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" Targeted photodynamic drugs: Design, Synthesis, and Applications "
Efrat Rubinstein
A. S. Scherz, Yoram
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Latin Dissertation
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English
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| Record Number
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54246
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| Doc. No
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TL24200
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| Call number
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3461780
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| Main Entry
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Efrat Rubinstein
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| Title & Author
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Targeted photodynamic drugs: Design, Synthesis, and Applications\ Efrat Rubinstein
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| College
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The Weizmann Institute of Science (Israel)
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| Date
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2008
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| Degree
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Ph.D.
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2008
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| Page No
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122
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| Abstract
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The abundance of integrin receptors in tumor tissue has prompted the search for their use as specific targets for diagnostic and therapeutic agents. Thus, conjugation of such agents to RGD peptides that show high affinity to vβ3 integrin was expected to provide the means for tumor targeting because this integrin plays a major role in tumor angiogenesis, formation of metastases, and pathological neovascularization. The concentrations achieved in a tumor tissue using different RGD-containing molecules have appeared sufficient for some imaging techniques but unfortunately have been found to be too low for mediating therapeutic effects. Recently, we were able to synthesize novel BChl-based photosensitizers conjugated with RGD-containing peptides (RGD-BChl conjugates) that home to a tumor site where, via integrin receptors, they accumulate to give effective diagnostic and therapeutic concentrations. More specifically, we designed and synthesized novel RGD-BChls (Chapter III) and assessed their biodistribution and pharmacokinetics using Inductively Coupled Plasma Mass Spectrometry (ICP-MS) (Chapter IV). We detected primary tumor sites and metastases by whole-body fluorescence imaging using an optical imaging system (IVIS 100®) (Chapter V). ICP-MS and whole-body fluorescence detection demonstrated that RGD-BChl conjugates selectively accumulate in cancer tissue at high concentrations for up to two days while virtually clearing from the rest of the body, thus enabling fluorescence tumor imaging and selective treatment at primary and metastatic sites. We assessed the selective therapeutic potential and its applicability to different tumor types using relevant vascular targeted photodynamic therapy (VTP) protocols (Chapters VI and VII). These results suggest that using novel RGD-BChl conjugates, specific targeting to a tumor may be achieved, enabling both vascular targeted imaging (VTI) and selective VTP of primary lesions as well as individual metastases of different tumor types. The retention time of RGD-BChl conjugates (pharmacokinetics) in the subject's circulation plays a key role in determining their accumulation at the target tissue. The high levels of RGD-BChl that accumulated in the tumor tissue indicates selective uptake and internalization of the conjugated molecules in malignant and normal cells (primarily endothelial cells and macrophages) comprising the tumor. The accumulation of RGD-BChl conjugates in the tumor tissue should enable detection of both primary lesions and metastases, and imaging of tumor sites. Therefore, noninvasive imaging methods for visual monitoring of integrin vβ3 expression in real-time could provide opportunities for detecting primary and metastatic lesions as well as for assessing therapeutic interventions. Based on the results of this study, we predict that targeting photodynamic agents to the endothelial cell compartment of the tumor vasculature enables localization, imaging, and treatment of primary lesions and individual metastases of different tumor types as well as other vascular diseases. This study also provides guidelines for the design and synthesis of RGD-BChl for treating diseases characterized by other types of integrins such as athereoscelrosis.
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| Subject
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Health and environmental sciences; Integrin receptors; Photodynamic agents; Targeted photodynamic drugs; Tumor targeting drugs; Pharmacy sciences; Oncology; 0572:Pharmacy sciences; 0992:Oncology
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A. S. Scherz, Yoram
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The Weizmann Institute of Science (Israel)
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