Safety, Pharmacokinetics and Biodistribution Studies of a β-galactoside Prodrug of Doxorubicin for Improvement of Tumor Selective Chemotherapy

Anthracycline antibiotics, particularly doxorubicin (DOX) and daunorubicin, have been used extensively in the treatment of human malignancies. However, cardiotoxicity and multidrug resistance are significant problems that limit the clinical efficacy of such agents. Rational design to avoid these side effects includes strategies such as drug targeting and prodrug synthesis. The DOX prodrug N-(β-D-glucopyranosylbenzyloxycarbonyl)-doxorubicin (prodrug 1) was synthesized for specific activation by β-galactosidase, which is expected to release in necrotic areas of tumor lesions. Described here is the safety, pharmacokinetics, and biodistribution studies of a β-galactoside prodrug of DOX. In vivo safety evaluation was done in the Ehrlich Ascites Carcinoma (EAC) tumor model. The dose of DOX was 8 mg/kg and the dose of prodrug was 8 mg/kg and 24 mg/kg of DOX equivalents. Our results on cytotoxicity, which demonstrated compression in the number of EAC cells and their viability, substantiate these data. Prodrug 1 w...