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1.
Adv Exp Med Biol ; 1232: 375-381, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893434

RESUMO

The value of optical redox imaging (ORI) of cells/tissues based on the intrinsic fluorescences of NADH (nicotinamide adenine dinucleotide) and oxidized flavoproteins (containing flavin adenine dinucleotide, i.e., FAD) has been demonstrated for potential biomedical applications including diagnosis, prognosis, and determining treatment response. However, the Chance redox scanner (a 3D cryogenic tissue imager) is limited by spatial resolution (~50 µm), and tissue ORI using fluorescence microscopy (single or multi-photon) is limited by the light penetration depth. Furthermore, viable or snap-frozen tissues are usually required. In this project, we aimed to study whether ORI may be achieved for unstained fixed tissue using a state-of-the-art modern Serial Two-Photon (STP) Tomography scanner that can rapidly acquire multi-plane images at micron resolution. Tissue specimens of mouse muscle, liver, and tumor xenografts were harvested and fixed in 4% paraformaldehyde (PFA) for 24 h. Tissue blocks were scanned by STP Tomography under room temperature to acquire the autofluorescence signals (NADH channel: excitation 750 nm, blue emission filter; FAD channel: excitation 860 nm, green emission filter). We observed remarkable signals with significant intra-tissue heterogeneity in images of NADH, FAD and redox ratio (FAD/(NADH+FAD)), which are worthy of further investigation for extracting biological information.


Assuntos
Tecnologia Biomédica , NAD , Imagem Óptica , Animais , Tecnologia Biomédica/instrumentação , Tecnologia Biomédica/métodos , Estudos de Viabilidade , Flavina-Adenina Dinucleotídeo , Xenoenxertos/diagnóstico por imagem , Camundongos , Oxirredução , Fótons
2.
Methods Mol Biol ; 1974: 355-369, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31099014

RESUMO

The use of cationic polymers to interact with negatively charged siRNA via charge complexation to form polyelectrolyte complexes has been widely studied ever since the 1998 report on RNA interference. These polyelectrolyte complex formulations aim to overcome the many pitfalls associated with the use of RNA interference as a potential cancer therapy. The triblock copolymer polyethylenimine-polycaprolactone-polyethylene glycol (PEI-PCL-PEG) contains the cation PEI and has been shown to be an efficient carrier capable of complexing with nucleic acids for gene delivery. This copolymer system also allows for targeting moieties to be linked to the micelleplex, thereby exploiting overexpressed receptors (such as the folate receptor) located within tumors. Additionally, we demonstrated recently that microfluidic mixing of PEI-PCL-PEG nanoparticles allows for the rapid, scaled-up production of micelleplexes while maintaining small and uniform particle distributions. The preparation of small and reproducible particles is imperative for clinical translation of nanomedicine and for tumor targeting via systemic administration. Furthermore, to enable tracing of its deposition in vivo after its administration, micelleplexes can be radiolabeled. To assess tumor targeting over time, the noninvasive imaging technique single-photon emission computed tomography (SPECT) offers the ability to examine the same subject at multiple time points and generate biodistribution profiles. Since the biodistribution and tumor targeting of the therapeutic load of micelleplexes is of foremost interest, we recently described an approach to modify siRNA with a DTPA (diethylenetriaminepentaacetic acid) chelator. Herein, we explain the details of encapsulating indium-labeled siRNA via microfluidic mixing in PEI-PCL-PEG nanoparticles with a folic acid targeting ligand for assessment of their in vivo tumor targeting in an orthotopic ovarian cancer model.


Assuntos
Microfluídica/métodos , Nanopartículas/química , Neoplasias Ovarianas/terapia , RNA Interferente Pequeno/genética , Animais , Linhagem Celular Tumoral , Feminino , Xenoenxertos/diagnóstico por imagem , Humanos , Camundongos , Nanopartículas/uso terapêutico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Ácido Pentético/química , Ácido Pentético/farmacologia , Poliésteres/química , Polietilenoglicóis/química , Polietilenoimina/química , RNA Interferente Pequeno/química , RNA Interferente Pequeno/farmacologia , Tomografia Computadorizada de Emissão de Fóton Único
3.
Theranostics ; 9(4): 974-985, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30867810

