In vivo detection of the effects of preconditioning on LNCaP tumors by a TNF-α nanoparticle construct using MRI

Abstract

The outcome of systemic and local therapies (e.g. chemotherapy, radiotherapy, surgery, focal ablation) for prostate cancer can be significantly improved by using tumor-specific adjuvants prior to treatment ("preconditioning"). We propose to use dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to monitor the in vivo response of a mouse model of prostate cancer treated with a vascular disruptive agent, TNF-α, delivered on a gold nanoparticle (NP-TNF). Six male nude mice bearing 4-5 week old LNCaP tumors were scanned at 9.4 T. DCE-MRI was performed two days before and 4-5 h after treatment with NP-TNF. An intraperitoneal (i.p.) bolus of gadolinium-DTPA (Gd) was administered and contrast enhancement was measured for 90 min. Concentration-time curves of Gd were calculated and the area under the Gd curve (AUGC) was determined pre- and post-treatment. NP-TNF treatment caused an increase in contrast uptake in tumors. Interestingly, the early concentration (10 min post Gd bolus i.p.) was similar in both untreated and treated conditions; however, 90 min after injection, [Gd] was 3.4 times higher than before treatment. AUGC doubled from (11 ± 6) [Gd] × min before treatment to (22 ± 9) [Gd] × min after treatment. An increase in signal enhancement was also observed in the muscle but to a lesser degree. We also evaluated the kinetics of intravenous Gd administration in mice bearing a jugular vein catheter to mimic the delivery method used in clinical trials. The overall treatment effects were independent of the delivery pathway of the contrast agent. In conclusion, we show that DCE-MRI is suitable to detect changes associated with a vascular disruptive agent in a mouse model of prostate cancer. The ability to characterize the effects of nanoparticle therapy in vivo with non-destructive methods is important, as such compounds, in combination with treatment strategies, are progressing towards clinical trials.