Mesenchymal Stem Cells (MSCs) migrate specifically to tumors in vivo, and coupled with their capacity to bypass immune surveillance, are attractive vehicles for tumor-targeted delivery of therapeutic agents. This study aimed to introduce MSC-mediated expression of the sodium iodide symporter (NIS) for imaging and therapy of breast cancer. Tumor bearing animals received an intravenous or intratumoral injection of NIS expressing MSCs (MSC-NIS), followed by 99mTcO4- imaging 3-14Days (D) later using a BazookaSPECT γ-camera. Tissue was harvested for analysis of hNIS expression by RQPCR. Therapy animals received an intraperitoneal injection of 131I or saline 14D following injection of MSC-NIS, and tumor volume was monitored for 8 weeks. BazookaSPECT imaging following injection of MSC-NIS revealed an image of animal intestines and chest area at D3, with a weak tumor image also visible. By D14, the tumor was visible with a significant reduction in radionuclide accumulation in non-target tissue observed. hNIS gene expression was detected in the intestines, heart, lungs and tumor at early timepoints but later depleted in non-target tissues and persisted at the tumor site. Based on imaging/biodistribution data, animals received a therapeutic dose of 131I 14D following MSC-NIS injection. This resulted in a significant reduction in tumor growth (Mean ± SEM, 236 ± 62mm3 versus 665 ± 204 mm3 in controls). The ability to noninvasively track MSC migration and transgene expression in real time prior to therapy is a major advantage to this strategy. This promising data supports the feasibility of this approach as a novel therapy for breast cancer.
This work outlines the design and construction of a single-photon emission computed tomography (SPECT) imaging system based on the concept of synthetic collimation. A focused multi-pinhole collimator is constructed using rapid-prototyping and casting techniques. The collimator projects the centre of the field of view (FOV) through forty-six pinholes when the detector is adjacent to the collimator, with the number reducing towards the edge of the FOV. The detector is then moved further from the collimator to increase the magnification of the system. The object distance remains constant, and each new detector distance is a new system configuration. The level of overlap of the pinhole projections increases as the system magnification increases, but the number of projections subtended by the detector is reduced. There is no rotation in the system; a single tomographic angle is used in each system configuration. Image reconstruction is performed using maximum-likelihood expectation-maximization (MLEM), and an experimentally measured system matrix. The system matrix is measured for each configuration on a coarse grid, using a point source. The pinholes are individually identified and tracked, and a Gaussian fit is made to each projection. The coefficients of these fits are used to interpolate the system matrix. The system is validated experimentally with a hot-rod phantom. The Fourier crosstalk matrix is also measured to provide an estimate of the average spatial resolution along each axis over the entire FOV. The 3D synthetic-collimator image is formed by estimating the activity distribution within the FOV, and summing the activities in the voxels along the axis perpendicular to the collimator face.
Mesenchymal Stem Cells (MSCs) have the ability to migrate specifically to tumours in vivo, and coupled with their capacity to bypass immune surveillance, are potentially attractive vehicles for tumor-targeted delivery of therapeutic agents. The aim of this study was to determine the potential of MSC-mediated expression of the sodium iodide symporter (NIS) for in vivo imaging and therapy of breast tumours. Expression of NIS allows cells to concentrate radionuclides including technetium-99m (Tc-99m) and 131-Iodine (131-I). This could potentially support imaging of NIS-expressing MSCs following engraftment, and 131-I therapy of surrounding tumour tissue based on the bystander effect of the radionuclide. Methods: Tumor bearing animals (MDA-MB-231 flank) were given an intravenous or intratumoral injection of NIS expressing human MSCs (MSC-NIS), followed by imaging 3, 7, 10 or 14 days later. Imaging was performed using a Bazooka SPECT γ-camera, following intraperitoneal injection of 2mCi/74MBq Tc-99m. Following imaging, animals were sacrificed and organs harvested for analysis of hNIS expression by RQ-PCR. A second group of animals received an intraperitoneal injection of 1mCi/37MBq 131-I or saline (controls) 14 days following intratumoral or intravenous injection of MSC-NIS, and tumour volume was tracked for 8 weeks. Results: Bazooka SPECT imaging of animals revealed uptake of tracer (Tc-99m) in the mouse thyroid/salivary glands and stomach, representing native NIS expression. Following injection of MSC-NIS, an image of animal intestines was also observed at D3, with a weak image of the tumour also visible. By Day14, uptake of tracer was visible at the site of the tumour with no significant image of non-target tissue observed. Expression of hNIS in harvested organs supported the imaging data, with hNIS detected in the intestines, heart, lungs and tumour at early timepoints. While NIS expression depleted in non-target tissues by D7, gene expression persisted at the tumour site. Based on imaging/biodistribution data, animals were given a therapeutic dose of 131-I 14 days following MSC-NIS injection to avoid toxicity to non-target organs. No adverse effect of injection of MSC-NIS or radionuclide was observed. Tracking of tumour volume revealed a significant reduction in tumour growth in animals that had received an intravenous injection of 131-I 14days following MSC-NIS injection (Mean ± SEM, 236 ± 62mm3 versus 665 ± 204 mm3 in controls). Following intratumoral injection of MSC-NIS + 131-I, although tumour size was reduced compared to controls (472 ± 80 mm3), the difference in volume was not significant. Conclusion: The ability to non-invasively track MSC migration and transgene expression in real time prior to therapy is a major advantage to this strategy. This promising data supports the viability of this approach as a novel therapy for metastatic breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5392. doi:10.1158/1538-7445.AM2011-5392
This work outlines the development of a multi-pinhole SPECT system designed to produce a synthetic-collimator image of a small field of view. The focused multi-pinhole collimator was constructed using rapid-prototyping and casting techniques. The collimator projects the field of view through forty-six pinholes when the detector is adjacent to the collimator. The detector is then moved further from the collimator to increase the magnification of the system. The amount of pinhole-projection overlap increases with the system magnification. There is no rotation in the system; a single tomographic angle is used in each system configuration. The maximum-likelihood expectation-maximization (MLEM) algorithm is implemented on graphics processing units to reconstruct the object in the field of view. Iterative reconstruction algorithms, such as MLEM, require an accurate model of the system response. For each system magnification, a sparsely-sampled system response is measured by translating a point source through a grid encompassing the field of view. The pinhole projections are individually identified and associated with their respective apertures. A 2D elliptical Gaussian model is applied to the pinhole projections on the detector. These coefficients are associated with the object-space location of the point source, and a finely-sampled system matrix is interpolated. Simulations with a hot-rod phantom demonstrate the efficacy of combining low-resolution non-multiplexed data with high-resolution multiplexed data to produce high-resolution reconstructions.
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