Thermoresponsive and suspension forming cyclotriphosphazene conjugate for delivery vehicle of antitumor drug camptothecin

Camptothecin (CPT) has been used as antitumor drug against a wide range of cancer cells. However, its clinical application is greatly hindered by insolubility and instability issues under physiological condition. Therefore, an appropriate CPT administration technique directed for living system is greatly anticipated. In this study, a delivery method for CPT in the form of thermoresponsive system was prescribed. A conjugate of cyclotriphosphazene and CPT was synthesized by substituting hexachlorocyclotriphosphazene with sodium salt of methoxy-poly (ethylene glycol) (Mw = 350), 20-O-trifluoroglycinylCPT, and isoleucine ethyl ester, respectively. The resulting cyclotriphosphazene-CPT was characterized via multinuclear (¹H and ³¹P) NMR as well as FT-IR. The current conjugate showed temperature induced phase transition (solution to suspension) with a lower critical solution temperature at 31 °C. Our result indicated that the stability issue related to the use of CPT in aqueous solution could be handled by acylation at 20-OH moiety. Additionally, antitumor activity of cyclotriphosphazene-CPT, to some extent, was found to be more profound than that of CPT alone as evaluated against human colorectal cancer cell HCT-116. Altogether, the current cyclotriphosphazene-CPT conjugate might offer a facile method in delivering CPT as a minimally invasive system for treating cancer.