 14 % of the trimer used. The micellar size of the Taxol loaded trimer was found to be 250 nm in diameter by aggregation compared with 12 nm of the trimers only. Both systemic and local delivery of Taxol may be afforded by using phosphazene trimers with a LCST higher and below body temperature, respectively. In order to overcome disadvantages of conventional platinum drug such as toxic side effects including nephrotoxicity and neurotoxicity, a new class of phosphazene trimer-platinum conjugates was synthesized, and their antitumor activity were studied. The oligopeptide esters of the trimer were functionalyzed by hydrolysis using barium hydroxide, followed by platination with (dach)Pt(SO4) to create new tumor?active trimer-platinum conjugate. These phosphazene trimer-Pt(II) conjugates were found to exhibit a LCST near body temperature and higher antitumor activity than cisplatin both in vitro and in vivo (T/C % >200 at dosage of 30 mg/kg). The present conjugates are promising candidates for selective local delivery of platinum anticancer drugs for the treatments of various solid tumors. Keywords: cyclotriphosphazene, thermosensitivity, LCST, micelle, Taxol, DLS, loading capacity, cytotoxicity, platinum anticancer drug, anticancer activity