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1.
Inorg Chem ; 50(13): 6210-9, 2011 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-21591746

RESUMO

A new tumor-seeking tridentate topology consisting of a phosphino dithioether ((HOCH(2))(2)PCH(2)CH(2)S(CH(2))(n)CH(2)SR; PS(2)) ligand framework for the production of kinetically inert and in vivo stable facial [(99m)Tc(CO)(3)(PS(2))](+) or [Re(CO)(3)(PS(2))](+) is described. The X-ray crystal structure of fac-Re(CO)(3)(PS(2))PF(6) is reported. The bioconjugation strategies for incorporating bombesin (BBN) peptides on to the PS(2) tripodal framework and, thereby, de novo designing of GRP receptor-seeking Tc(PS(2)-BBN)(CO)(3) are developed.


Assuntos
Bombesina/química , Monóxido de Carbono/química , Compostos Organometálicos/síntese química , Rênio/química , Compostos de Sulfidrila/química , Tecnécio/química , Cristalografia por Raios X , Cinética , Ligantes , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/química , Estereoisomerismo
2.
Bioconjug Chem ; 21(7): 1171-6, 2010 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-20536242

RESUMO

Analogues of the E. coli heat-stable enterotoxin (STh) are currently under study as both imaging and therapeutic agents for colorectal cancer. Studies have shown that the guanylate cyclase C (GC-C) receptor is commonly expressed in colorectal cancers. It has also been shown that STh peptides inhibit the growth of tumor cells expressing GC-C. The ability to determine GC-C status of tumor tissue using in vivo molecular imaging techniques would provide a useful tool for the optimization of GC-C-targeted therapeutics. In this work, we have compared receptor binding affinities, internalization/efflux rates, and in vivo biodistribution patterns of an STh analogue linked to N-terminal DOTA, TETA, and NOTA chelating moieties and radiolabeled with Cu-64. The peptide F(19)-STh(2-19) was N-terminally labeled with three different chelating groups via NHS ester activation and characterized by RP-HPLC, ESI-MS, and GC-C receptor binding assays. The purified conjugates were radiolabeled with Cu-64 and used for in vitro internalization/efflux, in vivo biodistribution, and in vivo PET imaging studies. In vivo experiments were carried out using SCID mice bearing T84 human colorectal cancer tumor xenografts. Incorporation of DOTA-, TETA-, and NOTA-chelators at the N-terminus of the peptide F(19)-STh(2-19) resulted in IC(50)s between 1.2 and 3.2 nM. In vivo, tumor localization was similar for all three compounds, with 1.2-1.3%ID/g at 1 h pi and 0.58-0.83%ID/g at 4 h pi. The principal difference between the three compounds related to uptake in nontarget tissues, principally kidney and liver. At 1 h pi, (64)Cu-NOTA-F(19)-STh(2-19) demonstrated significantly (p < 0.05) lower uptake in liver than (64)Cu-DOTA-F(19)-STh(2-19) (0.36 +/- 0.13 vs 1.21 +/- 0.65%ID/g) and significantly (p < 0.05) lower uptake in kidney than (64)Cu-TETA-F(19)-STh(2-19) (3.67 +/- 1.60 vs 11.36 +/- 2.85%ID/g). Use of the NOTA chelator for coordination of Cu-64 in the context of E. coli heat-stable enterotoxin analogues results in higher tumor/nontarget tissue ratios at 1 h pi than either DOTA or TETA macrocycles. Heat-stable enterotoxin-based radiopharmaceuticals such as these provide a means of noninvasively determining GC-C receptor status in colorectal cancers by PET.


Assuntos
Toxinas Bacterianas/química , Neoplasias Colorretais/diagnóstico , Radioisótopos de Cobre/química , Enterotoxinas/química , Tomografia por Emissão de Pósitrons/métodos , Animais , Proteínas de Escherichia coli , Feminino , Humanos , Camundongos , Camundongos Endogâmicos ICR , Camundongos SCID , Transplante de Neoplasias , Coloração e Rotulagem
3.
Anticancer Res ; 29(10): 3777-83, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19846908

RESUMO

BACKGROUND: Uroguanylin is an endogenous peptide agonist that binds to the guanylate cyclase C receptor (GC-C). GC-C is overexpressed in human colorectal cancer (CRC), and exposure of GC-C-expressing cells to GC-C agonists results in cell cycle arrest and/or apoptosis, highlighting the therapeutic potential of such compounds. This study describes the first use of radiolabeled uroguanylin analogs for in vivo detection of CRC. MATERIALS AND METHODS: The peptides uroguanylin and E(3)-uroguanylin were N-terminally labeled with the DOTA chelating group via NHS ester activation and characterized by RP-HPLC, ESI-MS, and GC-C receptor binding assays. The purified conjugates were radiolabeled with In-111 and used for in vivo biodistribution and SPECT imaging studies. In vivo experiments were carried out using SCID mice bearing T84 human colorectal cancer tumor xenografts. RESULTS: Alteration of the position 3 aspartate residue to glutamate resulted in increased affinity for GC-C, with IC(50) values of 5.0+/-0.3 and 9.6+/-2.9 nM for E(3)-uroguanylin and DOTA-E(3)-uroguanylin, respectively. In vivo, (111)In-DOTA-E(3)-uroguanylin demonstrated tumor uptake of 1.17+/-0.23 and 0.61+/-0.07% ID/g at 1 and 4 h post injection, respectively. The specificity of tumor localization was demonstrated by coinjection of 3 mg/kg unlabeled E(3)-uroguanylin, which reduced tumor uptake by 69%. Uptake in kidney, however, was dramatically higher for the uroguanylin peptides than for previously characterized radiolabeled E. coli heat-stable enterotoxin (STh) analogs targeting GC-C, and was also inhibited by coinjection of unlabeled peptide in a fashion not previously observed. CONCLUSION: Use of uroguanylin-targeting vectors for in vivo imaging of colorectal cancers expressing GC-C resulted in tumor uptake that paralleled that of higher affinity heat-stable enterotoxin peptides, but also resulted in increased kidney uptake in vivo.


