Evaluation of a series of new 99mTc-labeled bombesin-like peptides for early cancer detection.
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Bombesin (BN) is a peptide exhibiting a high affinity for the gastrin-releasing peptide (GRP) receptor, which is overexpressed by a variety of tumors, including breast or prostate cancer. The aim of the present study was the investigation of the complexes formed between a series of BN-like peptides and the nuclides (185/187)Re and 99mTc. The (185/187)Re complexes were formed via the precursor Regluconate. The radiolabeling of the derivatives with 99mTc was performed using either 99mTc-gluconate or 99mTc-MDP as the intermediate complex. For the in vitro evaluation of the new peptides, the cancer cell line PC3 was used. The in vivo behavior of the 99mTc-labeled BN-like peptides was evaluated in normal mice. All the derivatives showed specific uptake in the pancreas, an organ rich in BN receptors and high affinity for the cancer cell line PC3. The above preliminary results indicated that the new BN derivatives are promising for human cancer studies. (+info)
Interaction of radiolabeled antibodies with fungal cells and components of the immune system in vitro and during radioimmunotherapy for experimental fungal infection.
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BACKGROUND: The usefulness of radioimmunotherapy (RIT) for infectious diseases was recently demonstrated for several fungal and bacterial infections, but the mechanisms by which RIT is effective against microbes are uncertain. METHODS: We investigated the interaction between polysaccharide capsule-binding 18B7 monoclonal antibodies (MAbs) labeled with alpha-emitter 213Bi and Cryptococcus neoformans cells as well as between 213Bi-18B7 and components of immune system, both in vitro and in vivo. RESULTS: For 213Bi-18B7, the microbicidal effect was predominantly due to "direct-hit" killing, with some contribution from the "crossfire" effect. The efficacy of cell killing correlated with the binding capacity of the MAb to the capsule and was dependent on the MAb isotype. RIT also promoted the apoptosis-like death of fungal cells. Cooperation was observed in vitro between the antifungal activity of macrophages and RIT, suggesting the potential for synergistic action in vivo. RIT was associated with changes in concentration of the cytokines interleukin (IL)-2, IL-4, IL-10, tumor necrosis factor-alpha, and interferon-gamma, suggesting that the therapeutic effects of RIT may result from changes in the inflammatory response. CONCLUSIONS: The present results suggest that the antimicrobial efficacy of RIT involves killing through promotion of fungal cell apoptosis-like death, reduction in yeast capsule size, cooperation with macrophages, and modulation of the inflammatory response. (+info)
Radiolabeling of MAG3-morpholino oligomers with 188Re at high labeling efficiency and specific radioactivity for tumor pretargeting.
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We are investigating a novel pretargeting approach involving an initial IV injection of antitumor antibody conjugated with a phosphorodiamidate morpholino oligomer (MORF, a DNA analog) and the subsequent IV injection of the radiolabeled complement oligomer (cMORF). In this paper, the cMORF was labeled with (188)Re using MAG(3) as chelator for therapeutic applications. Since (c)MORFs are unstable in acidic condition, an optimal labeling pH was first selected and the other labeling factors were then examined. A labeling efficiency of greater than 90% can be achieved even at a concentration of MAG(3)-cMORF as low as 0.8 microM. The labeled cMORF is stable and capable of hybridizing to its complement. (+info)
Regiochemical control in the metal-catalyzed transposition of allylic silyl ethers.
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A novel mode of regiochemical control over the allylic [1,3]-transposition of silyloxy groups catalyzed by Re2O7 has been developed. This strategy relies on a cis-oriented vinyl boronate, generated from the Alder-ene reaction of homoallylic silyl ethers and alkynyl boronates, to trap out the allylic hydroxyl group. The resulting cyclic boronic acids are excellent partners for cross-coupling reactions. High chirality transfer is observed for the rearrangement of enantioenriched allylic silyl ethers. (+info)
Successful radiotherapy of tumor in pretargeted mice by 188Re-radiolabeled phosphorodiamidate morpholino oligomer, a synthetic DNA analogue.
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PURPOSE: Pretargeting has been attracting increasing attention as a drug delivery approach. We recently proposed Watson-Crick pairing of phosphorodiamidate morpholino oligomers (MORF) for the recognition system in tumor pretargeting. MORF pretargeting involves the initial i.v. injection of a MORF-conjugated antitumor antibody and the subsequent i.v. injection of the radiolabeled complement. Our laboratory has reported on MORF pretargeting for diagnosis using (99m)Tc as radiolabel. We now report on the use of MORF pretargeting for radiotherapy in a mouse tumor model using (188)Re as the therapeutic radiolabel. EXPERIMENTAL DESIGN: An initial tracer study was done to estimate radiation dose, and was followed by the radiotherapy study at 400 muCi per mouse with three control groups (untreated, MORF antibody alone, and (188)Re complementary MORF alone). RESULTS: Tracer study indicated rapid tumor localization of (188)Re and rapid clearance from normal tissues with a tumor area under the curve (AUC) about four times that of kidney and blood (the normal organs with highest radioactivity). Tumor growth in the study group ceased 1 day after radioactivity injection, whereas tumors continued to grow at the same rate among the three control groups. At sacrifice on day 5, the average net tumor weight in the study group was significantly lower at 0.68 +/- 0.29 g compared with the three control groups (1.24 +/- 0.31 g, 1.25 +/- 0.39 g, and 1.35 +/- 0.41 g; Ps < 0.05), confirming the therapeutic benefit observed by tumor size measurement. CONCLUSIONS: MORF pretargeting has now been shown to be a promising approach for tumor radiotherapy as well as diagnosis. (+info)
Targeted killing of virally infected cells by radiolabeled antibodies to viral proteins.
