Nano and Molecular Medicine presentations (MU)
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Item Development of Absorption and Fluorescence Probes Based on Mouse Model for Molecular Optical Imaging [abstract](2010) Ma, Lixin; Yu, Ping, Ph. D.; University of Missouri (System); Missouri Life Sciences Summit (2010: University of Missouri--Kansas City)In this work we summarize our collaborative research on a project to develop absorption and fluorescence targeting probes. Several groups from University of Missouri and Harry S. Truman Memorial Veteran's Hospital including Dr. Ma's group, Dr. Yu's group, Dr. Smith's group, Dr. Hoffman's group, and Professor Wynn Volkert have been involved in the project. Our goal is to develop probes based on mouse model for molecular optical imaging. In vivo imaging of targeted fluorescence molecular probes, or molecular imaging, is an emerging field in biomedical imaging. During the past forty years, three dimensional biomedical imaging technologies such as CT and MRI have been extensively used in human health and diseases. However, the human body is a complex and interactive biological system. A fundamental scientific barrier in previous biomedical imaging technologies is their limited ability to study physiological processes in vivo at the cellular and molecular levels. Molecular imaging technologies can overcome this barrier. Optical imaging modalities have the highest sensitivity compared to other imaging techniques. So they are good candidates for molecular imaging. We develop probes for two biomedical optical imaging techniques. The first technique is coherence domain imaging. This technique can be used to monitor interactions between targeted peptide conjugates and cancer cells at a tissue level. It requires absorption properties of the probe for effective molecular imaging. The second technique is fluorescence mediated tomographic imaging using an image-intensified CCD camera. This technique uses fluorescence of the probe for molecular imaging. Dye bombesin conjugates are synthesized for site-specific absorption and fluorescence imaging in human prostate and breast cancer cells. Bombesin (BBN), an amphibian analog to the endogenous ligand, binds to the gastrin releasing peptide receptors (GRPr) with high specificity and affinity. BBN conjugates have a specific significance in cancer detection and therapy due to high over-expression levels of GRPrs in human cancer cells. Previously, we have developed an Alexa Fluor 680 BBN peptide conjugate. This probe can not be used as an absorption probe in near-infrared imaging since its absorption peak is in the visible wavelength range. In addition, long wavelength fluorescence is desired because long wavelength photons can penetrate deeper into tissue when using the conjugates as a fluorescent probe. The new absorption and fluorescent probe we developed is based on the last eight-residues of BBN and labeled with Alexa Fluor 750 through an effective linker. The developed probe, AF750-BetaAla-BBN[7-14]NH2, exhibits optimal pharmacokinetic properties for targeting GRPr over-expressing cancer cells in mice. Absorption spectra have been measured and showed absorption peaks at 690nm, 720nm and 735nm. Fluorescent band is located at 755nm. Fluorescent microscopic imaging of the conjugates in human PC-3 prostate cancer and T-47D breast cancer cells indicated specific uptake and internalization in vitro. In vivo optical and MR imaging was performed in SCID mice bearing human breast and prostate xenografts. In vitro and in vivo studies have demonstrated the effectiveness of the fluorescent probe Alexa Fluor 750-BetaAla-BBN[7-14]NH2 to specifically target GRPr overexpressed cancer tissues.Item Early Breast Cancer Detection Using Fluorescence Mediated Tomographic Imaging [abstract](2010) Yu, Ping, Ph. D.; Ma, Lixin; University of Missouri (System); Missouri Life Sciences Summit (2010: University of Missouri--Kansas City)Development of reliable technologies for early detection and screening of breast cancer is significant since the overall accuracy of traditional mammography remains low for diagnosis of benign and malignant lesions. In vivo imaging of targeted molecular probes, or molecular imaging, is an emerging field for early detection of cancer. Nuclear molecular imaging modalities such as positron-emission tomography (PET) and single-photon-emission computed tomography (SPECT) have been used for obtaining functional information of cancerous tissue. However, these technologies are limited with low resolution for detection of subcentimetric tumor deposits and lack of an anatomical reference frame to accurately locate molecular events. On the other hand, MRI has high spatial resolution but relatively low sensitivity to targeting probes. Although several multimodality imaging technologies are being developed, the systems are highly incomplete and expensive. Optical imaging is particularly well suited for molecular imaging, as fluorescent probes are sensitive and can be specifically conjugated to small molecules, antibodies and proteins. Optical imaging has the advantages of being non-invasive, non-ionizing, and having high sensitivity for optical-labeled probe, relatively low cost and rapid imaging