Assuntos
Neoplasias Colorretais/diagnóstico por imagem , Radioisótopos de Índio , Peptídeos Natriuréticos , Compostos Radiofarmacêuticos , Sequência de Aminoácidos , Animais , Neoplasias Colorretais/metabolismo , Feminino , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/farmacocinética , Humanos , Radioisótopos de Índio/química , Radioisótopos de Índio/farmacocinética , Camundongos , Camundongos Endogâmicos ICR , Camundongos SCID , Dados de Sequência Molecular , Peptídeos Natriuréticos/química , Peptídeos Natriuréticos/farmacocinética , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Transplante Heterólogo
4.
Med Phys ; 35(9): 3866-74, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18841837

RESUMO

Advances in laboratory animal imaging have provided new resources for noninvasive biomedical research. Among these technologies is microcomputed tomography (microCT) which is widely used to obtain high resolution anatomic images of small animals. Because microCT utilizes ionizing radiation for image formation, radiation exposure during imaging is a concern. The objective of this study was to quantify the radiation dose delivered during a standard microCT scan. Radiation dose was measured using thermoluminescent dosimeters (TLDs), which were irradiated employing an 80 kVp x-ray source, with 0.5 mm A1 filtration and a total of 54 mA s for a full 360 deg rotation of the unit. The TLD data were validated using a 3.2 cm3 CT ion chamber probe. TLD results showed a single microCT scan air kerma of 78.0 +/- 5.0 mGy when using a poly(methylmethacrylate) (PMMA) anesthesia support module and an air kerma of 92.0 +/- 6.0 mGy without the use of the anesthesia module. The validation CT ion chamber study provided a measured radiation air kerma of 81.0 +/- 4.0 mGy and 97.0 +/- 5.0 mGy with and without the PMMA anesthesia module, respectively. Internal TLD analysis demonstrated an average mouse organ radiation absorbed dose of 76.0 +/- 5.0 mGy. The author's results have defined x-ray exposure for a routine microCT study which must be taken into consideration when performing serial molecular imaging studies involving the microCT imaging modality.


Assuntos
Dosimetria Termoluminescente/métodos , Tomografia Computadorizada por Raios X/métodos , Animais , Camundongos , Dosimetria Termoluminescente/instrumentação , Tomografia Computadorizada por Raios X/instrumentação
5.
Bioconjug Chem ; 19(9): 1803-12, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18712899

RESUMO

The high incidence of BB2 receptor (BB2r) expression in various cancers has prompted investigators to pursue the development of BB2r-targeted agents for diagnostic imaging, chemotherapy, and radiotherapy. Development of BB2r-targeted agents, based on the bombesin (BBN) peptide, has largely involved the use of the bifunctional chelate approach in which the linking group serves several key roles including pharmacokinetic modification. Understanding the in vivo properties of the various pharmacokinetic modifying linking groups is crucial for developing BB2r-targeted agents with improved targeting and clearance characteristics. The goal of this study was to systematically evaluate the pharmacokinetic profile of aliphatic hydrocarbon, aromatic, and poly(ethylene glycol) (ether) functional groups in order to obtain a better understanding of the in vivo properties of these pharmacokinetic modifiers. Specifically, we synthesized six radioconjugates with the structure 111In-DOTA- X-BBN(7-14)NH2, where X = 8-aminooctanoic acid (8-AOC), 5-amino-3-oxapentyl-succinamic acid (5-ADS), 8-amino-3,6-dioxaoctyl-succinamic acid (8-AOS), p-aminobenzoic acid (AMBA), Gly-AMBA, and Gly- p-aminomethylbenzoic acid (Gly-AM2BA). All of the (nat)In-conjugates demonstrated nanomolar binding affinities to the BB2r. In CF-1 mice, the BB2r uptake in the pancreas of radioconjugates containing aromatic linking groups was found to be significantly higher at 1 h postinjection than the radioconjugates with ether linker moieties. For PC-3 tumor-bearing SCID mice, the tumor uptake was found to be 6.66 +/- 2.00, 6.21 +/- 1.57, 6.36 +/- 1.60, 4.46 +/- 0.81, and 7.76 +/- 1.19 %ID/g for the 8-AOC, 8-ADS, AMBA, Gly-AMBA, and Gly-AM2BA radioconjugates, respectively, at 15 min postinjection. By 24 h postinjection, the radioconjugates containing aromatic groups exhibited the highest percentage tumor retention with 11.4%, 19.8%, 26.6%, 25.8%, and 25.5% relative to the 15 min values remaining in the tumor tissue for the 8-AOC, 8-ADS, AMBA, Gly-AMBA, and Gly-AM2BA radioconjugates, respectively. Fused Micro-SPECT/CT imaging studies performed at 24 h postinjection revealed substantial accumulation of radioactivity in the tumor tissue for all radioconjugates. In both biodistribution and Micro-SPECT/CT imaging studies, the radioconjugates containing aromatic linking groups typically exhibited significantly higher G.I. tract retention than the hydrocarbon or ether linking moieties. In conclusion, our studies indicate that radioconjugates incorporating aromatic linking groups, of the type investigated, generally demonstrated enhanced retention in BB2r expressing tissues in comparison to either the hydrocarbon or ether linking moieties. Furthermore, this investigation clearly demonstrates the significance of the linking group upon not only the in vivo clearance of the radiopharmaceutical, but also on the in vivo uptake and retention of the BB2r-targeted agent in tumor tissue. Future designs of BB2r-targeted agents should include a careful consideration of the effect linking group functionality has upon tumor targeting and retention.


