Fracking in Tumors: A Key Drug Transport Mechanism.

Abstract

To understand the pharmacokinetic and biophysical mechanisms governing how an intratumorally injected agent is ultimately retained and distributed within a tumor and how it can guide injections at the bedside. We injected a radiopaque agent at clinically relevant constant flows into nine freshly resected canine lung tumors while continuously monitoring the fluid pressure, <math xmlns="http://www.w3.org/1998/Math/MathML"><mrow><mi>P</mi> <mo>(</mo> <mi>t</mi> <mo>)</mo></mrow> </math> , within the injection needle. Quantification of agent retention was performed in six of the tumors from post-injection micro-CT images. The remaining three tumors were imaged continuously by fluoroscopy during the injection procedure to visualize how the agent was distributed. <math xmlns="http://www.w3.org/1998/Math/MathML"><mrow><mi>P</mi> <mo>(</mo> <mi>t</mi> <mo>)</mo></mrow> </math> consistently exhibited an initial linear increase to a sharply defined peak, followed by a transition phase toward an eventual steady-state plateau. These morphological features in <math xmlns="http://www.w3.org/1998/Math/MathML"><mrow><mi>P</mi> <mo>(</mo> <mi>t</mi> <mo>)</mo></mrow> </math> show striking similarities to those observed in the fluid pressures generated during petroleum fracking. This analogy, along with the micro-CT and fluoroscopy images, suggests that transport of the agent within a tumor during IT injection does not occur via flow through the pre-existing pores in the tumor tissue, as is conventionally thought. Instead, our data provide strong evidence of transport occurring through fracture-mediated pathways in the tissue created once a critical pressure is reached. This interpretation suggests that real-time monitoring of <math xmlns="http://www.w3.org/1998/Math/MathML"><mrow><mi>P</mi> <mo>(</mo> <mi>t</mi> <mo>)</mo></mrow> </math> can help the physician decide when an exit pathway has been created that allows the drug to flow from the injection site to the outside of the tumor. Halting the injection at this point in favor of its continuation at a new site in the tumor may help reduce systemic exposure to the injected agent and its attendant side effects. Accordingly, intraoperative monitoring of <math xmlns="http://www.w3.org/1998/Math/MathML"><mrow><mi>P</mi> <mo>(</mo> <mi>t</mi> <mo>)</mo></mrow> </math> could offer a low-cost non-invasive means of improving the efficacy and safety of IT injection for the treatment of malignant tumors.