Preparation and properties of acid-cleavable poly(vinyl alcohol)cis-aconityl-antitumor anthracycline conjugates

Macromolecular conjugates of poly(vinyl alcohol) (PVA) and daunomycin (DNR) and doxorubicin (DOX), were synthesized. These conjugates were designed to be stable in the circulation and allow the release of the drugs in the acidic conditions of tumor cells or the extracellular fluid of some solid tumor tissues. Aconityl-daunorubicin (ADNR) or aconityl-doxorubicin (ADOX) was synthesized. The free γ-carboxylic group of ADNR or ADOX molecule was coupled to PVA via octamethylenediamine spacer, resulting in the macromolecular conjugates of PVA-ADNR or PVA-ADOX, respectively. The acid-sensitive PVA-ADNR conjugate with the aconityl spacer exhibited a growth-inhibitory effect on the HL60 cell line whereas the conjugate with the succinyl spacer, which was acid-insensitive, showed no cytotoxic activity. PVA-ADOX also liberated DOX markedly under acidic conditions. PVA-ADOX inhibited the growth of Sarcoma 180 cells subcutaneously inoculated in mice. It was suggested that acid-sensitive PVA conjugates were suitable candidates for cancer treatment.