Assuntos
Bombesina , Neurotransmissores , Compostos Organometálicos , Neoplasias da Próstata , Compostos Radiofarmacêuticos , Ácido 4-Aminobenzoico/química , Animais , Ligação Competitiva , Bombesina/análogos & derivados , Caprilatos/química , Compostos Heterocíclicos com 1 Anel/química , Humanos , Marcação por Isótopo , Masculino , Camundongos , Camundongos SCID , Modelos Biológicos , Neurotransmissores/química , Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacocinética , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/radioterapia , Cintilografia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética
7.
J Nucl Med ; 48(8): 1327-37, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17631556

RESUMO

UNLABELLED: The BB2 receptor subtype, of the bombesin family of receptors, has been shown to be highly overexpressed in a variety of human tumors, including prostate cancer. Bombesin (BBN), a 14-amino acid peptide, has been shown to target the BB2 receptor with high affinity. 64Cu (half-life = 12.7 h, beta+: 18%, E(beta+ max) = 653 keV; beta-: 37%, E(beta- max) = 578 keV) is a radioisotope that has clinical potential for application in both diagnostic imaging and radionuclide therapy. Recently, new chelation systems such as 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid (CB-TE2A) have been reported to significantly stabilize the 64Cu radiometal in vivo. The increased stability of the 64Cu-CB-TE2A chelate complex has been shown to significantly reduce nontarget retention compared with tetraazamacrocycles such as 1,4,7,10-tetraazacyclodoadecane-N,N',N'',N'''-tetraacetic acid (DOTA). The aim of this study was to determine whether the CB-TE2A chelation system could significantly improve the in vivo stability of 64Cu bombesin analogs. The study directly compares 64Cu bombesin analogs using the CB-TE2A and DOTA chelation systems in a prostate cancer xenograft SCID (severely compromised immunodeficient) mouse model. METHODS: The CB-TE2A-8-AOC-BBN(7-14)NH2 and DOTA-8-AOC-BBN(7-14)NH2 conjugates were synthesized and radiolabeled with 64Cu. The receptor-binding affinity and internalization profile of each metallated conjugate was evaluated using PC-3 cells. Pharmacokinetic and small-animal PET/CT studies were performed using female SCID mice bearing PC-3 xenografts. RESULTS: In vivo BB2 receptor targeting was confirmed by tumor uptake values of 6.95 +/- 2.27 and 4.95 +/- 0.91 %ID/g (percentage injected dose per gram) at the 15-min time point for the 64Cu-CB-TE2A and 64Cu-DOTA radioconjugates, respectively. At the 24-h time point, liver uptake was substantially reduced for the 64Cu-CB-TE2A radioconjugate (0.21 +/- 0.06 %ID/g) compared with the 64Cu-DOTA radioconjugate (7.80 +/- 1.51 %ID/g). The 64Cu-CB-TE2A-8-AOC-BBN(7-14)NH2 radioconjugate demonstrated significant clearance, 98.60 +/- 0.28 %ID, from the mouse at 24 h after injection. In contrast, only 67.84 +/- 5.43 %ID of the 64Cu activity was excreted using the 64Cu-DOTA-8-AOC-BBN(7-14)NH2 radioconjugate because of nontarget retention. CONCLUSION: The pharmacokinetic and small-animal PET/CT studies demonstrate significantly improved nontarget tissue clearance for the 64Cu-CB-TE2A8-AOC-BBN(7-14)NH2. This is attributed to the improved in vivo stability of the 64Cu-CB-TE2A chelate complex as compared with the 64Cu-DOTA chelate complex.


Assuntos
Bombesina/análogos & derivados , Quelantes , Radioisótopos de Cobre , Compostos Organometálicos , Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Próstata/diagnóstico , Compostos Radiofarmacêuticos , Tomografia Computadorizada por Raios X/métodos , Animais , Linhagem Celular Tumoral , Feminino , Compostos Heterocíclicos com 1 Anel , Marcação por Isótopo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos SCID
8.
Mol Imaging ; 6(3): 171-80, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17532883

RESUMO

Gastrin-releasing peptide (GRP) receptors are overexpressed on several types of human cancer cells, including breast, prostate, small cell lung, and pancreatic cancers. Bombesin (BBN), a 14-amino acid peptide that is an analogue of human GRP, binds to GRP receptors with very high affinity and specificity. The aim of this study was to develop a new fluorescent probe based on BBN having high tumor uptake and optimal pharmacokinetics for specific targeting and optical imaging of human breast cancer tissue. In this study, solid-phase peptide synthesis was used to produce H(2)N-glycylglycylglycine-BBN[7-14]NH(2) peptide with the following general sequence: H(2)N-G-G-G-Q-W-A-V-G-H-L-M-(NH(2)). This conjugate was purified by reversed-phase high-performance liquid chromatography and characterized by electrospray-ionization mass spectra. The fluorescent probe Alexa Fluor 680-G-G-G-BBN[7-14]NH(2) conjugate was prepared by reaction of Alexa Fluor 680 succinimidyl ester to H(2)N-G-G-G-BBN[7-14]NH(2) in dimethylformamide (DMF). In vitro competitive binding assays, using (125)I-Tyr(4)-BBN as the radiolabeling gold standard, demonstrated an inhibitory concentration 50% value of 7.7 +/- 1.4 nM in human T-47D breast cancer cells. Confocal fluorescence microscopy images of Alexa Fluor 680-G-G-G-BBN[7-14]NH(2) in human T-47D breast cancer cells indicated specific uptake, internalization, and receptor blocking of the fluorescent bioprobe in vitro. In vivo investigations in SCID mice bearing xenografted T-47D breast cancer lesions demonstrated the ability of this new conjugate to specifically target tumor tissue with high selectivity and affinity.


