Introduction: The success of nanoparticle chemotherapy is primarily dependent on the access these agents have to tumors via the leaky vasculature, the so called Enhanced Permeation and Retention (EPR) effect. Yet, the extent of EPR in individual tumors varies widely, resulting in a correspondingly wide range of responses to the therapy. However, there exist no tools currently to rationally determine whether tumor blood vessels are amenable to nanocarrier mediated therapy in a patient-specific manner today. To address this need, we developed a long-circulating liposomal contrast nanoprobe for x-ray imaging based probing of tumor EPR status. In this work, the intratumoral uptake of the nanoprobe was imaged using a clinical digital mammography unit, and subsequently the animals were treated with liposomal doxorubicin of similar composition and particle size as the clinically used liposomal chemotherapy. One expects that the nanoprobe will accumulate in tumors in the same way that liposomal doxorubicin does by the EPR effect.

Methods: Using a clinical digital mammography unit, preliminary studies were performed to identify the agent dose that would result in adequate tumor enhancement without enhancement of the normal vasculature. This dose was used to image a rat breast tumor (n=14) over a period of three days using mammography, and subsequently the animals were treated with a single dose of liposomal doxorubicin (10 mg/kg doxorubicin) of similar composition and particle size as the probe. The predictive capability of the probe was characterized by analyzing the correlation between the tumor enhancement found during imaging and the tumor growth rate after treatment.

Results: The nanoprobe had a diameter of 103 nm and contained 155 mg/mL iodine (all encapsulated). A dose was identified that produced undetectable signal from the blood while the intratumoral accumulation of the probe produced adequate signal for detection. The high iodine content and the method of use allowed for quantification of the intratumoral, extravascular accumulation of the nanoprobe. The imaging measurements enabled identification of two subgroups prior to treatment: a ‘good prognosis' and a ‘bad prognosis' subgroup and indeed these demonstrated differential tumor growth rates. An inverse linear relationship between the contrast enhancement rate constant during imaging and the tumor growth rate constant during chemotherapy treatment was found.

Conclusions: To our knowledge, this is the first demonstration of a contrast agent capable of predicting the therapeutic efficacy of a clinically approved chemotherapeutic. Such an a priori determination would therefore facilitate personalized therapy, and spare potential non-responders from the rigors of a chemotherapy regimen.