Folate binding protein: therapeutic natural nanotechnology for folic acid, methotrexate, and leucovorin.
Blood serum proteins play a critical role in the transport, biodistribution, and efficacy of systemically-delivered therapeutics. Here, we have investigated the concentration- and ligand-dependent aggregation of folate binding protein (FBP), focusing in particular on folic acid, an important vitamin and targeting agent; methotrexate, an antifolate drug used to treat cancer and rheumatoid arthritis; and leucovorin which is used to decrease methotrexate toxicity. We employed atomic force microscopy to characterize, on a particle-by-particle basis, the volumes of the FBP nanoparticles that form upon ligand binding. We measured the distribution of FBP nanoparticle volumes as a function of ligand concentration over physiologically- and therapeutically-relevant ranges. At physiologically-relevant concentrations, significant differences in particle volume distributions exist that we hypothesize are consistent with different trafficking mechanisms for folic acid and methotrexate. In addition, we hypothesize leucovorin is trafficked and delivered like folic acid at therapeutically-relevant concentrations. We propose that changes in dosing procedures could improve the delivery and therapeutic index for methotrexate and other folic acid-targeted drug conjugates and imaging agents. Specifically, we suggest pre-binding the drugs to FBP may provide a better formulation for drug delivery of methotrexate for both cancer and rheumatoid arthritis. This would be analogous to pre-binding paclitaxel to albumin, which is already used in the clinic.
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA. mbanasza@umich.edu.
Rachel L
RL
Merzel
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA. mbanasza@umich.edu.
Sarah M
SM
Boutom
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA. mbanasza@umich.edu.
Junjie
J
Chen
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA. mbanasza@umich.edu.
Carolina
C
Frey
Department of Statistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
Kerby
K
Shedden
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA. mbanasza@umich.edu and Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
E Neil G
EN
Marsh
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA. mbanasza@umich.edu and Department of Biomedical Science and Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA and Program in Macromolecular Science and Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA.
Mark M
MM
Banaszak Holl
D016503:Drug Delivery Systems; D058975:Folate Receptor 1 / Q000737:chemistry*; D005492:Folic Acid / Q000008:administration & dosage*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage*; D008727:Methotrexate / Q000008:administration & dosage*; D053758:Nanoparticles; D014018:Tissue Distribution
D058975:Folate Receptor 1; D005492:Folic Acid; D002955:Leucovorin; D008727:Methotrexate