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Pharmacokinetic Properties of 2(nd)-Generation Fibroblast Growth Factor-1 Mutants for Therapeutic Application

Title: Pharmacokinetic Properties of 2(nd)-Generation Fibroblast Growth Factor-1 Mutants for Therapeutic Application.
Name(s): Xia, Xue, author
Babcock, Joseph, author
Blaber, Sachiko, author
Harper, Kathleen, author
Blaber, Michael, author
Type of Resource: text
Genre: text
Issuance: serial
Date Issued: 2012
Physical Form: computer
Physical Form: online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Fibroblast growth factor-1 (FGF-1) is an angiogenic factor with therapeutic potential for the treatment of ischemic disease. FGF-1 has low intrinsic thermostability and is characteristically formulated with heparin as a stabilizing agent. Heparin, however, adds a number of undesirable properties that negatively impact safety and cost. Mutations that increase the thermostability of FGF-1 may obviate the need for heparin in formulation and may prove to be useful "2nd-generation" forms for therapeutic use. We report a pharmacokinetic (PK) study in rabbits of human FGF-1 in the presence and absence of heparin, as well as three mutant forms having differential effects upon thermostability, buried reactive thiols, and heparin affinity. The results support the hypothesis that heparan sulfate proteoglycan (HSPG) in the vasculature of liver, kidney and spleen serves as the principle peripheral compartment in the distribution kinetics. The addition of heparin to FGF-1 is shown to increase endocrine-like properties of distribution. Mutant forms of FGF-1 that enhance thermostability or eliminate buried reactive thiols demonstrate a shorter distribution half-life, a longer elimination half-life, and a longer mean residence time (MRT) in comparison to wild-type FGF-1. The results show how such mutations can produce useful 2nd-generation forms with tailored PK profiles for specific therapeutic application.
Identifier: FSU_migr_biomed_faculty_publications-0041 (IID), 10.1371/journal.pone.0048210 (DOI)
Keywords: FGF-1, ischemic disease, heparin
Note: Originally published in PLoS One
Citation: Xia X, Babcock JP, Blaber SI, Harper KM, Blaber M. (2012) Pharmacokinetic properties of 2nd-generation Fibroblast Growth Factor-1 mutants for therapeutic application. PLoS ONE 7(11): e48210. doi:10.1371/journal.pone.0048210
Subject(s): Amino acids
Molecular biology
Developmental biology
Clinical biochemistry
Medical sciences
Persistent Link to This Record:
Owner Institution: FSU
Is Part of Series: Department of Biomedical Sciences Faculty Publications.
Is Part Of: PLoS One.
Issue: 11, 7