Esterase-responsive polymeric prodrug-based tumor targeting nanoparticles for improved anti-tumor performance against colon cancer

We report on the fabrication of a multifunctional polymeric prodrug covalently linked with an anticancer drug (bufalin, BUF) and tumor-targeting peptide (RGD) and investigate its anticancer performance against colon cancer in mice. The polymerizable monomer, 3-((2-(methacryloyloxy)ethyl) thio)propanoic acid (BSMA), was synthesized first. Atom radical transfer polymerization (ATRP) of BSMA and oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) afforded random copolymers, P(OEGMA-co-BSMA). The polymeric prodrug of BUF, P(OEGMA-co-BUF), was obtained by an esterification reaction between the carboxyl groups of P(OEGMA-co-BSMA) and the hydroxyl group of BUF. Finally, a tumor-targeting polymeric prodrug, P(OEGMA-co-BUF-co-RGD), was obtained via an aminolysis reaction of P(OEGMA-co-BUF) in the presence of RGD and the final drug content was determined to be ∼32.9 wt%. In aqueous media, P(OEGMA-co-BUF-co-RGD) self-assembles into micelles and the hydrodynamic diameter (Dh) of the micelles was determined to be ∼33.0 (±2.5) nm by dynamic laser light scattering (LLS). It was demonstrated that the tumor-targeting polymeric prodrug showed improved anticancer performance both in vitro and in vivo in comparison with that of free BUF.