Synthesis and Antitumor Activity of Poly(organophosphazene)/ Doxorubicin Conjugates

Doxorubicin shows a wide spectrum of activity for solid tumors such as sarcomas, adenocarcinomas and melanomas, but its strong side effects including myelosuppression, extravasation reaction and cardiotoxicity have been a serious problem.1 Polymer-anticancer drug conjugates have been studied in order to improve the side effects of the anticancer drugs. In comparison with low-molecular weight anticancer drugs, polymer-anticancer drug conjugates have been found to be accumulated more in tumor tissues than in normal tissues, which is called enhanced permeability and retention (EPR) effect.2~5 In addition, polymer-anticancer drug conjugates can afford to prolong the antitumor activity by releasing the drug with a controlled rate. Several polymerdoxorubicin conjugates have been studied, and among them, N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer/ doxorubicin conjugate is currently under clinical study,6,7 but there is no report on polyphosphazene/doxorubicin conjugate. In the previous studies, we have found that poly(organophosphazene)/(diamine)platinum conjugates exhibited high antitumor activity due to controlled release of the platinum moiety from the conjugates.8,9 We report here the synthesis and antitumor activity of poly(organophosphazene)/doxorubicin conjugates.