Chemistry Outside the Flask: Redefining Selectivity In Vivo with Image Guidance

Abstract

Fundamental to drug dosing and formulation strategies are the therapeutic index and maintaining a plasma concentration within a safe but therapeutic window. This holds true for oral, intravenous, transdermal, and intramuscular delivery methods. A key factor in plasma concentration is the half-life for any drug, because this affects the appropriate dose. Drugs with a very short half-life pose a particular challenge. Therefore, highly reactive compounds are not generally used for therapeutic purposes. However, targeted delivery under direct visualization, combined with cessation of blood flow in the area, could potentially allow the use of these highly reactive compounds. Such a strategy requires that little or none of the material reach systemic circulation to cause off-target toxicities. If this approach were applied to cancer, multiple mechanisms could be activated to disrupt cellular metabolism. We report our experience in a swine model using a strong electrophile, dichloroacetyl chloride, dissolved in a hydrophobic vehicle and delivered to the liver with high spatial selectivity using a microcatheter. Compared with positive controls, very little of the reaction product, dichloroacetate, a known inhibitor of pyruvate dehydrogenase kinase, was detected in plasma over 4 h. We further demonstrated persistence of the material for 24 h with highly localized and well-defined coagulative necrosis in the target vascular bed, without evidence of dose-limiting toxicity over the duration of the experiment.