Info

De natu rati on

A De natu ration

Circulation

Elimination

| Absorption

Medium

Recyclir g

Medium

Dégradation

Dégradation

Synthesis & Dégradation

Recycli

| Absorption

Synthesis & Dégradation

Recycli

Transport (diffusion/binding)

Degradation

Transport (diffusion/binding)

Degradation

FIGURE 1 In vitro and in vivo GF pharmacokinetic and pharmacodynamic considerations. (A) GF interactions with cells in in vitro culture models can be effectively modeled using a relatively simple set of parameters that describe the physical stability of the protein in the culture medium (denaturation), the reversible binding of the GF with cell surface binding sites (binding), cell signaling and internalization, and the intracellular fate of the GF that includes degradation (degradation) or released from the cell in intact or partially degraded form (recycling). Models that capture these steps can be correlated to biological response. (B) In vivo models need to consider additional components including active clearance (elimination) and interactions with the ECM. ECM absorption, transport, and release of GFs are controlled by the composition of the ECM, which is in constant flux as a result of synthesis and degradation. The homeostasis of the ECM can be modified dramatically by tissue injury, disease, and inflammation. Hence, models describing the pharmacokinetics and pharmacodynamics of ECM-binding GFs in vivo need to include parameters describing the binding, transport, and release from the ECM. Abbreviations: GF, growth factor; ECM, extracellular matrix.

that this class of bioactive proteins might represent a new type of systemic hormone. However, it has become clear that growth factors, in contrast to traditional hormones, do not generally act systemically as circulating proteins but are instead produced or released at local target sites. For example, the aggregation and degranulation of blood platelets at sites of injury lead to the release of a range of growth factors, including platelet-derived growth factor (PDGF) and transforming growth factor b (TGF-b), accounting for the high levels of these growth factors in the serum of clotted blood. In this way, blood platelets store growth factors for local release upon demand. Similarly, activated mast cells are known to release a range of growth factors including fibroblast growth factor 2 (FGF-2) vascular endothelial growth factor (VEGF), and nerve growth factor (8-13). Thus, eventual clinical applications of growth factors might be most effective if they are able to mimic the endogenous localized control of these potent proteins.

Within tissue environments, a number of growth factors are produced by resident cells that act via autocrine or paracrine mechanisms over relatively short distances. Indeed, the diffusive range of many growth factors appears quite limited in tissues even when the resident cells do not appear to be binding and responding to the growth factors present (14,15). This phenomenon is, in large part, a consequence of the fact that many growth factors physically bind to components of the ECM (5,16,17). Interactions between growth factors and their ECM-binding sites can lead to prolonged retention of growth factors in a latent state and can thus constitute a stored form of growth factor that can be activated upon release. Release of growth factors from ECM storage sites can be activated by degradation of the ECM by proteases and polysaccharide-degrading enzymes released by inflammatory cells or produced locally, or by alterations in the mass-action balance of growth factor-binding sites on cell surfaces and the ECM (14,18-22). Considerable research effort has been aimed at elucidating this sophisticated process of growth factor control, and results of these studies have begun to inform the design of the most appropriate means for controlled growth factor delivery to produce clinical benefit. ECM binding will likely prove to be a significant issue for most growth factors. However, it is clear that this issue is of major significance for the FGF and VEGF families where disappointing results from several clinical trials likely reflect the lack of appreciation of the consequences of ECM binding in modulating these growth factors (23-25).

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