RESUMO

Epidermal growth factor receptor (EGFR) is a transmembrane cell surface receptor that is frequently overexpressed and/or mutated in many cancers. Therapies targeting EGFR have poor outcomes due to the lack of reliable diagnostic tests to monitor EGFR. Current in vitro EGFR diagnostic methods are invasive, requiring biopsies, which limits tumor sampling and availability. EGFR molecular imaging provides non-invasive whole-body images capable of detecting primary tumors and metastases, which can be used to diagnose and monitor response to therapy. Methods: We evaluated properties of two anti-EGFR fragments, 8708 and 8709, as molecular-targeted imaging probes. 8708 and 8709 are anti-EGFR antigen binding fragments (Fabs) that recognize domain I/II of EGFR, which is distinct from epitopes recognized by current anti-EGFR therapeutic antibodies. We used complementarity determining region sequences from 8708 and 8709 Fabs to generate an anti-EGFR IgG and (scFv)2 and scFv-Fc antibody fragments. We expressed, purified, and labeled the IgG and fragments with IRDye800CW and used them to image EGFR-positive and -negative xenografts in CD-1 nude mice. 8709 scFv-Fc was also tested for competitive binding with the therapeutic anti-EGFR antibody nimotuzumab and for quantifying ratios of EGFR and EGFRvIII deletion mutant. Results: IRDye800CW-labeled 8708 (scFv)2 and 8709 scFv-Fc imaging probes showed high levels of accumulation and good retention in EGFR-positive xenografts, with peak accumulation occurring at 24 and 48 hours post injection, respectively. IRDye680RD-labeled 8709 scFv-Fc did not compete with IRDye800CW-labeled nimotuzumab for EGFR binding as assayed by flow cytometry using an EGFR-positive cell line. IRDye680RD-labeled 8709 scFv-Fc and IRDye800CW-labeled nimotuzumab used in combination were able to determine the ratio of cells expressing EGFR and a deletion mutant EGFRvIII. Conclusion: IRDye800CW-labeled 8708 (scFv)2 and 8709 scFv-Fc had desirable binding affinities, clearance times, and tumor accumulation to be used for imaging in combination with current EGFR targeted therapies. This study highlights the potential for using 8708 (scFv)2 and 8709 scFv-Fc as EGFR diagnostic and therapy monitoring tools.


Assuntos
Receptores ErbB/análise , Corantes Fluorescentes/metabolismo , Xenoenxertos/diagnóstico por imagem , Fragmentos de Imunoglobulinas/metabolismo , Neoplasias/diagnóstico por imagem , Anticorpos de Cadeia Única/metabolismo , Animais , Camundongos Nus , Transplante de Neoplasias , Coloração e Rotulagem , Transplante Heterólogo
4.
IEEE Trans Biomed Eng ; 66(3): 843-847, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30047868

RESUMO

OBJECTIVE: In vivo bioluminescence imaging (BLI) is a promising tool for monitoring the growth and metastasis of tumors. However, quantitative BLI research based on intravenous (IV) injection is limited, which greatly restricts its further application. To address this problem, we designed a pharmacokinetic (PK) model which is suitable for applying on IV administration of small amounts of D-Luciferin. METHODS: After three weeks of postimplantation, mkn28-luc xenografted mice were subjected to 40-min dynamic BLI immediately following D-Luciferin intravenous injection on days 1, 3, 5, 7, and 9. Furthermore, the PK model was applied on dynamic BLI data to obtain the sum of kinetic rate constants (SKRC). RESULTS: Results showed that the SKRC values decreased rapidly with the growth of the tumor. There was a statistical difference between the SKRC values measured at different time points, while the time point of luminous intensity peak was unaffected by the growth of the tumor. CONCLUSION: In short, our results imply that dynamic BLI combined with our PK model can predict tumor growth earlier and with higher sensitivity compared to the conventional method, which is crucial for improving drug evaluation efficacy. In addition, the dynamic BLI may provide a valuable reference for the noninvasive acquiring arterial input function, which may also provide a new application prospect for hybrid PET-optical imaging.


Assuntos
Medições Luminescentes/métodos , Imagem Óptica/métodos , Administração Intravenosa , Animais , Benzotiazóis/administração & dosagem , Benzotiazóis/farmacocinética , Xenoenxertos/diagnóstico por imagem , Masculino , Camundongos , Camundongos Nus , Imagem Molecular , Neoplasias Experimentais/diagnóstico por imagem
5.
Theranostics ; 8(17): 4856-4869, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30279742

RESUMO

In vivo imaging is influenced by the half-life, tissue penetration, biodistribution, and affinity of the imaging probe. Immunoglobulin G (IgG) is composed of discrete domains with known functions, providing a template for engineering antibody fragments with desired imaging properties. Here, we engineered antibody-based imaging probes, consisting of different combinations of antibody domains, labeled them with the near-infrared fluorescent dye IRDye800CW, and evaluated their in vivo imaging properties. Antibody-based imaging probes were based on an anti-HER3 antigen binding fragment (Fab) isolated using phage display. Methods: We constructed six anti-HER3 antibody-based imaging probes: a single chain variable fragment (scFv), Fab, diabody, scFv-CH3, scFv-Fc, and IgG. IRDye800CW-labeled, antibody-based probes were injected into nude mice bearing FaDu xenografts and their distribution to the xenograft, liver, and kidneys was evaluated. Results: These imaging probes bound to recombinant HER3 and to the HER3-positive cell line, FaDu. Small antibody fragments with molecular weight <60 kDa (scFv, diabody, and Fab) accumulated rapidly in the xenograft (maximum accumulation between 2-4 h post injection (hpi)) and cleared primarily through the kidneys. scFv-CH3 (80 kDa) had fast clearance and peaked in the xenograft between 2-3 hpi and cleared from xenograft in a rate comparable to Fab and diabody. IgG and scFv-Fc persisted in the xenografts for up to 72 hpi and distributed mainly to the xenograft and liver. The highest xenograft fluorescence signals were observed with IgG and scFv-Fc imaging probes and persisted for 2-3 days. Conclusion: These results highlight the utility of using antibody fragments to optimize clearance, tumor labeling, and biodistribution properties for developing anti-HER3 probes for image-guided surgery or PET imaging.