Assuntos
Bombesina/análogos & derivados , Neoplasias da Mama/diagnóstico , Corantes Fluorescentes/análise , Fragmentos de Peptídeos/análise , Receptores da Bombesina/análise , Animais , Bombesina/análise , Bombesina/síntese química , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos SCID , Microscopia de Fluorescência , Fragmentos de Peptídeos/síntese química , Transplante Heterólogo
9.
Anticancer Res ; 26(5A): 3243-51, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17094436

RESUMO

BACKGROUND: Radiolabeled analogs of the E. coli heat-stable enterotoxin (ST(h)) are currently under study as imaging and therapeutic agents for colorectal cancer. The aim of these studies is to compare in vitro and in vivo characteristics of two novel ST(h) analogs with appended DOTA chelating moieties. MATERIALS AND METHODS: ST(h) analogs were synthesized with pendant N-terminal DOTA moieties and radiolabeled with indium-111. In vitro cell binding was studied using cultured T-84 human colorectal cancer cells, and in vivo biodistribution studies were carried out using T-84 human colorectal tumor xenografts in SCID mice. RESULTS: Competitive radioligand binding assays employing T-84 human colon cancer cells demonstrated similar IC50 values for the F19-ST(h)(2-19) and F9-ST(h)(6-19) analogs. Addition of DOTA to the N-terminus of these peptides elicited distinctly different effects on binding affinities in vitro, effects that were largely unchanged by metallation with nonradioactive (nat)In. In vivo pharmacokinetic studies in SCID mice bearing T-84 human colon cancer-derived tumor xenografts demonstrated tumor uptake of 0.74 +/- 0.1% ID/g at 4 h post-injection (p.i.) for the 111In-DOTA-F19-ST(h)(2-19) analog, and significantly reduced tumor localization (0.27 + 0.08 % ID/g) for the 111In-DOTA-F9-ST(h)(6-19) analog. CONCLUSION: These results demonstrate that placement of a DOTA moiety immediately adjacent to Cys 6 in ST(h) significantly inhibits receptor binding in vitro and in vivo, highlighting the need for intervening spacer residues between the pharmacophore and the DOTA chelating moiety in effective ST(h)-based radiopharmaceutical constructs.


Assuntos
Toxinas Bacterianas/farmacocinética , Neoplasias do Colo/tratamento farmacológico , Enterotoxinas/farmacocinética , Proteínas de Escherichia coli/farmacocinética , Temperatura Alta , Animais , Toxinas Bacterianas/uso terapêutico , Ligação Competitiva , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/metabolismo , Enterotoxinas/química , Enterotoxinas/uso terapêutico , Proteínas de Escherichia coli/uso terapêutico , Feminino , Compostos Heterocíclicos com 1 Anel , Humanos , Radioisótopos de Índio/farmacocinética , Radioisótopos de Índio/uso terapêutico , Ligantes , Camundongos , Camundongos Endogâmicos ICR , Camundongos SCID , Ligação Proteica , Desnaturação Proteica , Cintilografia , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/uso terapêutico , Transplante Heterólogo , Células Tumorais Cultivadas
10.
Mol Imaging ; 5(2): 105-14, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16954024

RESUMO

Metastatic mouse models of melanoma have been characterized by gross necropsy examination, histopathology, and optical imaging. To determine if the time progression, extent, and metabolism of melanoma metastases could be monitored noninvasively, serial micro-CT and small-animal PET imaging studies were performed by using a mouse model of melanoma. Juvenile female C57BL/6 mice were injected intravenously with syngenic B16-F10 melanoma cells. Serial micro-CT imaging studies were performed on anesthetized mice. Mice were necropsied at the development of adverse clinical signs or at postinjection Day 30, and tissues were collected for histopathology. In a separate study of four mice, tumor viability was assessed with 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) and studied by using small-animal PET imaging. A total of 59% of the mice developed metastatic tumors. Micro-CT image analysis was able to identify and follow up to 36% of metastatic lesions. Examples of metastatic lesions identified and followed up by micro-CT imaging included a lung metastasis, mandibular metastasis, subcutaneous metastasis, and tibial/femoral metastasis. Micro-CT and small-animal PET fusion imaging successfully correlated anatomic localization of glucose metabolism of the metastatic tumors. Micro-CT and small-animal PET imaging were found to be highly effective in detection and characterization of lesions produced by this metastatic melanoma model.


Assuntos
Neoplasias Ósseas/secundário , Neoplasias Pulmonares/secundário , Melanoma Experimental/diagnóstico , Melanoma Experimental/patologia , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Animais , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Feminino , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/secundário
11.
Nucl Med Biol ; 33(4): 481-8, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16720239

RESUMO

The human E. coli heat-stable enterotoxin (ST(h), amino acid sequence N1SSNYCCELCCNPACTGCY19) binds specifically to the guanylate cyclase C (GC-C) receptor, which is present in high density on the apical surface of normal intestinal epithelial cells as well as on the surface of human colon cancer cells. Analogs of ST(h) are currently being used as vectors targeting human colon cancers. Previous studies in our laboratory have focused on development of 111Indium-labeled ST(h) analogs for in vivo imaging applications. Here, we extend the scope of this work to include targeting of the therapeutic radionuclides 90Y and 177Lu. The peptide DOTA-F19-ST(h)(1-19) was synthesized using conventional Fmoc-based solid-phase techniques and refolded in dilute aqueous solution. The peptide was purified by RP-HPLC and characterized by MALDI-TOF MS and in vitro receptor binding assay. The DOTA-conjugate was metallated with nonradioactive Lu(III)Cl3 and Y(III)Cl3, and IC50 values of 2.6+/-0.1 and 4.2+/-0.9 nM were determined for the Lu- and Y-labeled peptides, respectively. 177Lu(III)Cl3 and 90Y(III)Cl3 labeling yielded tracer preparations that were inseparable by C18 RP-HPLC, indicating that putative differences between Lu-, Y- and In coordination spheres are not observed in the context of labeled ST(h) peptides. In vivo biodistribution studies of the 177Lu-labeled peptide in severe combined immunodeficient (SCID) mice bearing T-84 human cancer tumor xenografts showed rapid clearance from the bloodstream, with >90 %ID in the urine at 1 h pi. Localization of the tracer within tumor xenografts was 1.86+/-0.91 %ID/g at 1 h pi, a value higher than for all other tissues with the exception of kidney (2.74+/-0.24 %ID/g). At 24 h pi, >98 %ID was excreted into the urine, and 0.35+/-0.23 %ID/g remained in tumor, again higher than in all other tissues except kidney (0.91+/-0.46 %ID/g). Biodistribution results at 24 h pi for the 90Y-labeled peptide mirrored those for the 177Lu analog, in agreement with the identical behavior of the labeled analogs by C18 RP-HPLC. These results demonstrate the ability of 177Lu- and 90Y-labeled ST(h) molecules to specifically target GC-C receptors expressed on T-84 human colon cancer cells.


