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

Area of Science:

• Pharmacology
• Oncology
• Interventional Radiology

Background:

• Maintaining therapeutic drug concentrations within a safe window is crucial for effective dosing across all delivery methods.
• Drugs with short half-lives and high reactivity present challenges for therapeutic use due to potential systemic toxicity.
• Targeted delivery strategies could enable the use of highly reactive compounds by limiting systemic circulation.

Purpose of the Study:

• To investigate the feasibility of using a highly reactive electrophile, dichloroacetyl chloride, for targeted liver cancer therapy in a swine model.
• To assess the localized delivery and systemic exposure of dichloroacetate following targeted administration.
• To evaluate the therapeutic effects and toxicity profile of this localized delivery approach.

Main Methods:

• A strong electrophile, dichloroacetyl chloride, was dissolved in a hydrophobic vehicle.
• The solution was delivered to the liver with high spatial selectivity using a microcatheter in a swine model.
• Plasma concentrations of the reaction product, dichloroacetate, were measured over 4 hours.
• Persistence and tissue effects were assessed over 24 hours.

Main Results:

• Minimal dichloroacetate was detected in plasma over 4 hours, indicating limited systemic circulation.
• The targeted delivery resulted in localized coagulative necrosis in the target vascular bed.
• The material persisted for 24 hours within the target area.
• No dose-limiting toxicity was observed during the experimental duration.

Conclusions:

• Highly reactive compounds can be safely and effectively delivered to target tissues using precise, image-guided methods.
• This localized delivery strategy minimizes systemic exposure, reducing the risk of off-target toxicities.
• Targeted delivery of dichloroacetyl chloride shows promise for localized cancer treatment by inducing necrosis with minimal systemic effects.