Intracoronary administration of FGF-2: a computational model of myocardial deposition and retention

Abstract

This study uses a computational model to characterize the myocardial deposition and retention of basic fibroblast growth factor (FGF-2) at the cellular level after intracoronary (IC) administration of exogenous FGF-2. The model is applied to the in situ conditions present within the myocardium of a dog for which the plasma pharmacokinetics resulting from IC injection of FGF-2 were recorded. Our estimates show that the processes involved in FGF-2 signaling are not diffusion limited; rather, the response time is determined by the reaction time of FGF-2 binding to cell surface receptors. Additionally, the processes of receptor secretion and internalization are found to play crucial roles in the FGF-2 dynamics; future experiments are required to quantify these processes. The model predictions obtained in this study suggest that IC administration of FGF-2 via either a single bolus or repetitive injections causes a transient increase (time scale of hours) in myocardial FGF-2 concentration if the endogenous level of free interstitial FGF-2 is low enough to allow permeation of FGF-2 molecules from the microvascular to the interstitial spaces. The model shows that the majority (64%) of the extracellular FGF-2 ligands are located within the interstitium, and similar fractions are found in the basement membrane and extracellular matrix. Among the FGF-2 molecules found within the interstitium, 2% are free and 98% are bound to interstitial heparan sulfate proteoglycans. These results support the theory of extracellular control of the bioavailability of FGF-2 via dynamic storage of FGF-2 within the basement membrane and extracellular matrix.

Angiogenic gene therapy in patients with nonrevascularizable ischemic heart disease: a phase 2 randomized, controlled trial of AdVEGF121 (AdVEGF121) versus maximum medical treatment

“…The lack of any clinical benefit in exercise tolerance was likely due to poor uptake of these protein factors from the coronary circulation and their short half-life, and thus, limited duration of activity of protein therapy. 7,8 Delivery of these proteins was also associated with dose-related toxicities resulting from systemic exposure, thus limiting the amount of growth factor that could be safely administered.…”

“…For instance, the early trials used intracoronary or intravenous injection of protein factors, and poor cardiac uptake and limited stability of these growth factors within the myocardium may have contributed to the lack of significant biological activity. 7,8 Similarly, randomized gene therapy trials have either lacked efficient transfection strategies or again relied on intracoronary delivery despite concerns from preclinical studies about the ability of this delivery strategy to effectively transduce the myocardium. 9 AdVEGF121, a replication-deficient adenoviral vector carrying the transgene encoding for VEGF121, has been shown to produce angiogenesis when injected directly into the myocardium in a number of different animal models [10][11][12][13] resulting in increased collateral blood flow to ischemic myocardium and improved cardiac function.…”

Spatiotemporal control over growth factor signaling for therapeutic neovascularization☆

“…The transport of delivered growth factors through the delivery systems, including polymer scaffolds, microspheres, or transplanted cells, has been modeled previously [107]. Assuming the effect of convection within tissues is negligible, the diffusivity of growth factors can be calculated based on known experimental parameters [108,110]. The half-lives of growth factors are also readily measured, and the binding kinetics of angiogenic factors to cell surface receptors can be modeled by taking into consideration the effect of VEGF receptors expression and the cellular internationalize rate of VEGF [111,112].…”

Computational Model of VEGF Spatial Distribution in Muscle and Pro-Angiogenic Cell Therapy

“…In skeletal muscle ECM, VEGF diffusion is hindered by collagen fibers (concentration: 75 mg/g ECM, fiber radius: 20 nm, fiber volume fraction: 0.14) and glycosaminoglycan chains (concentration: 5 mg/g ECM, fiber radius: 0.55 nm, fiber volume fraction: 7.8 10 À4 ) [36]. To obtain in vivo values of diffusivity, we followed a method previously outlined [37] HSPG and VEGF receptor density and kinetics. HSPG concentration in ECM and BM spaces were obtained from values measured in human myocardium [37].…”

“…To obtain in vivo values of diffusivity, we followed a method previously outlined [37] HSPG and VEGF receptor density and kinetics. HSPG concentration in ECM and BM spaces were obtained from values measured in human myocardium [37]. Currently, no in vivo measurements are available for the HSPG population in skeletal muscle.…”