Pharmacokinetics of local growth factor delivery in myocardial tissue

Abstract

An emerging approach for the treatment of ischemic heart disease is the induction of angiogenesis by means of the locally delivering growth factors to the myocardium. When deposited within heart tissue the compounds elicit a vascular response that is hoped to perfuse ischemic myocardium. There is, however, little quantitative data on macromolecular transport in myocardium, their fate after being delivered, how their transport is affected by structural properties of myocardial tissue, and in-vivo conditions such as the convection of blood in the highly vascular capillary network. Attempts to find effective ways of delivering therapeutic macromolecules to myocardium that could maximize the impact of the agents and minimize systemic toxicity and adverse side effects have been hampered by the minimal understanding of transport in the complex myocardial tissue under varying in-vivo conditions. This thesis investigates macromolecular transport mechanism in the myocardium by examining the role of diffusion, equilibrium average tissue binding, and capillary convection. Epidermal growth factor (EGF) and basic fibroblast growth factor (FGF-2) were chosen as model growth factor because of their potency of inducing endothelial mitosis and angiogenesis invitro. The "effective" diffusivity and partition coefficient of radiolabeled EGF and FGF-2 in rat myocardium were obtained with a diffusion cell in minimal time assuring tissue integrity and protein stability. A three-dimensional continuum pharmacokinetic model that takes into account realistic coronary capillary network configuration and morphometry was constructed to simulate transport of generic macromolecules in a highly vascular tissue such as the myocardium. Partition coefficients of EGF and FGF-2 were 0.26 and 1.34, and diffusivities 1.42 and 4.58 [mu]m2/s, respectively. The impact of vasculature was evaluated in a computational model constructed based on these findings. At steady state equilibrium, total drug deposition and penetration depth of macromolecules in physiologic range in myocardium were shown to be much less than that for solid tissue that is not perfused by capillary network. Drug transport varied inversely as functions of intimal permeability and capillary density. Results from this study provided insights into the design of myocardial drug delivery systems, and drug engineering with a hope to better angiogenic treatment for ischemic heart disease.