Assuntos
Toxinas Bacterianas/farmacocinética , Neoplasias do Colo/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Escherichia coli , Lutécio/farmacocinética , Peptídeos Natriuréticos/metabolismo , Radioisótopos de Ítrio/farmacocinética , Animais , Toxinas Bacterianas/química , Toxinas Bacterianas/uso terapêutico , Linhagem Celular Tumoral , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/radioterapia , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Feminino , Temperatura Alta , Humanos , Marcação por Isótopo/métodos , Lutécio/química , Lutécio/uso terapêutico , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos ICR , Radioisótopos/química , Radioisótopos/farmacocinética , Radioisótopos/uso terapêutico , Cintilografia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/uso terapêutico , Receptores de Superfície Celular/metabolismo , Distribuição Tecidual , Radioisótopos de Ítrio/química , Radioisótopos de Ítrio/uso terapêutico
12.
Breast Cancer Res Treat ; 98(1): 7-15, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16724166

RESUMO

Research into the interaction between the E. coli heat-stable enterotoxin (STh) and the guanylin receptor guanylate cyclase C (GC-C) has generated >100 synthetic analogs of the peptide, several of which have been investigated as imaging or therapeutic agents for colorectal cancers. The evidence presented here suggests that in addition to STh binding to GC-C expressing cell lines derived from human colon, STh also specifically binds to an as yet unidentified receptor expressed in high densities on the surface of cell lines derived from human breast cancers. In vitro whole-cell crosslinking studies using 125I-labeled F19-STh(1-19) demonstrate that the putative STh binding protein migrates as an approximately 120-125 kDa species by SDS-PAGE, significantly smaller than the glycosylated GC-C molecule found in the T84 human colon cancer cell line. RT-PCR using total RNA isolated from breast and colon cancer cell lines indicates that GC-C transcripts are undetectable in human breast cancer cell lines and abundant in human colon cancer cell lines. In vitro competitive binding studies using STh analogs and the estrogen receptor positive (ER+) T-47D cell line demonstrated IC50 values between 2.6 and 8.5 nM. Similar studies on the estrogen receptor negative (ER-) cell line MDA-MB-231 showed IC50's between 5.6 and 9.9 nM. Saturation binding analysis revealed receptor expression to fall between 40,000 and 120,000 sites per cell in these cell lines, receptor abundances equal to or greater than the abundance of GC-C in colorectal cancer cell lines. STh binding to these cells, although of similar affinity to STh binding to GC-C, is distinguishable from it on the basis of its ligand specificity. The characteristics of STh analogs as radiopharmaceutical agents were tested in an in vivo model utilizing T-47D human breast cancer cell xenografts in SCID mice. Clearance of STh analogs was rapid, primarily via renal excretion into the urine, with >85% ID excreted into the urine at 1 h p.i. Tumor uptake at 1 h p.i. in T-47D tumor cell xenografts was 0.67+/-0.23% ID/g, and was significantly decreased (p<0.05) upon co-administration of 4 mg/kg unlabeled STh. These results suggest that STh may find application for the imaging and treatment of breast cancer.


Assuntos
Neoplasias da Mama/terapia , Ensaios de Seleção de Medicamentos Antitumorais , Enterotoxinas/uso terapêutico , Escherichia coli/metabolismo , Radioisótopos de Índio/farmacologia , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Reagentes de Ligações Cruzadas/farmacologia , Feminino , Humanos , Técnicas In Vitro , Concentração Inibidora 50 , Camundongos , Camundongos SCID , Transplante de Neoplasias , Ligação Proteica
13.
Cancer Biother Radiopharm ; 21(2): 155-66, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16706636

RESUMO

The focus of this study was to evaluate the therapeutic benefit of combined gastrin-releasing peptide (GRP) receptor-targeted radiotherapy (TRT) with chemotherapy, using the PC-3 xenograft severe combined immunodeficiency (SCID) mouse model. (177)Lu-DOTA-8-AOC-BBN(7-14)NH(2) is a radiotherapeutic peptide that specifically targets the gastrin-releasing peptide receptor overexpressed on primary and metastatic prostate cancer. The chemotherapeutic agents, docetaxel and estramustine, were administered as single agents or in combination with the receptor-targeted radiotherapeutic agent. Combination receptor TRT/chemotherapy studies were begun 21 days postxenografting and were conducted as multiple-dose trials. The GRP receptor TRT agent was administered every 14 days, and single and combination chemotherapy dose regimens were given weekly. Tumor size, body weight, and body condition score were evaluated twice-weekly and a hematology profile once-weekly. Therapy study tumor volumes were evaluated by way of a repeated measures analysis of variance (ANOVA). Tumor volume measurements at 12 days postdose administration demonstrated a statistically significant (two-tailed P-value <0.05) tumor growth suppression in all experimental groups receiving GRP receptor-targeted radiotherapy, when compared to the control group. The two combined GRP receptor TRT/chemotherapy treatment groups demonstrated the greatest tumor growth suppression of all treatment groups. In comparing the two combined GRP receptor TRT/chemotherapy groups to the GRP receptor TRT alone group, a statistically significant difference was demonstrated for the combined groups by day 30, postdose administration. These data demonstrate that GRP receptor-targeted radiation therapy, using (177)Lu-DOTA-8-AOC-BBN(7-14)NH(2), used either alone or in combination with conventional chemotherapy, can suppress the growth of androgen- independent prostate cancer (AIPC).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bombesina/farmacologia , Fragmentos de Peptídeos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Animais , Análise Química do Sangue , Bombesina/administração & dosagem , Bombesina/farmacocinética , Docetaxel , Estramustina/administração & dosagem , Feminino , Lutécio/uso terapêutico , Masculino , Camundongos , Camundongos SCID , Modelos Moleculares , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/farmacocinética , Neoplasias da Próstata/metabolismo , Radioisótopos/uso terapêutico , Compostos Radiofarmacêuticos/farmacologia , Receptores da Bombesina/metabolismo , Taxoides/administração & dosagem , Proteína Tumoral 1 Controlada por Tradução , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Nucl Med Biol ; 32(7): 733-40, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16243649

