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The importance of the tumor microenvironment (TME) in tumor progression, invasion, and therapy is widely recognized. Intermittent and hypoxic oxygenation (pO2) and extracellular acidosis (pHe) of tumor tissues are among the most established hallmarks in solid TME, while extracellular inorganic phosphate (Pi) has been recently identified as a new signaling molecule of importance in tumorigenesis (marker of metastatic potential).
The αvβ3 and αvβ5 integrins are usually expressed at low levels in most adult epithelia but can be highly upregulated in some tumors. These integrins are involved in angiogenesis and metastasis of solid tumors, and their inhibition resulted in significant reduction of functional vessel density, retardation of tumor growth, and metastasis in vivo.
In this project we propose to develop theranostic multifunctional paramagnetic trityl probes for in vivo monitoring of basic physiological parameters (pO2, pH, Pi) using electron paramagnetic resonance-based techniques and patient-derived tumor xenograft (PDX) models.
Proposed trityl probes are designed to have minimal toxicity, a wide range of pharmacokinetic time, and antiangiogenic therapeutic effects due to high affinity of the probes to the αvβ3 integrins in tumor tissue.
The best probe formulations are used to construct a real-time TME profile during tumor development and antiangiogenic treatment using theranostic
We hypothesize that the TME signature can predict levels of success for αvβ integrins based on antiangiogenic therapy. Successful completion of this proposed project will result in development of new theranostic paramagnetic multifunctional probes which can be easily modified with appropriate targeting motif to study drug therapeutic effects.