Assuntos
Benzenossulfonatos/administração & dosagem , Neoplasias da Mama/diagnóstico por imagem , Corantes Fluorescentes/administração & dosagem , Xenoenxertos/diagnóstico por imagem , Fragmentos de Imunoglobulinas/administração & dosagem , Indóis/administração & dosagem , Imagem Óptica/métodos , Receptor ErbB-3/análise , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Camundongos Nus
6.
J Appl Oral Sci ; 26: e20170396, 2018 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-30020352

RESUMO

OBJECTIVE: It is necessary to preserve height and thickness of the alveolar bone to facilitate rehabilitation with osteointegratable implants or simply to maintain bone integrity after extraction. Biomaterials associated with resorbable or non-resorbable membranes, when placed in the region of the socket, may contribute to avoid this unwanted reabsorption. OBJECTIVE: The objective of this study was to evaluate the distance of the crest of alveolar ridge to the cementoenamel junction (CEJ) of the lower second molars and the bone density of the third molar socket filled with Gen-Tech®, 5 years after an exodontia using cone beam computed tomography (CBCT) to visualize the central region of the sockets, without overlapping of the buccal and lingual cortical bones. MATERIAL AND METHODS: A total of 12 individuals from an initial group of 39 patients submitted to extraction of the unruptured lower third molars and grafting of an association of inorganic bovine bone matrix, organic bovine bone matrix, collagen and bone morphogenetic proteins (BMP) (Gen-Tech®) on one side and the contralateral sockets filled only by clot, returned to control after 5 years, and were submitted to CBCT. The distance from the crest of alveolar bone to the CEJ and the bone density (BD) were measured using the i-CAT Vision Software. RESULTS: The results showed that the distance from the crest of alveolar bone to the CEJ in the control group was similar to that observed before the exodontia; in the experimental group, this distance was smaller. Considering the BD measurement, a significantly higher density was observed in the experimental group (p<0.05). CONCLUSION: Part of the biomaterial was not absorbed and allowed the stability of the evaluated parameters after 5 years, being able to be used as a bone substitute in the socket.


Assuntos
Substitutos Ósseos , Transplante Ósseo/métodos , Xenoenxertos/diagnóstico por imagem , Dente Serotino/diagnóstico por imagem , Colo do Dente/diagnóstico por imagem , Alvéolo Dental/diagnóstico por imagem , Dente Impactado/diagnóstico por imagem , Adolescente , Adulto , Animais , Densidade Óssea , Proteínas Morfogenéticas Ósseas/uso terapêutico , Bovinos , Tomografia Computadorizada de Feixe Cônico , Feminino , Humanos , Masculino , Teste de Materiais , Dente Serotino/cirurgia , Reprodutibilidade dos Testes , Fatores de Tempo , Extração Dentária/métodos , Alvéolo Dental/transplante , Dente Impactado/cirurgia , Resultado do Tratamento , Adulto Jovem
7.
Contrast Media Mol Imaging ; 2018: 8046541, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29853810

RESUMO

Objective: To synthesize 68Ga-Glu-urea-Lys(Ahx)-HBED-CC (68Ga-PSMA-11) with a synthesis module and investigate PET-CT imaging to monitor PSMA expression during prostate cancer (PCa) progression and tumor growth in mice bearing subcutaneous PCa xenografts. Method: The radiochemical purity and stability of 68Ga-PSMA-11 were determined via radio-HPLC. The PCa cell lines of different PSMA expression levels (PC3, VCAP±, CWR22RV1+, and LNCaP++) were selected to mimic the PCa progression. 68Ga-PSMA-11 biodistribution was studied by dissection method and in vivo imaging with micro PET-CT. The expression levels of PSMA in tumor cells and tissues were analyzed by immunofluorescence, flow cytometry, and western blot. The correlation between PSMA expression and radio-uptake was also evaluated. 2-PMPA preadministration served as a block group. Results: The radiochemical purity of 68Ga-PSMA-11 was 99.6 ± 0.1% and stable in vitro for 2 h. The equilibrium binding constant (Kd) of 68Ga-PSMA-11 to LNCaP, CWR22Rv1, PC-3, and VCAP cells was 4.3 ± 0.8 nM, 16.4 ± 1.3 nM, 225.3 ± 20.8 nM, and 125.6 ± 13.1 nM, respectively. Results of tumor uptake (% ID and % ID/g or % ID/cm3) of 68Ga-PSMA-11 in biodistribution and micro PET imaging were LNCaP > CWR22RV1 > PC-3 and VCAP due to different PSMA expression levels. It was confirmed by flow cytometry, western blot, and immunofluorescence. Tumor uptake (% ID/cm3) of 68Ga-PSMA-11 increased with the tumor anatomical volume in quadratic polynomial fashion and reached the peak (when tumor volume was 0.5 cm3) earlier than tumor uptake (% ID). Tumor uptake (% ID/cm3) of 68Ga-PSMA-11 based on functional volume correlated well with the PSMA expression in a linear manner (y = 9.35x + 2.59, R2 = 0.8924, and p < 0.0001); however, low dose 2-PMPA causes rapid renal clearance of increased tumor/kidney uptake of 68Ga-PSMA-11. Conclusions: The 68Ga-PSMA-11 PET-CT imaging could invasively evaluate PSMA expression during PCa progression and tumor growth with % ID/cm3 (based on functional volume) as an important index. Low dose 2-PMPA preadministration might be a choice to decrease kidney uptake of 68Ga-PSMA-11.


