In vitro/in vivo assessment of novel 99mTc-bombesin conjugates in human cancer tissue [abstract]

Abstract only availableReceptor-specific, radiolabeled peptides are becoming increasingly popular as targeting vectors for the development of new diagnostic radiopharmaceuticals. The over-expression of certain receptors such as the gastrin releasing peptide receptor (GRPr) on human cancer cells makes this method of drug development a viable tool for tumor targeting in vivo. Breast, pancreatic, prostate, gastric, colon, and small-cell lung cancer have demonstrated GRPr expression. In this project, we have conjugated a diaminoproionic acid (DPR) bifunctional chelator to bombesin (BBN) peptide targeting vector by solid phase peptide synthesis. BBN is an analogue of human gastrin releasing peptide (GRP) that binds to the GRPr with high affinity and specificity. Conjugates of the general structure [DPR-(X)-BBN(7-14)NH2] (X = a series of amino acid pharmacokinetic modifiers) were purified by reverse-phase high-performance liquid chromatography and characterized by electrospray-ionization mass spectrometry. Radiolabeling investigations of with fac-[99mTc(CO)3(H2O)3]+ (Isolink®) provided for metallated conjugates of the following general structure: [99mTc(CO)3-DPR-(X)-BBN(7-14)NH2]. These new conjugates demonstrated the ability to target specific human tumors in rodent models. Subsequent radiolabeling studies of [DPR-(X)-BBN(7-14)NH2] with fac-[188Re(CO)3(H2O)3]+, the therapeutic surrogate precursor of Tc-99m, have given us the potential to treat specific human tumors via these new targeting vectors. Detailed radiolabeling protocols, in vitro cell binding studies, and in vivo biodistribution assays will be reported.Harry S. Truman Memorial VA Hospita

Design, synthesis, and evaluation of radiolabeled bombesin conjugates for the diagnosis of breast cancer

The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file.Title from PDF of title page (University of Missouri--Columbia, viewed on March 25, 2010).Vita.Thesis advisor: Charles J. Smith."December 2009"Ph. D. University of Missouri-Columbia 2009.[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Gastrin-releasing peptide (GRP) receptors are overexpressed on approximately two thirds (62-71%) of primary breast carcinomas and all (100%) of the corresponding metastatic sites. These receptors may be targeted with bombesin (BBN), a tetradecapeptide initially isolated from the skin of the fire bellied toad Bombina bombina, which binds to GRP receptors with both high affinity and specificity. These facts were exploited to develop a series of [superscript 99m]Tc-(CO)[subscrip 3]-X-Y-BBN(7-14)NH2 derivatives, where X = PZ1 or DPR and Y = [Beta]Ala, GGG, GSG, Peg5, Peg8, SGS, or SSS, whose ability to detect and diagnose breast cancer was analyzed. Among these conjugates, the 99mTc-(H[subscript 2]O) (CO)[subscript 3]-DPR-Y-BBN(7-14)NH2 analogs containing the amino acid spacer sequences GSG and SSS exhibited the highest levels of receptor-mediated accumulation and retention in the GRP receptor positive tissues of T47-D tumor-bearing SCID mice. Due to both their moderate residualization in tumor tissue and their rapid clearance from nontarget tissues, these derivatives demonstrated favorable tumor-to-background ratios, which allowed for the clear visualization of tumor tissue. This tumor tissue was clearly visible despite the presence of low levels of background radioactivity.Includes bibliographical reference

99mTc-DPR-SSS-BBN for diagnosis of human cancers [abstract]

Abstract only availableReceptor-specific, radiolabeled peptides have become increasingly popular as targeting vectors for the development of new diagnostic radiopharmaceuticals. The over-expression of certain receptors such as the gastrin releasing peptide receptor (GRPr) on human cancer cells makes this method of drug development a viable tool for tumor targeting in vivo. Breast, pancreatic, prostate, gastric, colon, and small-cell lung cancer have demonstrated GRPr expression. In this project, we have conjugated a diaminoproionic acid (DPR) bifunctional chelator to bombesin (BBN) peptide targeting vector by solid phase peptide synthesis. BBN is an analogue of human gastrin releasing peptide (GRP) that binds to the GRPr with high affinity and specificity. A conjugate, [DPR-SSS-BBN(7-14)NH] was purified by reverse-phase high-performance liquid chromatography and characterized by electrospray-ionization mass spectrometry. Radiolabeling investigations of with fac-[99mTc(CO)3(H2O)3]+ (Isolink®) provided for the metallated conjugate [99mTc(CO)3-DPR-SSS-BBN(7-14)NH2]. This new conjugate demonstrated the ability to target specific human tumors in rodent models. In vitro cell binding studies, and in vivo biodistribution assays will be reported.Life Sciences Undergraduate Research Opportunity Progra