RESUMO

Research laboratories around the world are currently focusing their efforts toward the development of radiometallated, site-directed, diagnostic/therapeutic agents based upon small peptides such as octreotide, neurotensin, alpha-melanocyte stimulating hormone, vasointestinal peptide and others. Bombesin (BBN) or derivatives of bombesin are also of significant interest. Bombesin is a 14-amino-acid peptide with very high affinity for the BB2 or gastrin-releasing peptide receptor (GRPr). Over-expression of the GRPr on a variety of human cancers (i.e., breast, prostate, pancreatic, small cell lung, etc.) provides potential efficacy toward development of radiometallated BBN derivatives for targeting and, hence, diagnosis/treatment of these specific diseases. New derivatives are being developed that are also capable of targeting the BB1 and BB3 receptor subtypes that are over-expressed on cancer cells. This review highlights some of the more recent developments toward design of BBN receptor-specific radiopharmaceuticals that have taken place over the past 2 years.


Assuntos
Bombesina/metabolismo , Peptídeos/metabolismo , Radioisótopos/metabolismo , Receptores da Bombesina/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Bombesina/química , Bombesina/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Desenho de Fármacos , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Neoplasias/radioterapia , Peptídeos/química , Peptídeos/uso terapêutico , Radioisótopos/química , Radioisótopos/uso terapêutico , Cintilografia , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Compostos Radiofarmacêuticos/uso terapêutico
15.
Cancer Biother Radiopharm ; 20(4): 436-49, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16114992

RESUMO

Several short-lived, high-energy beta emitters are being proposed as the radionuclide components for molecular- targeted potential cancer therapeutic agents. The laboratory mice used to determine the efficacy of these new agents have organs that are relatively small compared to the ranges of these high-energy particles. The dosimetry model developed by Hui et al. was extended to provide realistic beta-dose estimates for organs in mice that received therapeutic radiopharmaceuticals containing (90)Y, (188)Re, (166)Ho, (149)Pm, (64)Cu, and (177)Lu. Major organs in this model included the liver, spleen, kidneys, lungs, heart, stomach, small and large bowel, thyroid, pancreas, bone, marrow, carcass, and a 0.025-g tumor. The study as reported in this paper verifies their results for (90)Y and extends them by using their organ geometry factors combined with newly calculated organ self-absorbed fractions from PEREGRINE and MCNP. PEREGRINE and MCNP agree to within 8% for the worst-case organ with average differences (averaged over all organs) decreasing from 5% for (90)Y to 1% for (177)Lu. When used with typical biodistribution data, the three different models predict doses that are in agreement to within 5% for the worst-case organ. The beta-absorbed fractions and cross-organ-deposited energy provided in this paper can be used by researchers to predict mouse-organ doses and should contribute to an improved understanding of the relationship between dose and radiation toxicity in mouse models where use of these isotopes is favorable.


Assuntos
Radioisótopos de Cobre/uso terapêutico , Hólmio/uso terapêutico , Lutécio/uso terapêutico , Promécio/uso terapêutico , Radioisótopos/uso terapêutico , Compostos Radiofarmacêuticos/farmacocinética , Rênio/uso terapêutico , Radioisótopos de Ítrio/uso terapêutico , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Nus , Modelos Estatísticos , Modelos Teóricos , Radioimunoterapia , Radiometria , Distribuição Tecidual
16.
Bioconjug Chem ; 15(4): 872-80, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15264876

RESUMO

Three human Escherichia coli heat-stable peptide (STh) analogues, each containing a DOTA chelating group, were synthesized by SPPS and oxidative refolding and compared in in vitro and in vivo systems. One analogue, DOTA-F19-STh(1-19), contains an N-terminal DOTA group attached via an amide bond linkage to an STh moiety which is essentially wild-type except for a Tyr to Phe alteration at position 19 of the molecule. A second analogue, DOTA-R1,4,F19-STh(1-19), differs from the first in that asparagine residues in positions 1 and 4 have been altered to arginine residues in order to examine the effect of positively charged groups in the linker domain. A third analogue, DOTA-11AUN-F19-STh(1-19), differs from the first in that it incorporates an 11-aminoundecanoic acid spacer group between the DOTA group and the first asparagine residue. In vitro competitive binding assays utilizing T-84 human colon cancer cells demonstrated that significant alterations to the N-terminal region of the STh molecule were well tolerated and did not significantly affect binding affinity of STh for the guanylyl cyclase C (GC-C) receptor. Internalization and efflux studies of the indium-labeled species demonstrated that inclusion of positive charge in the linker moiety inhibits internalization of the compound within tumor cells. The characteristics of the three analogues were compared in an in vivo model utilizing T-84 human colon cancer cell xenografts in SCID mice. Clearance of all analogues was rapid, primarily via renal excretion into the urine, with >89% ID excreted into the urine at 1 h pi for all analogues. The 111In-DOTA-R1,4,F19-STh(1-19) and 111In-DOTA-11AUN-F19-STh(1-19) analogues both had longer residence times in the blood than did the 111In-DOTA-F19-STh(1-19) analogue, probably accounting for increased %ID/g values for tumors and nontarget tissues at 1 h pi. At 4 h pi, significant differences between analogues were only seen with respect to metabolic routes of excretion, indicating that increased blood residence time did not result in increased tumor residualization. Reduction of hepatic uptake of these compounds, however, could have significance in the development of agents for the imaging of hepatic metastases. The ability to manipulate in vivo pharmacodynamics and tumor uptake of radiolabeled STh peptides through modification of linker moieties is under continuing investigation in order to produce optimal imaging and therapeutic radiopharmaceuticals.