Assuntos
Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Próstata/diagnóstico por imagem , Compostos Radiofarmacêuticos/síntese química , Animais , Antígenos de Superfície/análise , Antígenos de Superfície/química , Linhagem Celular Tumoral , Progressão da Doença , Radioisótopos de Gálio , Glutamato Carboxipeptidase II/análise , Glutamato Carboxipeptidase II/química , Xenoenxertos/diagnóstico por imagem , Humanos , Rim/metabolismo , Masculino , Camundongos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Compostos Radiofarmacêuticos/farmacocinética
8.
Clin Implant Dent Relat Res ; 20(3): 424-433, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29575547

RESUMO

OBJECTIVE: The aim of this study is to evaluate the analytical difference between the use of xenograft (control group) and graftless tenting (test group) technique after sinus lift procedure with simultaneous implant placement. MATERIALS AND METHODS: Seventeen patients and 20 sinuses where operated for sinus lift procedures using lateral window approach with simultaneous implant placement. Deproteinized bovine bone (Xenograft) was used as a filling material in control group while nongrafted sinus lifting was performed in the test group. Multislice CT was obtained preoperatively and CBCT were obtained immediately postoperative and 6 months after operation. Osstell readings were taken at the time of implant placement and implant exposure (6 months) RESULTS: Mean bone height gain in the xenograft group was 8.59 ± 0.74 while that of the tenting group was 4.85 ± 0.5 and it was statistically significant (P < .05). Mean bone density values in the xenograft group was 375.59 ± 49.38 while that of the tenting group was 269.08 ± 16.27 and it was statistically significant (P < .05). Mean ISQ values for the xenograft group was 78.3 ± 5.08 while that of the tenting group was 74 ± 3.19 and it was statistically significant (P < .05). CONCLUSIONS: Within the limitation of this study, sinus lift procedures with simultaneous implant placement using xenograft as a filling material or graftless technique are considered reliable procedures, however, the use of xenograft provide better results in all aspects regarding (bone height gain, bone density, and implant stability).


Assuntos
Transplante Ósseo/métodos , Implantação Dentária Endo-Óssea/métodos , Implantes Dentários , Maxila/cirurgia , Seio Maxilar/cirurgia , Mucosa Nasal/cirurgia , Levantamento do Assoalho do Seio Maxilar/métodos , Adulto , Animais , Substitutos Ósseos/uso terapêutico , Bovinos , Prótese Dentária Fixada por Implante , Falha de Restauração Dentária , Feminino , Xenoenxertos/diagnóstico por imagem , Xenoenxertos/transplante , Humanos , Masculino , Maxila/diagnóstico por imagem , Seio Maxilar/diagnóstico por imagem , Membranas Artificiais , Pessoa de Meia-Idade , Mucosa Nasal/diagnóstico por imagem , Osteotomia/métodos , Retalhos Cirúrgicos , Adulto Jovem
9.
IEEE Trans Med Imaging ; 37(1): 241-250, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29293430

RESUMO

Ultrasound molecular imaging (USMI) is accomplished by detecting microbubble (MB) contrast agents that have bound to specific biomarkers, and can be used for a variety of imaging applications, such as the early detection of cancer. USMI has been widely utilized in preclinical imaging in mice; however, USMI in humans can be challenging because of the low concentration of bound MBs and the signal degradation caused by the presence of heterogenous soft tissue between the transducer and the lesion. Short-lag spatial coherence (SLSC) beamforming has been proposed as a robust technique that is less affected by poor signal quality than standard delay-and-sum (DAS) beamforming. In this paper, USMI performance was assessed using contrast-enhanced ultrasound imaging combined with DAS (conventional CEUS) and with SLSC (SLSC-CEUS). Each method was characterized by flow channel phantom experiments. In a USMI-mimicking phantom, SLSC-CEUS was found to be more robust to high levels of additive thermal noise than DAS, with a 6dB SNR improvement when the thermal noise level was +6dB or higher. However, SLSC-CEUS was also found to be insensitive to increases in MB concentration, making it a poor choice for perfusion imaging. USMI performance was also measured in vivo using VEGFR2-targeted MBs in mice with subcutaneous human hepatocellular carcinoma tumors, with clinical imaging conditions mimicked using a porcine tissue layer between the tumor and the transducer. SLSC-CEUS improved the SNR in each of ten tumors by an average of 41%, corresponding to 3.0dB SNR. These results indicate that the SLSC beamformer is well-suited for USMI applications because of its high sensitivity and robust properties under challenging imaging conditions.


