Conjugate of Doxorubicin with a Thermosensitive Polymer Drug Carrier

Abstract

A temperature-responsive drug delivery system that is soluble in aqueous solutions below its phase transition temperature but hydrophobically collapsing and aggregating at higher temperatures was prepared. A ternary copolymer of N-isopropylmethacrylamide, N-propylmethacrylamide and 4-nitrophenyl N-methacryloylglycylglycinate was synthesized. The reaction of the 4-nitrophenyl ester groups with hydrazine resulted in a polymer hydrazide which enabled the attachment of doxorubicin (DOX) via a pH-sensitive hydrazone bond. The system exhibited phase separation in aqueous solutions at a temperature of about 41'C and released free DOX at pH 5.0 at a rate higher by one order of magnitude than at pH 7.4. In combination with local hyperthermia, the system is expected to be valuable for the delivery of chemotherapeutic agents in the treatment of solid tumors. The relation between the temperature of the phase transition of the system and the cloud point temperature (CPT) as well as the necessity to distinguish between the CPT and the lower critical solution temperature (LCST) is discussed and the factors influencing the results of determination of the CPT (its definition, concentration of the polymer solution, rate of heating, presence of cosolutes, chemical structure of polymer and its heterogeneity) are analysed in detail.