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Objective: To evaluate the usefulness of the apparent diffusion coefficient (ADC) in differentiating between benign and malignant LR-3 lesions classified by Liver Imaging Reporting and Data System 2018 (LI-RADS v2018). Methods: Retrospectively analyzed 88 patients with liver nodules confirmed by pathology and classified as LR-3 by LI-RADS. All patients underwent preoperative contrast-enhanced MR examination, and the following patient-related imaging features were collected: tumor size,nonrim APHE, nonperipheral "washout", enhancing "capsule", mild-moderate T2 hyperintensity, fat in mass, restricted diffusion, and nodule-in-nodule architecture. We performed ROC analysis and calculated the sensitivity and specificity. Results: A total of 122 lesions were found in 88 patients, with 68 benign and 54 malignant lesions. The mean ADC value for malignant and benign lesions were 1.01 ± 0.15 × 103 mm2/s and 1.41 ± 0.31 × 103 mm2/s, respectively. The ADC value of malignant lesions was significantly lower than that of benign lesions, p < 0.0001. Compared with other imaging features, ADC values had the highest AUC (AUC = 0.909), with a sensitivity of 92.6% and a specificity of 74.1% for the differentiation of benign and malignant lesions. Conclusions: ADC values are useful for differentiating between benign and malignant liver nodules in LR-3 classification, it improves the sensitivity of LI-RADS in the diagnosis of HCC while maintaining high specificity, and we recommend including ADC values in the standard interpretation of LI-RADSv2018.
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BACKGROUND: The role of carbohydrate antigen 19-9 (CA 19-9) in response assessment among patients with intrahepatic cholangiocarcinoma (iCCA) remains unknown. The authors studied the association of the CA 19-9 response (defined as a reduction >50% from baseline) with the radiologic response and the outcome in patients with unresectable iCCA. METHODS: A prospective cohort of 422 patients who were initially diagnosed with unresectable iCCA, had baseline CA 19-9 levels ≥100 U/mL, and received treatment with systemic therapies at the authors' institution between January 2017 and December 2021 were enrolled in this study. The radiologic response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. A landmark assessment of the CA 19-9 response and the radiologic response was performed. The associations between CA 19-9 response and imaging response, progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: Two hundred sixty-seven patients (63.3%) had a CA 19-9 response. A CA 19-9 response was observed in 123 of 132 (93.2%) radiologic responders and in 144 of 290 (49.7%) radiologic nonresponders (p < .001). CA 19-9 responders outperformed nonresponders in median PFS (10.6 vs. 3.6 months; hazard ratio [HR], 4.8 months; 95% confidence interval [CI], 3.8-6.0 months; p < .001) and OS (21.4 vs. 6.3 months; HR, 5.3 months; 95% CI, 4.2-6.7 months; p < .001). The common independent predictors of both OS and PFS included metastasis, CA 19-9 nonresponder status, and radiologic nonresponder status in multivariable analysis. CONCLUSIONS: CA 19-9 response is a valuable addition to assess tumor response and is associated with improved outcomes in patients with iCCA. Achieving a CA 19-9 response should be one of the therapeutic objectives of patients with iCCA after systemic therapies. PLAIN LANGUAGE SUMMARY: A decline in carbohydrate antigen 19-9 levels from elevated baseline levels should be one of the therapeutic aims of patients with intrahepatic cholangiocarcinoma who are managed with systemic therapies.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Estudos Prospectivos , Colangiocarcinoma/tratamento farmacológico , Ductos Biliares Intra-Hepáticos/diagnóstico por imagem , Ductos Biliares Intra-Hepáticos/patologia , Carboidratos/uso terapêutico , Estudos RetrospectivosRESUMO
A multimeric MRI blood pool contrast agent based on the closo-borane motif is reported. Twelve copies of an amphiphilic DTPA chelate with amine end groups are appended on carbonate-functionalized closo-borane motif using carbamate linkages. The presence of peripheral phenyl groups on the modified DTPA chelates results in high human serum albumin binding, high relaxivity, and excellent contrast enhancement in vitro and in vivo.
