Image-guided chemistry altering biology: An in vivo study of thermoembolization

Abstract

RationaleAdvances in image-guided drug delivery for liver cancer have shown a significant survival benefit. However, incomplete treatment is common and residual disease is often found in explanted liver specimens. In addition, the need to treat a malignancy from multiple mechanisms at the same time for optimal outcomes is becoming more widely appreciated. To address this, we hypothesized that an exothermic chemical reaction could be performed in situ. Such a strategy could in principle combine several angles of attack, including ischemia, hyperthermia, acidic protein denaturation, and metabolic modulation of the local environment.MethodsThe University of Texas MD Anderson Cancer Center Institutional Animal Care and Use Committee approved this study. Outbred swine (25–35 kg, 5 control and 5 experimental) were treated under general anesthesia. Embolization was performed with coaxial microcatheter technique in a segmental hepatic arterial branch using either ethiodized oil as control or with thermoembolic solutionBlood samples were obtained before, immediately after, and the day following the procedure just before CT scans and euthanasia. Livers were explanted and samples were obtained for histologic analysis.ResultsAll animals survived the procedure and laboratory values of the control and experimental groups remained within normal limits. The control group had a diffuse or cloudy pattern of attenuation on follow-up CT scan the day after, consistent with gradual antegrade sinusoidal transit of the embolic material. The experimental group had clearly defined vascular casts with some degree of peripheral involvement. At histology, the control group samples had the appearance of normal liver, whereas the experimental group had coagulative necrosis in small pale, punctate areas extending several hundred microns away from the treated vessels and a brisk inflammatory response just outside the margins.ConclusionIn situ chemistry via thermoembolization shows early promise as a fundamentally new tactic for image-guided therapy of solid tumors.

Mathematical modeling of mass and energy transport for thermoembolization

“…Short-term systemic studies document the safety [55] of the thermoembolization approach. In in vivo studies, liver enzyme levels did not reveal any acute decompensation, indicating that the procedure is well-tolerated in the animal models.…”

Temperature mapping of exothermicin situchemistry: imaging of thermoembolization via MR

“…For a perfused in vivo thermoembolization, the heating dynamics are expected to be different than this work’s unperfused ex vivo kidney experiments. However, prior work has demonstrated the acute and durable termination of perfusion of in vivo porcine liver [17], suggesting the exothermic injection will remain in the vessel and heat adjacent tissue. While a robust means of predicting damage attributed to thermoembolization is not yet proposed, MRTI makes modeling treatment outcomes more plausible.…”

“…Thermoembolization is a procedure in which an exothermic chemical reaction is delivered via transarterial catheter. Recent investigations into the biological effects of this technique indicate that it might offer unique advantages versus current techniques [15-17]. An exothermic reaction, such as hydrolysis of an acid chloride, could offer a number of different avenues for local tissue destruction based on the distribution of the resulting heat and reaction product(s).…”

Correlation of molecular and morphologic effects of thermoembolization in a swine model using mass spectrometry imaging

“…During induction, buprenorphine was also administered at 0.02 mg/kg given intramuscularly for analgesia, with provision for additional postprocedure dosing as needed. Animals were closely monitored before and after procedure with no significant alterations in laboratory values as previously reported …”

“…Recently, a fundamentally new strategy for HCC therapy has been developed. This approach, termed thermoembolization, is focused on the local delivery of reactive compounds via image‐guided catheter techniques to cause local tissue destruction . An example of such a reaction is illustrated in Figure A, where hydrolysis of an electrophilic reagent would release two equivalents of acid in situ and a considerable amount of heat energy.…”