time. The primary objective of this project is to develop a three-dimensional fluorescence mediated tomography (FMT) system based on a frequency domain heterodyne technique that uses an image-intensified CCD camera. The proposed technique provides the highest resolution and sensitivity and faster acquisition rates in the measurement of the phase and amplitude for frequency domain diffuse photons. The fluorescence tomography system will be used within PET and MRI scanners for dual imaging of molecular targets of cancer cells. The proposed research will develop/refine a combined FMT/PET/MRI technology utilizing FMT as a bridge to integrate PET and MRI and form a multimodal imaging platform. The developed frequency domain heterodyne imaging system will gain a factor of 10 in sensitivity via reducing phase-amplitude cross-talk compared to a homodyne system using ICCD. The proposed multimodality imaging system FMT/PET will improve spatial resolution with a factor of 4. The technology developed in this proposal can be used in the development of tumor targeting pharmaceuticals for cancer diagnosis and therapy.Item The Vision of the International Institute of Nano and Molecular Medicine (I2NM2)(2010-02) Hawthorne, M. Frederick; Lee, Mark W.; Kueffer, Peter; Fang, Li; Yang, Shuo; Jalisatgi, Satish S.; Lewis, Michael R.; Ruthengael, Varyanna; University of Missouri (System); Missouri Life Sciences Summit (2010: University of Missouri--Kansas City)The translational research effort in boron neutron capture therapy (BNCT) described below and recently initiated at the University of Missouri International Institute of Nano and Molecular Medicine and the University of Missouri Research Reactor would benefit from collaboration with a research group knowledgeable in modeling human tumors using small animal hosts and cellular biology as it relates to therapeutic results and the treatment of experimental data. The boron-10 (10B) isotope is unique among light elements for its high neutron cross-section and low inherent toxicity. When subjected to relatively benign thermal neutrons, the 10B nucleus undergoes a neutron capture reaction forming an excited 11B species. This unstable nucleus subsequently undergoes essentially instantaneous fission to release 2.4 MeV of kinetic energy in the form of a pair of 7Li3+ and 4He2+ ions, which are confined to the volume of about one cell. Therefore, preferential accumulation of 10B-containing structures within cancerous cells can lead to selective destruction of these cells. This process is more commonly known as Boron Neutron Capture Therapy (BNCT) for cancer. The key to the implementation of this potentially powerful and selective therapy is the delivery of at least 30 parts per million (ppm) of 10B within the tumor tissue while minimizing superfluous 10B within the surrounding healthy tissue. This difference in 10B concentration is often denoted through the boron concentration in tumor to boron concentration in blood ratio, with a higher ratio being preferable. Herein we describe the synthesis and results of biodistribution experiments with two nano-scale boron delivery agents: liposomes and oligomeric phosphate diesters (OPDs). Liposomes, containing both amphiphilic (KC2B9H11(CH2)15CH3, MAC) and hydrophilic (Na3B20H17NH3, TAC) components and ranging in diameter from 30 to 100 nm, showed tumor boron accumulations as high as 50 ppm and tumor to blood ratios over 8. OPDs, ranging in size from 1 to 5 nm in diameter, also exhibited preferential tumor accumulations of 30 ppm at tumor to blood ratios as high as 35 to 1. In both cases, liposomes and OPDs greatly outperformed currently available small boron-containing pharmaceuticals at the same injected dose of 10B. Studies in which OPDs were fluorescently labeled proved their localization within the cellular nucleus, increasing the relative efficacy of these species due to their proximity to the DNA target. In conclusion, both liposomes and OPDs show great promise as nano-sized delivery vehicles for BNCT.Item The Vision of the International Institute of Nano and Molecular Medicine (I2NM2)(2010-02) Hawthorne, M. Frederick; University of Missouri (System); Missouri Life Sciences Summit (2010: University of Missouri--Kansas City)The International Institute of Nano and Molecular Medicine (I2NM2) of the University of Missouri-Columbia is embarking upon an in-depth study of cancer therapy using the boron neutron capture reaction, the only binary radiation therapy of its type. To accomplish this extensive study the I2NM2 will lead by devising delivery vehicles for boron-10 which are specific for cancer cells. This study could benefit from collaboration with a research group interested in assisting us in the very extensive evaluation of new boron species in bio-distribution at I2NM2 and therapeutic work at the MU nuclear reactor (MURR). This would, above all, involve maintaining the supply of tumor-bearing mice using a variety of tumor models, cellular biology as it relates to therapeutic results, and treatment of experimental therapeutic data. The ultimate purpose of this initial study would be identification of superior boron target species which could then be evaluated in larger animals and eventually in humans.