Assuntos
Processamento de Imagem Assistida por Computador/métodos , Modelos Biológicos , Imagem Molecular/métodos , Ultrassonografia/métodos , Animais , Artefatos , Xenoenxertos/química , Xenoenxertos/diagnóstico por imagem , Humanos , Camundongos , Neoplasias Experimentais/química , Neoplasias Experimentais/diagnóstico por imagem , Imagens de Fantasmas , Sensibilidade e Especificidade , Razão Sinal-Ruído , Suínos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/análise , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
10.
Int J Cancer ; 142(10): 2118-2129, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29277891

RESUMO

A crucial point for the management of pancreatic ductal adenocarcinoma (PDAC) is the decrease of R1 resections. Our aim was to evaluate the combination of multispectral optoacoustic tomography (MSOT) with fluorescence guided surgery (FGS) for diagnosis and perioperative detection of tumor nodules and resection margins in a xenotransplant mouse model of human pancreatic cancer. The peptide cRGD, conjugated with the near infrared fluorescent (NIRF) dye IRDye800CW and with a trans-cyclooctene (TCO) tag for future click chemistry (cRGD-800CW-TCO), was applied to PDAC bearing immunodeficient nude mice; 27 days after orthotopic transplantation of human AsPC-1 cells into the head of the pancreas, mice were injected with cRGD-800CW-TCO and imaged with fluorescence- and optoacoustic devices before and 2, 6 and 24 hr after injection, before they were sacrificed and dissected with a guidance of FGS imaging system. Fluorescence imaging of cRGD-800CW-TCO allowed detection of the tumor area but without information about the depth, whereas MSOT allowed high resolution 3 D identification of the tumor area, in particular of small tumor nodules. Highly sensitive delineation of tumor burden was achieved during FGS in all mice. Imaging of whole-mouse cryosections, histopathological analysis and NIRF microscopy confirmed the localization of cRGD-800CW-TCO within the tumor tissue. In principle, all imaging modalities applied here were able to detect PDAC in vivo. However, the combination of MSOT and FGS provided detailed spatial information of the signal and achieved a complete overview of the distribution and localization of cRGD-800CW-TCO within the tumor before and during surgical intervention.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico por imagem , Imagem Óptica/métodos , Neoplasias Pancreáticas/diagnóstico por imagem , Técnicas Fotoacústicas/métodos , Animais , Benzenossulfonatos , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Linhagem Celular Tumoral , Ciclo-Octanos , Modelos Animais de Doenças , Feminino , Corantes Fluorescentes , Xenoenxertos/diagnóstico por imagem , Humanos , Indóis , Camundongos , Imagem Multimodal/métodos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Peptídeos Cíclicos , Cirurgia Assistida por Computador/métodos
11.
Brain Pathol ; 28(4): 475-483, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-28481062

RESUMO

To assess the clinical relevance of transgenic and patient-derived xenograft models of adamantinomatous craniopharyngioma (ACP) using serial magnetic resonance imaging (MRI) and high resolution post-mortem microcomputed tomography (µ-CT), with correlation with histology and human ACP imaging. The growth patterns and radiological features of tumors arising in Hesx1Cre/+ ;Ctnnb1lox(ex3)/+ transgenic mice, and of patient-derived ACP xenografts implanted in the cerebral cortex, were monitored longitudinally in vivo with anatomical and functional MRI, and by ex vivo µ-CT at study end. Pathological correlates with hematoxylin and eosin stained sections were investigated. Early enlargement and heterogeneity of Hesx1Cre/+ ;Ctnnb1lox(ex3)/+ mouse pituitaries was evident at initial imaging at 8 weeks, which was followed by enlargement of a solid tumor, and development of cysts and hemorrhage. Tumors demonstrated MRI features that recapitulated those of human ACP, specifically, T1 -weighted signal enhancement in the solid tumor component following Gd-DTPA administration, and in some animals, hyperintense cysts on FLAIR and T1 -weighted images. Ex vivo µ-CT correlated with MRI findings and identified smaller cysts, which were confirmed by histology. Characteristic histological features, including wet keratin and calcification, were visible on µ-CT and verified by histological sections of patient-derived ACP xenografts. The Hesx1Cre/+ ;Ctnnb1lox(ex3)/+ transgenic mouse model and cerebral patient-derived ACP xenografts recapitulate a number of the key radiological features of the human disease and provide promising foundations for in vivo trials of novel therapeutics for the treatment of these tumors.


