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SPIO-Loaded Nanotubular Capsules as Ultra-Sensitive MRI Probes for Breast Cancer Detection
Background: Conventional breast cancer detection methods, such as mammography, give false positives for tumor detection which generally results in invasive surgical resection. Magnetic resonance imaging (MRI) is a clinical imaging technique that has broad applications in non-invasive diagnosis and post-therapy assessment of breast cancer. However, the high concentrations of agent necessary for detection severely limit their applications in monitoring molecular processes in vivo. Successful development of ultra-sensitive MRI probes (with detection limit at or below nM) is necessary to expand the capabilities of MRI in providing in vivo functional biochemical information. The use of exogenous MR contrast agents (e.g., superparamagnetic iron oxide, SPIO) can dramatically increase the sensitivity of MR detection especially when the SPIO particles are clustered. A cylindrical contrast agent design will provide a new platform to increase MR contrast agent sensitivity to detect breast cancer. Objective/Hypothesis: The objective is to develop cRGD-functionalized, SPIO-loaded silica nanotubular capsules (NTCs) to achieve a highly sensitive and specific detection of angiogenic tumor vessels by MRI. We hypothesize that the cylindrical shape of the NTCs will increase magnetization characteristics and improve the sensitivity of breast cancer detection. Moreover, encoding of NTC outer surface with cancer targeting peptide, cyclic RGD, will allow for cancer-specific imaging of tumor angiogenesis. Specific Aims: (1) Develop and characterize cRGD-encoded, SPIO loaded silica nanotubular capsules (NTCs) in vitro. (2) Evaluate in vivo efficacy of cRGD-encoded, SPIO-loaded nanotubular capsules (cRGD-SPIO-NTCs) using MRI. Study Design: Silica nano test tubes will be template synthesized using well established methods, followed by the loading of SPIO particles in the inner tube cavity. The tubes will be capped (previously developed methodology) to prevent SPIO leakage. Dissolving the template will render free NTCs, which will be functionalized with cRGD. SLK cells will be used for in vitro cellular uptake studies while mice injected with MCF-7 and MB-MDA-231 breast tumor xenografts will be used for in vivo studies using MRI. Results will be compared against SPIO-NTCs (no cRGD) and cRGD-NTCs (no SPIO). Potential Outcomes and Benefits of the Research: These studies will help establish a novel MRI molecular probe to image breast cancer cells at the onset of tumor growth. Early detection by targeting tumor angiogenesis may allow patients to obtain more effective treatments with fewer resulting side effects and less invasive procedures. Our ultra-sensitive probe design is advantageous because the concentration of NTCs required for detection will be greatly reduced, resulting in the ability to monitor molecular processes in vivo without disrupting any natural processes, while providing a method of detection before the onset of symptoms.
Advances in cancer detection in recent years have changed the field of cancer therapy because we are now able to detect certain cancers before the onset of symptoms. One method currently gaining interest for the detection of breast cancer is magnetic resonance imaging (MRI). MRI has gained a great deal of interest recently because it is a non-invasive method that can be used to detect cancers; however, one drawback to MRI is that a high concentration of the detection agent required, which severely limits their applications in monitoring molecular processes in vivo. We believe our new design for an ultra-sensitive MRI probe will dramatically change the detection limits and targeting ability for early breast cancer diagnosis using MRI. Most cancers, including breast cancer, begin with abnormal cells growing out of control forming a tumor. If undetected or untreated, a tumor can continue to grow until it spreads cancer to other parts of the body. During this growing stage, chemicals are released that promote new capillary formation to supply the tumor with blood. It is during this time that a unique cancer biomarker forms on the cell surface. It has been shown that this biomarker can be targeted by specific ligands, or complements to this biomarker. We propose to attach these ligands to the outside of our probes and then monitor their targeting ability by MRI. This method will allow us to target tumors at the first onset of growth, even before any symptoms are experienced by the patient. Also, the manner in which we produce our probes should give us ultra-sensitivity. Most of the current MRI probes are spherical in shape. Therefore, to increase the contrast agent payload (what makes agents visible by MRI) inside the sphere, the sphere has to be made larger in all directions. This poses a problem because the bigger the sphere gets the less likely it is to (1) get inside of the cell and (2) actually make it to its target site (large particles are cleared from the body). Our tubular probe design should alleviate these issues. The tubular shape allows us to only change one dimension to increase the payload. In this manner, entrance into the cell is not prohibited and the payload is increased significantly. The asymmetric shape will also serve to increase imaging capabilities. This is important because high concentrations of probes are required for conventional MRI methods, which can in turn cause unwanted side effects. Our ultra-sensitive probes will allow us to detect and monitor cancers, while injecting the minimal concentration require for MRI detection. The development of new ultra-sensitive MRI probes that can target specific cancer cells early in the cancer?s growth will dramatically change the treatments required and increase the survival rate of cancer victims.