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Improving Drug Delivery to Tumors

© David Olle

Interstitial fluid is the fluid found in the spaces between tissues and organs, and is outside the vascular and lymphatic systems. The interstitial spaces are important for the transport of nutrients and drugs from blood vessels to neighboring cells. In normal tissues, equilibrium takes place where the fluid entering the interstitial spaces is balanced by the fluid leaving the spaces, so pressure does not build up. Although a vascular system develops in the growing tumor, the blood vessels are defective in shape and structure. The defective blood vessels limit the flow of nutrients, oxygen, and drugs to the cancer cells. As a result, the cancer cells are hypoxic, or oxygen deficient. In addition to inhibiting delivery of drugs to the tumor site, the tumor vessels tend to leak excess fluid into the interstitial spaces. Tumors typically have a poor or nonexistent lymphatic system, so drainage of the excess fluid does not take place. Tumors also have a more rigid, inflexible connective tissue. All of these factors increase the tumor interstitial fluid pressure to the point where it almost equals the capillary fluid pressure inhibiting the outflow of capillary contents. Cancer patients with high tumor interstitial fluid pressure have a poorer prognosis independent of other clinical factors. 2

Compounds that lower tumor interstitial fluid pressure

All of the following compounds have been shown to increase drug uptake in tumors of laboratory animals. 1They all act by promoting or inhibiting compounds in the body that are related to the structure and functioning of blood vessels or interstitial tissue. However, the timing of administration is critical, and depends on an in-depth knowledge of their action. For example, if a compound is administered much before the chemotherapeutic drug, the tumor could receive additional nutrients that could increase their growth rate.

1.Vascular endothelial growth factor inhibitors- this approach aims to normalize the structure of tumor blood vessels caused by excess secretion of VEGF. As a result, there is increased blood flow, and decreased permeability in the blood vessels.

2. Platelet derived growth factor antagonists and prostaglandin E - these inhibitors decrease the activities of interstitial tissue (fibroblasts) that are present in increased amounts in tumors. This results in a decreased tendency for swelling of these tissues. 3PDGF antagonists do not normalize blood vessels.

3. Bradykinin agonists - these compounds stimulate the activity of bradykinin, resulting in increased dilation and permeability of blood vessels.

4. Tumor necrosis factor alpha - this compound is known as a cytokine in the immune system. The mechanism of its action is unclear.