Synthesis and Evaluation of a Folate-linked Anti-cancer Prodrug

Doxorubicin (DOX) is a highly active anti-cancer drug for the clinical use, but its therapeutic effectiveness is limited by its severe cardio toxic side effects and dose limiting. In order to over come these limitations, we produced a folate-bovine serum albumin(BSA)-cis-aconitic anhydride-doxorubicin (FA-BSA-CAD) conjugates. Folic acid (FA) is an essential vitamin and has high affinity to folate receptor (FR). FA was bound to BSA for increasing the active targeting of the conjugates. BSA was used as a carrier to provide passive tumor targeting by the enhanced permeability and retention (EPR) effect. DOX is conjugated with BSA with a pH sensitive linker cis-aconitic anhydride (CAA), which can be hydrolyzed in acidic lyzosomal environment. The conjugate was purified and separated by a Sephadex G-25 column. The successful synthesized of FA-BSA-CAD conjugates was further confirmed by mass spectrometry, UV-visible spectroscopy and FTIR. The therapeutical efficacy of the product was evaluated on three different tumor lines (BEL-7402, MDA-MB-231, MCF-7), with normal cell line as control (HELF). Results indicated that FA-BSA-CAD has selectively targeting ability to tumor cell lines, with less toxicity to the normal cells. In addition, the therapeutical efficacy is obvious increased compared to the pure DOX.