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Boranos , Meios de Contraste , Quelantes , Humanos , Imageamento por Ressonância Magnética , Ácido PentéticoRESUMO
Radiotherapy is an important component of cancer treatment modalities. With the rapid development of three-dimensional conformal, intensity-modulated, image-guided radiotherapy and the efficacy of radiotherapy continues to improve. Autophagy, as a catabolic process, is characterized by the formation of a double-membrane vesicle. Radiotherapy is known to induce autophagy in both cancer and normal cells. Here, we reviewed the interaction of radiotherapy and autophagy in the process of cancer treatment. The potential role of autophagy modification in enhancing radiotherapy treatment will also be reviewed.
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Autofagia , Neoplasias/radioterapia , Radioterapia Conformacional , Radioterapia de Intensidade Modulada , Humanos , Dosagem RadioterapêuticaRESUMO
Lipopolysaccharide binding protein (LBP) has been reported to be associated with prognosis in colorectal carcinoma and renal cell carcinoma; however, the clinical significance of LBP in human primary hepatocellular carcinoma (HCC) is inconclusive. We aimed to investigate the clinical significance and prognostic value of LBP in human primary HCC. In the present study, 346 patients with HCC who underwent curative resection were retrospectively analyzed. LBP protein expression was evaluated using western blot analysis and immunohistochemistry. LBP scores collected from immunohistochemical analysis were obtained by multiplying staining intensity and the percentage of positive cells. An outcome-based best cutoff-point was calculated by X-tile software. Moreover, Kaplan-Meier curves and Cox regressions were used for prognosis evaluation. LBP was frequently overexpressed in HCC compared with that in peritumor tissues (five pairs by western blot analysis, P=0.0533; 77 pairs by immunohistochemistry, P=0.0171), and LBP expression was positively associated with tumor-node-metastasis stage and tumor differentiation. Patients who had high LBP expression had decreased overall survival and time to recurrence compared with patients with low LBP expression. Furthermore, patients who were both serum α-fetoprotein positive and had high LBP expression had poor prognoses. Univariate and multivariate Cox analyses indicated that this combination was an independent prognostic factor [overall survival: Hazard ratio (HR), 1.458; 95% confidence interval (CI), 1.158-1.837; P=0.001; time to recurrence: HR,1.382; 95% Cl, 1.124-1.700; P=0.002]. In conclusion, LBP is highly expressed in HCC, and high LBP expression combined with serum α-fetoprotein may predict poor outcomes in patients with HCC following curative resection.
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A multimeric MRI contrast agent based on the closo-borane motif is reported. Twelve copies of a modified AAZTA chelate with an alkyne end group are appended on an azide-functionalized closo-borane motif using Cu(i) catalyzed click chemistry. The presence of two water molecules on the Gd-bound AAZTA chelate results in high relaxivity for the closomer in vitro/in vivo.
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Acetatos/química , Azepinas/química , Boranos/química , Quelantes/química , Meios de Contraste/química , Complexos de Coordenação/química , Imageamento por Ressonância Magnética , Acetatos/síntese química , Azepinas/síntese química , Boranos/síntese química , Quelantes/síntese química , Meios de Contraste/síntese química , Complexos de Coordenação/síntese química , Estrutura MolecularRESUMO
Triple-negative breast cancer (TNBC) is a devastating disease worldwide, for which targeted imaging and therapeutic agents remain elusive. There has been growing awareness that carbohydrates are valuable as drug candidates and targeting agents for a variety of human diseases, including cancers that overexpress carbohydrate receptors on the cell surface. Here, we develop a two-dimensional (2D) glycocluster by means of simple, stepwise self-assembly for the targeted delivery of theranostic agents to TNBC cells that express mannose receptors (MRs) on the cell surface. Human serum albumin, which contains a variety of hydrophobic pockets capable of accommodating small molecules, was used to simultaneously encapsulate a mannose-based glycoprobe and a commercial photosensitizer (i.e., Ce6). The multicomponent "neoglycoprotein" formed was used to self-assemble with 2D MnO2, producing 2D glycoclusters, which could be selectively internalized by a TNBC cell line (MDA-MB-231) as facilitated by binding to the transmembrane MR. The intracellular degradation of the 2D MnO2 backbone by biothiols then released Ce6 for cell imaging and, subsequently, photodynamic therapy. This study provides insights into the development of carbohydrate-based materials for targeted, stimuli-responsive theranostics of TNBC.