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BACKGROUND: The HIV epidemic is a major threat to health in the developing and western worlds. A modality that targets and kills HIV-1-infected cells could have a major impact on the treatment of acute exposure and the elimination of persistent reservoirs of infected cells. The aim of this proof-of-principle study was to demonstrate the efficacy of a therapeutic strategy of targeting and eliminating HIV-1-infected cells with radiolabeled antibodies specific to viral proteins in vitro and in vivo. METHODS AND FINDINGS: Antibodies to HIV-1 envelope glycoproteins gp120 and gp41 labeled with radioisotopes bismuth 213 ((213)Bi) and rhenium 188 ((188)Re) selectively killed chronically HIV-1-infected human T cells and acutely HIV-1-infected human peripheral blood mononuclear cells (hPBMCs) in vitro. Treatment of severe combined immunodeficiency (SCID) mice harboring HIV-1-infected hPBMCs in their spleens with a (213)Bi- or (188)Re-labeled monoclonal antibody (mAb) to gp41 resulted in a 57% injected dose per gram uptake of radiolabeled mAb in the infected spleens and in a greater than 99% elimination of HIV-1-infected cells in a dose-dependent manner. The number of HIV-1-infected thymocytes decreased 2.5-fold in the human thymic implant grafts of SCID mice treated with the (188)Re-labeled antibody to gp41 compared with those treated with the (188)Re-control mAb. The treatment did not cause acute hematologic toxicity in the treated mice. CONCLUSIONS: The current study demonstrates the effectiveness of HIV-targeted radioimmunotherapy and may provide a novel treatment option in combination with highly active antiretroviral therapy for the eradication of HIV. (+info)
Rhenium-186(Sn)HEDP for treatment of painful osseous metastases: results of a double-blind crossover comparison with placebo.
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Rhenium-186 (tin) hydroxyethylidene diphosphonate (HEDP) is a new radiopharmaceutical that simultaneously localizes in multiple skeletal metastases in patients with advanced cancer. A single intravenous administration of 30-35 mCi (1110-1295 MBq) is associated with a prompt, significant relief of osseous pain in about 80% of such patients. The efficacy of this new compound was evaluated further by utilizing a double-blind crossover comparison with 99mTc-methylene diphosphonate (MDP) as a radioactive placebo. The new rhenium compound resulted in a significantly (p less than 0.05) greater decrease in pain than did treatment with the radioactive placebo. Rhenium-186(Sn)HEDP appears to be a useful new compound for the palliation of painful skeletal metastases. (+info)
Synthesis and biologic evaluation of 64Cu-labeled rhenium-cyclized alpha-MSH peptide analog using a cross-bridged cyclam chelator.
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Early detection of cutaneous melanoma is essential, as prognosis with metastatic melanoma is poor. Previous studies showed that (64)Cu-DOTA-ReCCMSH(Arg(11)) (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid), a cyclic analog of alpha-melanocyte-stimulating hormone (alpha-MSH), has the potential for the detection of malignant melanoma using PET. However, (64)Cu-DOTA-ReCCMSH(Arg(11)) demonstrated high background in nontarget tissues due to the in vivo instability of the Cu-DOTA moiety. CBTE2A (CBTE2A is 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane) has been shown to be a more stable copper chelate with improved in vivo stability, resulting in an improvement in clearance from nontarget tissues. The goal of this study was to conjugate CBTE2A to the alpha-MSH targeting ReCCMSH(Arg(11)) peptide for labeling to (64)Cu and to investigate whether the increased metal-chelate stability with CBTE2A would improve imaging quality. METHODS: The recyclized peptide CBTE2A-ReCCMSH(Arg(11)) was synthesized using a solid-phase peptide synthesizer followed by rhenium cyclization. In vivo characteristics of (64)Cu-CBTE2A-ReCCMSH(Arg(11)) were examined with small-animal PET and acute biodistribution studies in B16/F1 tumor-bearing mice. RESULTS: Biodistribution studies showed high and rapid receptor-mediated tumor uptake with values similar to those reported for (64)Cu- and (86)Y-labeled DOTA-ReCCMSH(Arg(11)). Nontarget organ concentration for (64)Cu-CBTE2A-ReCCMSH(Arg(11)) was considerably lower than that of the (64)Cu-DOTA analog, resulting in significantly higher tumor-to-nontarget tissue ratios. Compared with (86)Y-DOTA-ReCCMSH(Arg(11)), (64)Cu-CBTE2A-ReCCMSH(Arg(11)) demonstrated increased tumor retention and kidney clearance. Small-animal PET images showed that the tumor could be clearly visualized at all time points (0.5-24 h). CONCLUSION: Our data suggest the superior stability of the (64)Cu-CBTE2A moiety compared with (64)Cu-DOTA, making (64)Cu-CBTE2A-ReCCMSH(Arg(11)) an ideal candidate for the PET of malignant melanoma. (+info)