William K. Park, Aaron W. Maxwell, Victoria Frank, Michael Primmer, Jarod Paul, Cynthia Susai, Scott Collins, Tiffany Borjeson, Greyson Baird, Kara Lombardo, Damian Dupuy
The greatest challenge in image-guided thermal ablation (IGTA) of liver tumors is a relatively high recurrence rate (ca. 30%) due to incomplete ablation. To meet this challenge, we have developed a novel Thermal Accelerator (TA) to demonstrate its capability to, 1) augment microwave (MW) energy from a distance unattainable by antenna alone; 2) turn into a gel at body temperature; 3) act as a CT or US contrast. We have examined the TA efficiency using in vitro and ex vivo models: microwave power, TA dose, frequencies and TA-to-tip distance were varied, and temperature readings compared with and without TA. Using the in vitro model, it was established that both the rate and magnitude of increase in ablation zone temperature were significantly greater with TA under all tested conditions (p<0.0001). On ultrasound imaging, the TA was echogenic as gel. On CT, TA density was proportional to dose, with average values ranging from 329 HU to 3071 HU at 10 mg/mL and 1,000mg/mL, respectively. TA can be accurately deposited to a target area using CT or US as image-guidance and augment MW energy effectively so that ablation time is significantly reduced, which will contribute to complete ablation. The preliminary results obtained from in vivo experiments using swine as an animal model are consistent with the observations made in in vitro and en vivo studies.
William K. C. Park, David Mills, Sierin Lim, Barindra Sana, Victoria Frank, Brendan Kenyon, Michael Primmer, Jarod Paul, Greyson Baird, Edward Walsh, Damian Dupuy
Purpose: A ferritin-containing nanoparticle conjugated with a target-specific antibody was investigated as a MRI contrast agent for tumor detection. A genetically modified ferritin to markedly improve Fe (III) payload (up to 7,000 Fe ions), was chemically tethered to a monoclonal antibody against rat Nectin-like molecule 5 (Necl-5). Necl-5 is a cell surface glycoprotein that is highly expressed on the cell surface of many common epithelial cancers, including prostate cancer. It was previously demonstrated that this novel nanoconjugate agent exhibited effective in vitro targeting of Necl- 5 expressing tumor cells and exhibited strong MRI contrast characteristics via shortening of T2. Here, we demonstrate that the nanoconjugate-Necl-5 interaction can be exploited to target and detect tumor in vivo by MRI. Procedure: Using an in vivo tumor model (i.e., tumor size 0.5-1 cm, immunodeficient beige/nude/xid mouse, xenograft injection with transformed rat prostate cells), efficacy of the conjugate targeting the tumor was examined. We used two injection strategies, a direct and a tail vein injection (0.8 mg, 300 μL per subject). Pre-injection baseline and postinjection scans were performed with the following spin-echo sequence parameters: Field of view = 90x53mm, reconstruction matrix size = 192x114, slice thickness = 1mm (10 slices), repetition time (TR) = 2070 ms, echo times (TE) = 11-198 ms in 11ms steps (18 echoes), number of averages = 2, acquisition time per scan = 7min 56s. Results: All T2 data obtained were converted to R2 for demonstration purposes (R2 = 1/T2). The tail vein injected conjugate significantly increased R2 response (22.9 ± 5.2 s-1) as compared to control (13.5 ±1.7 s-1) at 4 h. The weaker R2 increase was noted (15.2 ± 2.0 s-1) at 24 h. No notable changes in R2 were observed in surrounding tissues regardless the stages of the measurement. We also measured the initial conjugate kinetics for both injection methods with respect to the ability of targeting the tumor. Direct injection of the nanoconjugate in to the center of the tumor showed a stronger and more rapid increase in R2 than the tail vein injection. Conclusion: The nanoconjugate interacts strongly and selectively in situ with Necl-5 overexpressing tumor cells. Direct injection of the nanoconjugate into the body of the tumor caused a more significant in situ R2 increase in MRI than the tail vein injection. Varying degrees of R2 increase within the tumor mass is likely to represent different distribution patterns of the conjugate, reflective of tumor heterogeneity.
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