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Nanomedicina Teranóstica/métodos , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Feminino , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Receptor de Manose , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/metabolismo , Fotoquimioterapia/métodos , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Espectrometria de Fluorescência/métodosRESUMO
Cholangiocarcinoma (CCA) is the as the most frequently observed biliary tract malignancy, which has low survival rate in addition to constrained treatment options. However, the fundamental molecular mechanism underlying malignant progression of CCA is quite ambiguous. Recent studies reported that long non-coding RNA (lncRNA) might play critical roles in regulating chemo-resistant of multiple types of cancer. In this study, our results indicate that the LncRNA-EPIC1 expression were significantly increased in cholangiocarcinoma tissues, compared to adjacent normal tissues. And also, its expression also increased in several CCA cancer cell lines than that in human normal immortalized cholangiocyte cell. Loss-and-gain of Lnc-EPIC1 contributes to the CCA cell growth, colony formation, cell apoptosis and also cell cycle. Myc has been reported to directly interact with Lnc-EPIC1 in several cancer cells. Myc targets, including Cyclin A/D and CDK9 were downregulated by Lnc-EPIC1 siRNA. Myc knockout also suppresses the CCA cell growth, colony formation and cell apoptosis. However, Lnc-EPIC1 knockdown failed to enhance the Myc-KO-induced suppression of CCA tumor progression. RNA immunoprecipitation (RIP) results showed the direct interaction between Lnc-EPIC1 and Myc. Taken together, our results show that Lnc-EPIC1 promotes CCA cancer progression by targeting Myc.
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Neoplasias dos Ductos Biliares/genética , Proliferação de Células/genética , Colangiocarcinoma/genética , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/genética , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular , Linhagem Celular Tumoral , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Progressão da Doença , Humanos , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Interferência de RNA , RNA Longo não Codificante/metabolismoRESUMO
Niemann-Pick C1-like 1 (NPC1L1) and Niemann-Pick C2 (NPC2) is a critical mediator of cholesterol absorption. The aim of the present study was to investigate the prognostic value of NPC1L1 and NPC2 in human primary hepatocellular carcinoma (HCC). The expression level of NPC1L1 and NPC2 were evaluated by Immunohistochemistry, Westen blot and Real-time Quantitative PCR. Protein expression level in tissue was represented by integral optic density (IOD). For prognosis analyses, outcome-based cut-point was calculated by X-tile software. Kaplan-Meier analysis, Cox regression analysis were used evaluate prognostic value of NPC1L1 and NPC2 and NPC1L1/NPC2 combination. Both of NPC1L1 and NPC2 were significantly decreased in HCC tissues than peritumoral liver tissues (61 pairs of tissue for Immunohistochemistry and 10 pairs of tissues for Western blot and Real-time Quantitative PCR), respectively. (n=61: p=0.0005 for NPC1L1 and p=0.0001 for NPC2; n=10: p=0.0002 for NPC1L1 and p=0.0489 for NPC2). Kaplan-Meier analyses in 265 HCC cases were showed that the low expression level of NPC1L1 and NPC2 and NPC1L1/NPC2 combination were significantly correlated with poor overall survival (OS) and shorter time to recurrence (TTR). In addition, univariate and multivariate Cox analyses showed that the expression level of NPC1L1/NPC2 combination in HCC was an independent prognostic factor for OS and TTR. Conclusion: NPC1L1 and NPC2 were lowly expressed in HCC compared with peritumoral liver tissues, and low expression of NPC1L1 and NPC2 in HCC tissues may indicate poor outcome of HCC patients after surgery. NPC1L1/NPC2 combination is an independent prognostic factor for OS and TTR in postoperative HCC patients.
