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

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.