1 research outputs found
Conjugation Dependent Interaction of Folic Acid with Folate Binding Protein
Serum proteins play
a critical role in the transport, uptake, and
efficacy of targeted drug therapies, and here we investigate the interactions
between folic acid–polymer conjugates and serum folate binding
protein (FBP), the soluble form of the cellular membrane-bound folate
receptor. We demonstrate that both choice of polymer and method of
ligand conjugation affect the interactions between folic acid–polymer
conjugates and serum FBP, resulting in changes in the folic acid-induced
protein aggregation process. We have previously demonstrated that
individual FBP molecules self-aggregate into nanoparticles at physiological
concentrations. When polyÂ(amidoamine) dendrimer–folic acid
conjugates bound to FBP, the distribution of nanoparticles was preserved.
However, the dendritic conjugates produced larger nanoparticles than
those formed in the presence of physiologically normal human levels
of folic acid, and the conjugation method affected particle size distribution.
In contrast, polyÂ(ethylene glycol)–folic acid conjugates demonstrated
substantially reduced binding to FBP, did not cause folic acid-induced
aggregation, and fully disrupted FBP self-aggregation. On the basis
of these results, we discuss the potential implications for biodistribution,
trafficking, and therapeutic efficacy of targeted nanoscale therapeutics,
especially considering the widespread clinical use of polyÂ(ethylene
glycol) conjugates. We highlight the importance of considering specific
serum protein interactions in the rational design of similar nanocarrier
systems. Our results suggest that prebinding therapeutic nanocarriers
to serum FBP may allow folate-specific metabolic pathways to be exploited
for delivery while also affording benefits of utilizing an endogenous
protein as a vector