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The effect of cirrhosis on the characteristics of intrahepatic cholangiocarcinoma (ICC) has not been fully elucidated. The purpose of this study was to investigate how cirrhosis affects the clinicopathological characteristics and survival of surgically treated ICC patients. A total of 1,312 ICC patients surgically treated between January 2007 and December 2011 at a single institution were retrospectively reviewed and the clinicopathological data were compared between cirrhotic and non-cirrhotic patients. Univariate and multivariate analyses were performed to identify significant and independent prognostic factors in this cohort. A total of 302 patients (23.0%) were cirrhotic. Compared with cirrhotic patients, the tumors in non-cirrhotic patients were usually larger, less differentiated, and more likely to have lymphatic metastasis, vascular and perineural invasion. Following resection, cirrhotic patients achieved a longer survival compared with non-cirrhotic patients (16.0 vs. 13.0 months, respectively; P<0.038). Multivariate analysis demonstrated that hepatitis B virus infection and cirrhosis were independent favorable prognostic factors, while the presence of cholelithiasis, elevated carbohydrate antigen 19-9 and carcinoembryonic antigen levels, multiple tumors, lymphatic metastasis, vascular invasion and positive surgical margin status were independent unfavorable prognostic factors. Overall, the clinicopathological characteristics of ICC patients with and without cirrhosis differed significantly. Compared with cirrhotic patients, in whom the biological behavior of ICC was similar to that of HCC, non-cirrhotic patients exhibited higher-risk pathological characteristics, lower curative resection rate and worse survival.
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Matrix metalloproteinases (MMPs), particularly gelatinases (MMP-2/-9), are involved in neurovascular impairment after stroke. Detection of gelatinase activity in vivo can provide insight into blood-brain barrier disruption, hemorrhage, and nerve cell injury or death. We applied gelatinase-activatable cell-penetrating peptides (ACPP) with a cleavable l-amino acid linker to examine gelatinase activity in primary neurons in culture and ischemic mouse brain in vivo We found uptake of Cy5-conjugated ACPP (ACPP-Cy5) due to gelatinase activation both in cultured neurons exposed to n-methyl-d-aspartate and in mice after cerebral ischemia. Fluorescence intensity was significantly reduced when cells or mice were treated with MMP inhibitors or when a cleavage-resistant ACPP-Cy5 was substituted. We also applied an ACPP dendrimer (ACPPD) conjugated with multiple Cy5 and/or gadolinium moieties for fluorescence and magnetic resonance imaging (MRI) in intact animals. Fluorescence analysis showed that ACPPD was detected in sub-femtomole range in ischemic tissues. Moreover, MRI and inductively coupled plasma mass spectrometry revealed that ACPPD produced quantitative measures of gelatinase activity in the ischemic region. The resulting spatial pattern of gelatinase activity and neurodegeneration were very similar. We conclude that ACPPs are capable of tracing spatiotemporal gelatinase activity in vivo, and will therefore be useful in elucidating mechanisms of gelatinase-mediated neurodegeneration after stroke.
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Peptídeos Penetradores de Células/química , Gelatinases/análise , Acidente Vascular Cerebral/diagnóstico por imagem , Animais , Isquemia Encefálica/diagnóstico por imagem , Carbocianinas/química , Células Cultivadas , Gelatinases/metabolismo , Imageamento por Ressonância Magnética/métodos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Sondas Moleculares/química , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/etiologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/patologiaRESUMO
Intrahepatic cholangiocarcinoma (ICC) is usually confirmed in advanced stage at the time of diagnosis or after surgical exploration, however, indication of surgical treatment is usually controversial for ICC in advanced stages. This retrospective study aims to evaluate clinical value of surgery for such tumors, in order to identify the appropriate patients who will benefit from surgery, and to evaluate the prognostic accuracy of the current staging system for advanced ICC. From January 2007 to December 2011, 387 consecutive surgically treated patients with ICC in AJCCstage â £ were evaluated. Survival was compared among different patients grouped by different elements of AJCC staging system. The prognostic importance of extent of lymph node (LN) metastasis relative to the AJCC N and M classification system was assessed. Our data showed that survival was much better for patients in AJCCstage â £A group (median survival time, MST, 9.0 months) than in AJCCstage â £B group (MST, 5.0 months) (P<0.001). While in AJCCstage â £B group, survival for patients in AnyTN23M0 subgroup (MST, 9.0 months) was much better than in AnyTN0M1 subgroup (MST, 3.0 months); and better than in AnyTN23M1 subgroup (MST, 4.0 months) (P<0.001). Overall, R0 and R1 liver resection should be indicated for patients in AJCCstage â £A group and AnyTN23M0 subgroup in AJCCstage â £B group, as patients in these groups will benefit from surgery with relatively better survival. Staging of advanced ICC by N23 instead of M1 for extended LN metastasis classification is superior in comparison with the AJCC staging system.