Assuntos
Craniofaringioma/diagnóstico por imagem , Craniofaringioma/patologia , Modelos Animais de Doenças , Animais , Craniofaringioma/genética , Xenoenxertos/diagnóstico por imagem , Xenoenxertos/patologia , Proteínas de Homeodomínio/genética , Humanos , Imagem por Ressonância Magnética , Masculino , Camundongos Transgênicos , Pessoa de Meia-Idade , Proteínas Repressoras/genética , Microtomografia por Raio-X , beta Catenina/genética
12.
Ultrasound Med Biol ; 43(12): 2891-2903, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28964615

RESUMO

High tissue pressures prevent chemotherapeutics from reaching the parenchyma of pancreatic ductal adenocarcinoma, which makes it difficult to treat this aggressive disease. Researchers currently use invasive probes to monitor the effectiveness of pressure-reducing therapies, but this practice introduces additional complications. Here, we hypothesize that Young's modulus is a good surrogate for tissue pressure because collagen density and hyaluoronic acid, the key features of the tumor microenvironment responsible for high tissue pressures, also affect modulus elastograms. To corroborate this hypothesis, we used model-based quasi-static elastography to assess how the Young's modulus of naturally occurring AsPc-1 pancreatic tumors varies with collagen density and hyaluoronic acid concentration. We observed that Young's moduli of orthotopically grown xenograft tumors were 6 kPa (p < 0.05) higher than that of their subcutaneously grown counterparts. We also observed a strong correlation between Young's modulus and regions within the tumors with high collagen (R2 ≈ 0.8) and hyaluoronic acid (R2 ≈ 0.6) densities. These preliminary results indicate that hyaluronic acid and collagen density, features of the pancreatic ductal adenocarcinoma tumor microenvironment responsible for high tissue pressure, influence Young's modulus.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico por imagem , Técnicas de Imagem por Elasticidade/métodos , Xenoenxertos/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Animais , Modelos Animais de Doenças , Módulo de Elasticidade , Humanos , Camundongos , Ratos
13.
Acta Oncol ; 56(12): 1754-1762, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28661213

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor outcome. Resistance to treatment is associated with impaired vascularity, extensive hypoxia, and interstitial hypertension. In this study, the potential of dynamic contrast-enhanced (DCE)-MRI as a method for assessing the microvascular density (MVD), the fraction of hypoxic tissue, and the interstitial fluid pressure (IFP) of PDACs was investigated. MATERIAL AND METHODS: Intramuscular BxPC-3, Capan-2, MIAPaCa-2, and Panc-1 PDAC xenografts were used as preclinical models of human PDACs. DCE-MRI with Gd-DOTA as contrast agent was conducted with a 7.05-T scanner, and the DCE-MRI series were analyzed voxelwise by using the Tofts pharmacokinetic model. Tumor MVD and hypoxia were measured in histological preparations by using pimonidazole as a hypoxia marker and CD31 as a marker of endothelial cells. IFP was measured with a Millar catheter. RESULTS: Ktrans (the volume transfer constant of Gd-DOTA) increased with increasing MVD and decreased with increasing hypoxic fraction, but was not associated with IFP. Any association between ve (the fractional distribution volume of Gd-DOTA) and MVD, hypoxic fraction, or IFP could not be detected. CONCLUSIONS: This study shows that DCE-MRI is a useful modality for assessing important features of the microenvironment of PDAC xenografts and thus provides the basis for future preclinical and clinical DCE-MRI investigations of PDAC.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico por imagem , Xenoenxertos/diagnóstico por imagem , Hipóxia/metabolismo , Microvasos/patologia , Neoplasias Pancreáticas/diagnóstico por imagem , Microambiente Tumoral , Animais , Carcinoma Ductal Pancreático/irrigação sanguínea , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Meios de Contraste , Líquido Extracelular , Feminino , Compostos Heterocíclicos , Xenoenxertos/irrigação sanguínea , Xenoenxertos/metabolismo , Xenoenxertos/patologia , Humanos , Imagem por Ressonância Magnética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Nitroimidazóis/metabolismo , Compostos Organometálicos , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Pressão
14.
Top Magn Reson Imaging ; 25(5): 237-243, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27748709

RESUMO

The aim of this study was to use the combined carbogen-ultrasmall superparamagnetic iron oxide (CUSPIO) magnetic resonance imaging (MRI) method, which uses spatial correlations in independent susceptibility imaging biomarkers, to investigate and compare the impact of tumor size and anatomical site on vascular structure and function in vivo. Mice bearing either subcutaneous or orthotopic PC3 LN3 prostate tumors were imaged at 7 T, using a multi-gradient echo sequence to quantify R2, before and during carbogen (95% O2/5% CO2) breathing, and subsequently following intravenous administration of USPIO particles. Carbogen and USPIO-induced changes in R2 were used to inform on hemodynamic vasculature and fractional blood volume (%), respectively. The CUSPIO imaging data were also segmented to identify and assess five categories of R2 response. Small and large subcutaneous and orthotopic tumor cohorts all exhibited significantly (P < 0.05) different median baseline R2, ΔR2carbogen, and fractional blood volume. CUSPIO imaging showed that small subcutaneous tumors predominantly exhibited a negative ΔR2carbogen followed by a positive ΔR2USPIO, consistent with a well perfused tumor vasculature. Large subcutaneous tumors exhibited a small positive ΔR2carbogen and relatively low fractional blood volume, suggesting less functional vasculature. Orthotopic tumors revealed a large, positive ΔR2carbogen, consistent with vascular steal, and which may indicate that vascular function is more dependent on site of implantation than tumor size. Regions exhibiting significant ΔR2carbogen, but no significant ΔR2USPIO, suggesting transient vascular shutdown over the experimental timecourse, were apparent in all 3 cohorts. CUSPIO imaging can inform on efficient drug delivery via functional vasculature in vivo, and on appropriate tumor model selection for pre-clinical therapy trials.


