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