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Neoplasias dos Ductos Biliares/cirurgia , Colangiocarcinoma/cirurgia , Neoplasias Hepáticas/cirurgia , Prognóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Feminino , Hepatectomia , Humanos , Neoplasias Hepáticas/patologia , Linfonodos/patologia , Linfonodos/cirurgia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de NeoplasiasRESUMO
The synthesis, relaxivity measurements and in vivo assessment of a carborane-GdDOTA-monoamide (CB-GdDOTA-MA) amphiphilic conjugate as a blood pool contrast agent (BPCA) is reported. This BPCA exhibited excellent binding (87.4%) with human serum albumin (HSA) and showed a higher relaxivity value (r1 = 6.8 mM(-1) s(-1), 7 T) as compared to the clinically used BPCA, MS-325 (r1 = 5.1 mM(-1) s(-1), 9.4 T) in PBS. The blood pool contrast enhancement (CE) capability of CB-GdDOTA-MA was evaluated by performing MR angiography (MRA) in CF1 mice (n = 4) at a Gd dose of 0.1 mmol per kg body weight. The significant CE of blood vessels persisted for about 3-4 min post-injection (p.i.) and quickly diminishes over time. The significant CE of the bladder for up to 3 h p.i. indicated that the renal system is the primary clearance pathway for CB-GdDOTA-MA. However, the CE of liver tissues and intestine (up to 24 h p.i.) is suggestive of a significant hepatic uptake of the CB-GdDOTA-MA.
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Boranos/síntese química , Meios de Contraste/síntese química , Imagem do Acúmulo Cardíaco de Comporta , Compostos Heterocíclicos/síntese química , Imageamento por Ressonância Magnética , Compostos Organometálicos/síntese química , Animais , Boranos/química , Meios de Contraste/química , Compostos Heterocíclicos/química , Humanos , Angiografia por Ressonância Magnética , Camundongos , Compostos Organometálicos/química , Albumina Sérica/metabolismo , Espectrofotometria AtômicaRESUMO
BACKGROUND: To investigate the clinical features of undifferentiated embryonal sarcoma of the liver (UESL) to improve its preoperative diagnostic accuracy. METHODS: The clinical, imaging, and histopathologic findings of 16 UESL patients whose disease was pathologically confirmed but preoperatively misdiagnosed were retrospectively analyzed. RESULTS: Among these 16 patients, 9 were clinically misdiagnosed as primary liver cancer, 3 as hepatoblastoma, and 4 as malignant hepatic mass. In 12 patients who were presented due to abdominal discomfort, ultrasound showed that predominantly solid lesions, whereas computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated predominantly cystic masses within irregular soft tissue. Contrast-enhanced imaging showed enhancement intralesional foci, multiple internal septations, and edges. The postoperative pathology showed the cutting surface of tumors was variegated, with solid and cystic gelatinous areas, hemorrhage, and necrosis. Intracytoplasmic hyaline globules were commonly present among cancer cells. CONCLUSIONS: UESL is a rare clinical condition without specific clinical manifestations. The inconsistencies between ultrasound and CT/MRI findings may be helpful to improve the preoperative diagnosis accuracy.