Assuntos
Dióxido de Carbono/química , Compostos Férricos/química , Imagem por Ressonância Magnética , Nanopartículas de Magnetita , Neovascularização Patológica/diagnóstico por imagem , Oxigênio/química , Neoplasias da Próstata/diagnóstico por imagem , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Compostos Férricos/metabolismo , Xenoenxertos/diagnóstico por imagem , Humanos , Masculino , Tamanho da Partícula
15.
J Nucl Med ; 57(4): 601-7, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26719375

RESUMO

Liposomal chemotherapy offers several advantages over conventional therapies, including high intratumoral drug delivery, reduced side effects, prolonged circulation time, and the possibility to dose higher. The efficient delivery of liposomal chemotherapeutics relies, however, on the enhanced permeability and retention (EPR) effect, which refers to the ability of macromolecules to extravasate leaky tumor vessels and accumulate in the tumor tissue. Using a panel of human xenograft tumors, we evaluated the influence of the EPR effect on liposomal distribution in vivo by injection of pegylated liposomes radiolabeled with (111)In. Liposomal accumulation in tumors and organs was followed over time by SPECT/CT imaging. We observed that fast-growing xenografts, which may be less representative of tumor development in patients, showed higher liposomal accumulation than slow-growing xenografts. Additionally, several other parameters known to influence the EPR effect were evaluated, such as blood and lymphatic vessel density, intratumoral hypoxia, and the presence of infiltrating macrophages. The investigation of various parameters showed a few correlations. Although hypoxia, proliferation, and macrophage presence were associated with tumor growth, no hard conclusions or predictions could be made regarding the EPR effect or liposomal uptake. However, liposomal uptake was significantly correlated with tumor growth, with fast-growing tumors showing a higher uptake, although no biological determinants could be elucidated to explain this correlation.


Assuntos
Xenoenxertos/diagnóstico por imagem , Tela Subcutânea/transplante , Animais , Vasos Sanguíneos , Proliferação de Células , Humanos , Hipóxia/diagnóstico por imagem , Radioisótopos de Índio , Lipossomos , Vasos Linfáticos/diagnóstico por imagem , Macrófagos/diagnóstico por imagem , Camundongos , Nanomedicina/métodos , Permeabilidade , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Braz J Med Biol Res ; 48(10): 923-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26445336

RESUMO

Pancreatic adenocarcinoma is important in oncology because of its high mortality rate. Deaths may be avoided if an early diagnosis could be achieved. Several types of tumors overexpress gastrin-releasing peptide receptors (GRPr), including pancreatic cancer cells. Thus, a radiolabeled peptide derivative of gastrin-releasing peptide (GRP) may be useful as a specific imaging probe. The purpose of the present study was to evaluate the feasibility of using (99m)Tc-HYNIC-ßAla-Bombesin(7-14)as an imaging probe for Capan-1 pancreatic adenocarcinoma. Xenographic pancreatic tumor was developed in nude mice and characterized by histopathological analysis. Biodistribution studies and scintigraphic images were carried out in tumor-bearing nude mice. The two methods showed higher uptake by pancreatic tumor when compared to muscle (used as control), and the tumor-to-muscle ratio indicated that (99m)Tc-HYNIC-ßAla-Bombesin (7-14)uptake was four-fold higher in tumor cells than in other tissues. Scintigraphic images also showed a clear signal at the tumor site. The present data indicate that (99m)Tc-HYNIC-ßAla-Bombesin (7-14) may be useful for the detection of pancreatic adenocarcinoma.


Assuntos
Adenocarcinoma/diagnóstico por imagem , Bombesina/análogos & derivados , Compostos de Organotecnécio/farmacocinética , Neoplasias Pancreáticas/diagnóstico por imagem , Adenocarcinoma/patologia , Animais , Bombesina/farmacocinética , Linhagem Celular Tumoral , Peptídeo Liberador de Gastrina/análogos & derivados , Xenoenxertos/diagnóstico por imagem , Xenoenxertos/patologia , Humanos , Masculino , Camundongos Nus , Músculos/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Fragmentos de Peptídeos/farmacocinética , Cintilografia
17.
Chem Commun (Camb) ; 51(70): 13488-91, 2015 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-26214147

RESUMO

We report a supramolecular approach for the preparation of photostable NIR nanovesicles based on a cyanine dye derivative as a photoacoustic (PA) contrast agent for high-performance nano-imaging.


