Cyclotriphosphazene-Pt-DACH Conjugates with Dipeptide Spacers for Drug Delivery Systems

Abstract

An intelligent drug delivery system that exhibits a thermosensitive phase transition from a soluble to insoluble state was developed to deliver drugs into a tumor. Cyclotriphosphazene-Pt-DACH (trans(+/-)-1,2-diaminocyclohexane) conjugates with dipeptide spacers were synthesized by successive reaction steps. The conjugates exhibited a reversible and thermosensitive phase transition with lower critical solution temperature in aqueous media that was varied by the substitution of different hydrophilic/hydrophobic side groups. The conjugate had similar cytotoxicity as cisplatin, but much greater than carboplatin against various human cancer cell lines. The conjugate was much more potent than cisplatin against the cisplatin-resistant cell line, A2780/CP70. The biodistribution and pharmacokinetic studies indicate that the present thermosensitive conjugate exhibits locally controlled drug delivery feature that could circumvent surgery treatment and reduce toxic side effects due to systemic administration.