Formaldehyde-doxorubicin dual polymeric drug delivery system for higher efficacy and limited cardiotoxicity of anthracyclines

We report the synthesis of a dual delivery system composed chemically bound pH-responsive formaldehyde polymer prodrugs and doxorubicin loaded nanoparticles to increase therapeutic index by working in synergy with enable formation DOX-DNA adducts limiting cardiotoxicity anthracyclines. Polyacrylates bearing 1,2- 1,3- pendant diols were synthesized via reversible addition fragmentation chain transfer (RAFT) polymerization conjugate formaldehyde, forming 5- or 6-membered acetal rings tunable conjugation percentages (1.5–10 wt%) for controlled release acidic environments tumor extracellular matrix. The formaldehyde-conjugated are then combined polyester formed intermolecular crosslinking oxime click chemistry less than 200 nm size containing 14 wt% encapsulated Doxorubicin (DOX). Release kinetics show sustained both DOX at pH 5.0, mimicking low environment whereas insignificant was recorded physiological pH. cell viability combination evaluated 4 T1 breast cancer cells resulting considerably death about 4-fold compared free alone. protective effect towards DOX- induced damages observed Lactate dehydrogenase assays cardiomyocytes (P1-3). polymeric is first reported example co-administration, demonstrating potential significant an improved anti-cancer efficacy reduced DOX.