Assuntos
Quelantes/química , Proteínas de Escherichia coli/química , Temperatura Alta , Animais , Linhagem Celular Tumoral , Quelantes/metabolismo , Quelantes/farmacocinética , Cromatografia Líquida de Alta Pressão , Proteínas de Escherichia coli/administração & dosagem , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/farmacocinética , Feminino , Humanos , Radioisótopos de Índio , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Peso Molecular , Transplante de Neoplasias , Ligação Proteica , Desnaturação Proteica , Renaturação Proteica , Distribuição Tecidual
17.
Cancer Res ; 63(14): 4082-8, 2003 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-12874010

RESUMO

Bombesin (BBN), a 14 amino acid peptide, is an analogue of human gastrin-releasing peptide (GRP) that binds to GRP receptors (GRPrs) with high affinity and specificity. The GRPr is overexpressed on a variety of human cancer cells, including prostate, breast, lung, and pancreatic cancers. The specific aim of this study was to develop (99m)Tc(I)-radiolabled BBN analogues that maintain high specificity for the GRPr in vivo. A preselected synthetic sequence via solid phase peptide synthesis was designed to produce 2,3-diaminopropionic acid (Dpr)-BBN conjugates with the following general structure: Dpr-Ser-Ser-Ser-Gln-Trp-Ala-Val-Gly-His-Leu-Met-(NH(2)). The new BBN constructs were purified by reversed phase high-performance liquid chromatography. Electrospray mass spectrometry was used to characterize the nonmetallated BBN conjugates. Re(I)-BBN conjugates were prepared by the reaction of [Re(Br)(3)(CO)(3)](2-) and Dpr-Ser-Ser-Ser-Gln-Trp-Ala-Val-Gly-His-Leu-Met-(NH(2)) with gentle heating. Electrospray mass spectrometry was used to determine the molecular constitution of the new Re(I) conjugates. The (99m)Tc conjugates were prepared at the tracer level by preconjugation, postlabeling approach from the reaction of [(99m)Tc(H(2)O)(3)(CO)(3)](+) and corresponding ligand. The (99m)Tc and Re(I) conjugates behaved similarly under identical reversed phase high-performance liquid chromatography conditions. Results from in vitro and in vivo models demonstrated the ability of these derivatives to specifically target GRPrs on human, prostate, cancerous PC-3 cells.


Assuntos
Bombesina/análogos & derivados , Compostos de Organotecnécio/síntese química , Compostos de Organotecnécio/farmacocinética , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/metabolismo , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Receptores da Bombesina/metabolismo , beta-Alanina/análogos & derivados , beta-Alanina/química , Sequência de Aminoácidos , Animais , Bombesina/farmacocinética , Feminino , Humanos , Marcação por Isótopo/métodos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos SCID , Cintilografia , Espectrometria de Massas por Ionização por Electrospray , beta-Alanina/farmacocinética
18.
J Nucl Med ; 44(5): 823-31, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12732685

RESUMO

UNLABELLED: Gastrin-releasing peptide (GRP) receptors have been shown to be expressed with high densities on several types of cancer cells including prostate, breast, small cell lung, and pancreas cancers. Bombesin (BBN) has been known to bind to GRP receptors with high affinity and specificity. The aim of these studies was to develop new (111)In-labeled BBN analogs having high tumor uptake and optimal pharmacokinetics for specific targeting of human prostate cancers. METHODS: A novel series of dodecanetetraacetic acid (DOTA)-X-BBN[7-14]NH(2) (X = 0, beta-Ala, 5-Ava, 8-Aoc, or 11-Aun) conjugates and their In(III)/(111)In complexes exhibiting high GRP-receptor-binding affinities were synthesized and characterized. RESULTS: In vitro competitive binding assays, using PC-3 androgen-independent human prostate cancer cells, demonstrated values of <2.5 nmol/L for inhibitory concentration of 50% for analogs with beta-Ala, 5-Ava, and 8-Aoc spacers. In vivo biodistribution studies of the (111)In-DOTA-X-BBN[7-14]NH(2) conjugates performed on CF-1 mice at 1 h after injection have revealed that the uptake of radioactivity in the pancreas, a GRP-receptor-expressing tissue, increased as a function of hydrocarbon spacer length (i.e., from 0.20 +/- 0.04 percentage injected dose [%ID] per gram for the analog with no spacer to a maximum of 26.97 +/- 3.97 %ID/g for the analog with 8-Aoc spacer). The radioactivity was cleared efficiently from the blood pool by excretion mainly through the renal/urinary pathway (e.g., 71.6 +/- 1.8 %ID at 1 h after injection for 8-Aoc spacer analog). In vivo pharmacokinetic studies of the (111)In-DOTA-8-Aoc-BBN[7-14]NH(2) conjugate conducted on PC-3 human prostate cancer-derived xenografts in SCID mice showed a specific uptake of radioactivity in tumor, with 3.63 +/- 1.11 %ID/g observed at 1 h after injection. High tumor-to-blood and tumor-to-muscle ratios of approximately 6:1 and 45:1, respectively, were achieved at 1 h after injection. Relative to the radioactivity observed in the tumor at 1 h after injection, 43%, 19%, and 9% of the radioactivity was retained at, respectively, 24, 48, and 72 h after injection. CONCLUSION: These studies showed that radiometallated DOTA-X-BBN[7-14]NH(2) constructs with hydrocarbon spacers ranging from 5 to 8 carbon atoms are feasible candidates for further development as diagnostic and therapeutic radiopharmaceuticals for patients with GRP-positive cancers.


