Growth factor kinetics in vivo and in vitro
It is important to understand that there is a big difference between in vivo and in vitro stability of growth factors. In-vivo, growth factor half-lives can be just a few minutes. But the same growth factors have in-vitro half-lives of a few hours. What causes this?
Growth factors are key cell signalling molecules. Recombinant growth factors have a myriad of applications in research and therapy although their short half-lives and widespread expression of their receptors in healthy as well as diseased tissues present challenges. Understanding growth factor kinetics is key to their application.
In humans, growth factor levels are typically measured in the blood. This tissue is readily accessible and understanding serum stability is important for determining dosing for therapeutic recombinant growth factors.
Half-life depends on the speed with which individual growth factor molecules are either degraded (by proteases) or removed. The shorter serum stability of growth factors compared with cell culture stability is primarily due to their removal owing to the filtering effects of the kidneys. For example, IL-2, a cytokine used to treat some types of cancer by potentiating cytotoxic T-cell activity against cancer cells, has an initial half-life in serum of just a few minutes when administered intravenously. This half-life tends to increase over time and can be increased by using a different mode of administration. For example, intra-peritoneally (into the abdominal cavity) injection effectively removes the bulk of the drug from the kidneys' filtering.
To properly understand the pharmacodynamics of a drug, it is important to measure its levels in the target tissue. Once growth factors escape serum and enter tissues, they escape the filtering effects of the kidney thereby increasing their half-life. Moreover, components of the extracellular matrix, such as heparin, can bind to and stabilize growth factors, further increasing their half-lives. Thus, it can be expected that growth factors used therapeutically can have higher levels of potency if they have targeted delivery to diseased tissues especially if they escape filtration.
In the image above, cancer drugs delivered intravenously (yellow triangles) face hurdles to delivery. (1) They bind normal tissue causing side effects. (2) They degrade in the blood and are filtered out and metabolized by kidneys. (3) When they reach a tumour site, they have to cross the blood vessel wall and then permeate through the tumour. As a result, relatively small amounts of drug reach their target and tumour recesses are not reached. Specialist immune cells, called macrophages (white circles), actively infiltrate tumours.
PODS growth factors from Cell Guidance Systems package growth factors within a protein crystal lattice. As these degrade under the influence of proteases, a steady stream of growth factors is released. This simple concept allows the sustained, localized delivery of growth factors in vivo for therapeutic applications. PODS bind to and are taken up efficiently by phagocytic immune cells including microglia, monocytes and macrophages. Research into using these immune cells to deliver PODS to diseases such as cancer is ongoing. If you would like to learn more or discover the utility of PODS in research and therapy, don't hesitate to get in touch with us.
IMAGE Serum half-life is affected by the kidneys CREDIT Cell Guidance Systems
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