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BACKGROUND: Following the onset of focal ischemic stroke, the brain experiences a series of alterations including infarct evolvement, cellular proliferation in the penumbra, and behavioral deficits. However, systematic study on the temporal and spatial dependence of these alterations has not been provided. RESULTS: Using multiple approaches, we assessed stroke outcomes by measuring brain injury, dynamic cellular and glial proliferation, and functional deficits at different times up to two weeks after photothrombosis (PT)-induced ischemic stroke in adult mice. Results from magnetic resonance imaging (MRI) and Nissl staining showed a maximal infarction, and brain edema and swelling 1-3 days after PT. The rate of Bromodeoxyuridine (Brdu)-labeled proliferating cell generation is spatiotemporal dependent in the penumbra, with the highest rate in post ischemic days 3-4, and higher rate of proliferation in the region immediate to the ischemic core than in the distant region. Similar time-dependent generation of proliferating GFAP+ astrocytes and Iba1+ microglia/macrophage were observed in the penumbra. Using behavioral tests, we showed that PT resulted in the largest functional deficits during post ischemic days 2-4. CONCLUSION: Our study demonstrated that first a few days is a critical period that causes brain expansion, cellular proliferation and behavioral deficits in photothrombosis-induced ischemic model, and proliferating astrocytes only have a small contribution to the pools of proliferating cells and reactive astrocytes.
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Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Transtornos Mentais/fisiopatologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Animais , Comportamento Animal , Isquemia Encefálica/etiologia , Trombose Intracraniana/complicações , Trombose Intracraniana/patologia , Trombose Intracraniana/fisiopatologia , Luz , Masculino , Transtornos Mentais/etiologia , Transtornos Mentais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Análise Espaço-Temporal , Acidente Vascular Cerebral/etiologiaRESUMO
A vertex-differentiated icosahedral closo-B(12)(2-) core was utilized to construct a α(v)ß(3) integrin receptor-targeted (via cRGD peptide) high payload MRI contrast agent (CA-12) carrying 11 copies of Gd(3+)-DOTA chelates attached to the closo-B(12)(2-) surface via suitable linkers. The resulting polyfunctional MRI contrast agent possessed a higher relaxivity value per-Gd compared to Omniscan, a small molecular contrast agent commonly used in clinical settings. The α(v)ß(3) integrin receptor specificity of CA-12 was confirmed via in vitro cellular binding experiments and in vivo MRI of mice bearing human PC-3 prostate cancer xenografts. Integrin α(v)ß(3)-positive MDA-MB-231 cells exhibited 300% higher uptake of CA-12 than α(v)ß(3)-negative T47D cells. Serial T1-weighted MRI showed superior contrast enhancement of tumors by CA-12 compared to both a nontargeted 12-fold Gd(3+)-DOTA closomer control (CA-7) and Omniscan. Contrast enhancement by CA-12 persisted for 4 h postinjection, and subsequent enhancement of kidney tissue indicated a renal elimination route similar to Omniscan. No toxic effects of CA-12 were apparent in any mice for up to 24 h postinjection. Post-mortem ICP-OES analysis at 24 h detected no residual Gd in any of the tissue samples analyzed.