Assuntos
Radioisótopos de Índio , Neoplasias da Próstata/diagnóstico por imagem , Compostos Radiofarmacêuticos , Receptores da Bombesina/análise , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos SCID , Cintilografia , Distribuição Tecidual , Células Tumorais Cultivadas
19.
Anticancer Res ; 23(1A): 63-70, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12680195

RESUMO

BACKGROUND: Bombesin (BBN), a 14 amino acid peptide, is an analogue of human gastrin-releasing peptide (GRP) that binds to GRP receptors (GRPr) with high affinity and specificity. The GRPr is over-expressed on a variety of human cancer cells including prostate, breast, lung, and pancreatic cancers. The specific aim of this study was to develop a 188Re(I)-radiolabeled BBN analogue that maintains high specificity for the GRPr in vivo. MATERIALS AND METHODS: A preselected synthetic sequence via solid phase peptide synthesis (SPPS) was designed to produce a Dpr-BBN (Dpr = Diaminopropionic acid) conjugate with the following general structure: Dpr-X-Q-W-A-V-G-H-L-M-(NH2), where the spacer group, X = Serylserylserine. The new BBN-construct was purified by reversed phase-HPLC (RP-HPLC). The non-radioactive Re(I)-BBN conjugate was prepared by the reaction of [Re(Br)3(CO)3]2- and Dpr-SSS-bombesin(7-14)NH2 with heating. ES-MS was used to determine the molecular constitution of the non-metallated and metallated Re (I)--conjugates. The 188 Re-conjugate was prepared at the tracer level by the pre-conjugation, postlabeling approach from the reaction of [188Re(H2O)3(CO)3]+ and corresponding ligand. RESULTS: The 188Re- and non-radioactive Re(I)conjugate behaved similarly under identical RP-HPLC conditions. In vitro cell displacement assays showed that the new conjugate has an IC50 value of approximately 1 nM. In vitro cell binding assays showed that the new conjugate is rapidly internalized and exhibits long-term retention, demonstrating the agonistic efficacy of the radiolabel. In vivo targeting of human prostate, PC-3 tumor xenografts indicated uptake and retention of the new radioconjugate for time-point < or = 24 hours. CONCLUSION: Results from in vitro and in vivo models demonstrated the ability of these derivatives to specifically target GRP receptors on human, prostate and cancerous PC-3 cells. This new construct holds potential for the development of a therapeutic entity for the treatment of prostate cancer.


Assuntos
Bombesina/análogos & derivados , Bombesina/síntese química , Bombesina/farmacocinética , Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacocinética , Radioisótopos/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Receptores da Bombesina/metabolismo , Rênio/química , Animais , Bombesina/metabolismo , Humanos , Marcação por Isótopo/métodos , Masculino , Camundongos , Camundongos SCID , Compostos Organometálicos/metabolismo , Neoplasias da Próstata/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Rênio/metabolismo , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Nucl Med Biol ; 30(2): 101-9, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12623108

RESUMO

Bombesin (BBN), a 14 amino acid peptide, is an analogue of human gastrin releasing peptide (GRP) that binds to GRP receptors (GRPr) with high affinity and specificity. The GRPr is over expressed on a variety of human cancer cells including prostate, breast, lung, and pancreatic cancers. The specific aim of this study was to identify a BBN analogue that can be radiolabeled with (177)Lu and maintains high specificity for GRPr positive prostate cancer tumors in vivo. A preselected synthetic sequence via solid phase peptide synthesis (SPPS) was designed to produce a DOTA-BBN (DOTA = 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid) conjugate with the following general structure: DOTA-X-Q-W-A-V-G-H-L-M-(NH(2)), where the spacer group, X = omega-NH(2)(CH(2))(7)COOH (8-Aoc). The BBN-construct was purified by reversed phase-HPLC (RP-HPLC). Electrospray Mass Spectrometry (ES-MS) was used to characterize both metallated and non-metallated BBN-conjugates. The new DOTA-conjugate was metallated with (177)Lu(III)Cl(3) or non-radioactive Lu(III)Cl(3). The (177)Lu(III)- and non-radiolabeled Lu(III)-conjugates exhibit the same retention times under identical RP-HPLC conditions. The (177)Lu-DOTA-8-Aoc-BBN[7-14]NH(2) conjugate was found to exhibit optimal pharmacokinetic properties in CF-1 normal mice. In vitro and in vivo models demonstrated the ability of the (177)Lu-DOTA-8-Aoc-BBN[7-14]NH(2) conjugate to specifically target GRP receptors expressed on PC-3 human prostate cancer cells.


Assuntos
Biomarcadores Tumorais/metabolismo , Bombesina/farmacocinética , Fragmentos de Peptídeos/farmacocinética , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/metabolismo , Receptores da Bombesina/metabolismo , Animais , Bombesina/sangue , Bombesina/síntese química , Feminino , Humanos , Marcação por Isótopo/métodos , Masculino , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos ICR , Camundongos SCID , Transplante de Neoplasias , Especificidade de Órgãos , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/síntese química , Neoplasias da Próstata/sangue , Radiometria/métodos , Cintilografia , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual , Células Tumorais Cultivadas
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