Effects of cellular and tissue pharmacokinetics on control released growth factors

Abstract

Aim: To examine the effects of cellular and tissue pharmacokinetics on control released growth factors. Motivation: The resurgence of interest in controlled drug delivery reflects the increasing appreciation of the importance of local pharmacokinetics in defining the efficacy and potency of bioactive compounds. Despite promising data in vitro, growth factor use in vivo has generally failed to live up to its full potential. Without a theoretical framework to consider local pharmacology, there remains no consensus approach for improving the clinical outcomes of control released growth factors. As a result, a series of experiments incorporating cellular pharmacokinetics, computational modeling, and tissue pharmacokinetics were conducted. CellularPharmacokinetics: The effect of ligand-receptor trafficking was examined on the potency of sustained release versus bolus administration of two growth factors that differed by intracellular trafficking kinetics. Sustained delivery potency was demonstrated to be dependent on both ligand and receptor trafficking and could be predicted based on trafficking considerations.

(cont.) Computational Models: Computational models were conceptualized to describe the relationship between controlled-delivery, transport, receptor ligand pharmacokinetics, and tissue response. Theoretical predictions were made about potential approaches for optimizing local delivery and about the spatial correlation of tissue concentrations with tissue response. Tissue Pharmacokinetics: The roles of physiological transport forces and proteolytic constraints on control released growth factor were examined. Partitioning and convection were shown to be dominant forces in governing drug distribution. A novel method based on intramolecular fluorescence quenching was implemented to describe the proteolytic constraints of local fibroblast growth factor delivery in an ex vivo carotid explant model. Conclusion: Both experimental and theoretical models of cellular and tissue interactions of growth factors have suggested concepts that may be relevant for local growth factor delivery.