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Quelantes , Meios de Contraste , Integrina alfaVbeta3/química , Imageamento por Ressonância Magnética , Neoplasias Experimentais/diagnóstico , Neoplasias da Próstata/diagnóstico , Animais , Linhagem Celular Tumoral , Quelantes/síntese química , Quelantes/química , Meios de Contraste/síntese química , Meios de Contraste/química , Gadolínio/química , Compostos Heterocíclicos com 1 Anel/química , Humanos , Integrina alfaVbeta3/biossíntese , Masculino , Camundongos , Camundongos SCID , Estrutura Molecular , Peptídeos Cíclicos/química , Vitamina B 12/químicaRESUMO
BACKGROUND: Development of high affinity and specificity molecular imaging probes that increase accuracy for early detection of lymph node (LN) metastases is important for improving survivorship in prostate cancer. We evaluated the specificity, sensitivity, and accuracy of fluorescence-labeled bombesin (BBN) peptides to detect LN and systematic metastases in orthotopic mouse models bearing gastrin releasing peptide receptor (GRPR)-positive human prostate cancer. METHODS: PC-3 cells were orthotopically implanted in severe combined immunedeficient or thymic nude (nu/nu) male mice. Tumor growth was monitored using magnetic resonance imaging. Alexa Fluor 680 conjugated BBN[7-14]NH2 (AF680-BBN) peptides were administered intravenously at 4-7 weeks post-tumor-implantation. Near-infrared fluorescence (NIRF) imaging was performed for up to 6 hr post-injection. The imaging sensitivity and specificity were assessed by co-registration of AF680-BBN NIRF imaging and luciferase bioluminescence imaging of the PC-3/Luc+ orthotopic mouse model. RESULTS: AF680-BBN showed a high binding affinity and selectivity to GRPR-positive cancer in vitro and in vivo. LN and peritoneal metastases were detected by NIRF imaging, and confirmed by histopathology. Tumor-to-muscle (T/M) ratio was the highest at 2-hr post-injection (4.12 ± 1.77). Blocking experiments, using unlabeled BBN as the inhibiting agent, significantly reduced the T/M ratio (1.64 ± 0.21, P = 0.02). AF680-BBN NIRF imaging had a sensitivity of 89.4%, specificity of 92.9%, and accuracy of 90.2% for the detection of metastases in mice. CONCLUSIONS: [corrected] The studies suggest the potential of use and development of NIR-fluorescent BBN probes as site-directed agents to help improve the current detection and LN staging accuracy in prostate cancer.
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Bombesina/análogos & derivados , Corantes Fluorescentes , Linfonodos/metabolismo , Fragmentos de Peptídeos , Neoplasias da Próstata/metabolismo , Receptores da Bombesina/metabolismo , Animais , Linhagem Celular Tumoral , Histocitoquímica , Humanos , Linfonodos/patologia , Masculino , Camundongos , Camundongos Nus , Camundongos SCID , Microscopia de Fluorescência , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
An icosahedral closo-B(12)(2-) scaffold supports 12 copies of Gd(3+)-chelate held in close proximity with each other by suitable linkers which employ azide-alkyne click chemistry. This design is the first member of a new class of polyfunctional MRI contrast agents carrying a high payload of Gd(3+)-chelate in a sterically constrained configuration. The resulting contrast agent shows higher relaxivity values at high magnetic fields. MRI contrast agents currently in use are not as effective in this regard, presumably due to a lack of steric constraint of gadolinium centers and lower water exchange rates. In vivo MRI studies in mice show excellent contrast enhancement even at one-seventh of the safe clinical dose (0.04 mmol Gd/kg) for up to a 1 h exposure.
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Meios de Contraste , Imageamento por Ressonância Magnética , Neoplasias Experimentais/diagnóstico , Compostos Organometálicos , Neoplasias da Próstata/diagnóstico , Animais , Boranos/química , Meios de Contraste/síntese química , Meios de Contraste/química , Feminino , Gadolínio/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos SCID , Estrutura Molecular , Nanoestruturas/química , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Polímeros/químicaRESUMO
Macrophages play a key role in the initial pathogenesis of kidney ischemia-reperfusion (I-R) injury, but the mechanism of their spatial and temporal recruitment from circulation remains uncertain. This study aimed to evaluate the feasibility of magnetic resonance imaging (MRI) for detecting intravenously administered superparamagnetic iron oxide (SPIO)-labeled macrophages in an experimental renal I-R mouse model. Unilateral kidney I-R mice were imaged with a 4.7-T MRI scanner before and after administration of SPIO-labeled macrophages (RAW 264.7). On MR images, adoptive transfer of SPIO-labeled macrophages in the acute phase (1-2 days after I-R) caused a band-shaped signal-loss zone resulting from macrophage infiltrations, in the outer medullary region of injured kidneys. MRI detection of macrophages homing to an injured kidney may facilitate early detection and investigation of the pathogenesis of acute kidney injury and be a strategy for determining the treatment of acute renal failure. From the Clinical Editor: This study evaluated the feasibility of magnetic resonance imaging for detecting superparamagnetic iron oxide (SPIO)-labeled macrophages in a renal ischemia-reperfusion mouse model. Similar strategies in humans may facilitate early detection and stratification of acute kidney injury.