DEVELOPMENT OF AN X-RAY AND ULTRASOUND IMAGEABLE POLOXAMER-BASED GEL FOR IMAGE-GUIDED LOCAL PERCUTANEOUS DRUG DELIVERY

Abstract

Intratumoral dosing of anti-cancer agents using long needles under image guidance faces challenges due to the invisibility and unpredictable leakage of low viscous agents that leads to adverse effects. To address this, an ultrasound and x-ray imageable drug-loaded gel was developed and tailored for liver delivery. The hypothesis is that by incorporating highly viscous materials and imageable components into drug formulations, we can improve the visibility and reproducibility of the intratumoral drug delivery process. This thesis tested the hypothesis with ex vivo and in vivo tissue. First, 4mL of a pre-heated (37°C) ex vivo bovine liver was injected with gel containing iodine, microbubbles, and doxorubicin as x-rays, ultrasound, and drug respectively. The gel was imageable under ultrasound and x-rays. The gels in tissue were highly localized with circularities of 0.7, and sphericities of 0.9 (1 makes a perfect circle and sphere). Both imaging modalities were able to be predictable for each milliliter injected with a circular pattern growing from the needle tip. The area of the injected 4mL was 3.3cm2. Direct injections with iodine (without gel) were amorphous with high degree of leakage and were not predictable. The acoustic intensity from ultrasound imaging was 150 times higher than the intensity of formulations without gel which contrast clearly from tissue. The in vivo testing involved the dual imageable gel testing in swine liver to assess gel with doxorubicin distribution as well as pharmacokinetics compared to free injected doxorubicin. The results showed high degree of localization for gel containing doxorubicin under perfusionconditions with 0.7 sphericities and circularities from ultrasound and x-ray imaging, respectively, with minimal leakage to vessels. The volume localized without leakage was 5 times higher in the gel with doxorubicin than free doxorubicin. Pharmacokinetic parameters acquired using high performance liquid chromatography equipment showed that doxorubicin concentration in tissue was one million times at the liver injection site compared to liver, spleen, heart, and lung for gel with doxorubicin and free doxorubicin. In addition, gel with doxorubicin formulation provided 3 times lower doxorubicin concentration in kidney than free doxorubicin. The area under the curve and maximum concentration in blood over 4 h was 4 times higher in blood for swine treated with free doxorubicin which may indicate lower systemic exposure of doxorubicin mitigating side effects. In conclusion, gel with doxorubicin were visible under ultrasound and x-rays with high degree of localization in vivo and ex vivo, opening the possibility towards a predictable, precise, and safer delivery of anticancer agents.