Assuntos
Técnicas Fotoacústicas , Espectroscopia de Luz Próxima ao Infravermelho , Animais , Carbocianinas/química , Meios de Contraste/química , Estabilidade de Medicamentos , Xenoenxertos/diagnóstico por imagem , Humanos , Luz , Camundongos , Estrutura Molecular , Nanotecnologia , Neoplasias/diagnóstico por imagem , Radiografia
18.
Genet Mol Res ; 14(2): 6395-400, 2015 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-26125844

RESUMO

The objective of this study was to determine the ability of bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) to repair large segmental radial bone defects in rabbits. We treated calf cancellous bones with 3 mg/L BMP (Group A), 5 µg/L FGF (Group B), or 3 mg/L BMP plus 5 µg/L FGF (Group C). A bone damage model was established using healthy radii from rabbits. The complexes were implanted in the areas of the bone defects in the radii. After successful transplantation, the rabbits underwent radiographic imaging, and bone graft specimens were detected by histopathology methods. Biomechanical indexes were also assessed in order to observe the healing status of the bone defects. Our results indicated that the repair of bone defects was significantly better in Group C compared to the other 2 groups. Therefore, we concluded that combining BMP and FGF significantly promoted bone defect repair and achieved effects that were superior to the use of BMP alone.


Assuntos
Proteínas Morfogenéticas Ósseas/administração & dosagem , Regeneração Óssea/efeitos dos fármacos , Transplante Ósseo , Fatores de Crescimento de Fibroblastos/administração & dosagem , Animais , Desenvolvimento Ósseo/efeitos dos fármacos , Regeneração Óssea/genética , Bovinos , Fêmur/diagnóstico por imagem , Fêmur/efeitos dos fármacos , Fêmur/crescimento & desenvolvimento , Xenoenxertos/diagnóstico por imagem , Xenoenxertos/efeitos dos fármacos , Coelhos , Radiografia , Cicatrização/efeitos dos fármacos
19.
J Oral Implantol ; 41 Spec No: 366-71, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24702157

RESUMO

The aim of the present study was to use cone-beam computerized tomography (CBCT) to assess horizontal bone augmentation using block grafts, harvested from either the iliac crest (IC) or mandibular ramus (MR) combined with particulate xenograft and a collagen membrane for in the severe maxillary anterior ridge defects (cases Class III-IV according to Cadwood and Howell's classification). Fourteen healthy partially edentulous patients requiring extensive horizontal bone reconstruction in the anterior maxilla were selected for the study. Nineteen onlay block grafts (from IC or MR) were placed. The amount of horizontal bone gain was recorded by CBCT at 3 levels (5, 7, and 11 mm from the residual ridge) and at the time of bone grafting as well as the time of implant placement (≈5 months). Both block donor sites provided enough ridge width for proper implant placement. Nonetheless, IC had significantly greater ridge width gain than MR (Student t test) (4.93 mm vs 3.23 mm). This was further confirmed by nonparametric Mann-Whitney test (P = .007). Moreover, mean pristine ridge and grafted ridge values showed a direct association (Spearman coefficient of correlation = .336). A combination of block graft, obtained from the IC or MR, combined with particulate xenograft then covered with an absorbable collagen membrane is a predictable technique for augmenting anterior maxillary horizontal ridge deficiency.


Assuntos
Aumento do Rebordo Alveolar/métodos , Autoenxertos/transplante , Transplante Ósseo/métodos , Tomografia Computadorizada de Feixe Cônico/métodos , Xenoenxertos/transplante , Maxila/cirurgia , Implantes Absorvíveis , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Atrofia , Autoenxertos/diagnóstico por imagem , Substitutos Ósseos/uso terapêutico , Colágeno , Xenoenxertos/diagnóstico por imagem , Humanos , Ílio/cirurgia , Mandíbula/cirurgia , Maxila/diagnóstico por imagem , Maxila/patologia , Membranas Artificiais , Pessoa de Meia-Idade , Minerais/uso terapêutico , Procedimentos Cirúrgicos Reconstrutivos/métodos , Coleta de Tecidos e Órgãos/métodos , Sítio Doador de Transplante/cirurgia , Adulto Jovem
20.
J Oral Maxillofac Surg ; 72(9): 1660-70, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24985960

RESUMO

PURPOSE: Previous studies have shown that the subperiosteal tunneling procedure in vertical ridge augmentation accelerates healing after grafting and prevents graft exposure, with minor postoperative complications. It is conceivable that new bone formation would be greater with the tunneling procedure than with the flap procedure, because the former is minimally invasive. This hypothesis was tested in this study by comparing new bone formation between the flap and tunneling procedures after vertical ridge augmentation using xenogenous bone blocks in a canine mandible model. MATERIALS AND METHODS: Two Bio-Oss blocks were placed on the edentulous ridge in each side of the mandibles of 6 mongrel dogs. The blocks in each side were randomly assigned to grafting with a flap procedure (flap group) or grafting with a tunneling procedure (tunneling group). RESULTS: The mean percentage of newly formed bone within the block was 15.3 ± 6.6% in the flap group and 46.6 ± 23.4% in the tunneling group. CONCLUSION: Based on data presented in this study, when a tunneling procedure is used to place xenogenous bone blocks for vertical ridge augmentation, bone formation in the graft sites is significantly greater than when a flap procedure is used.


Assuntos
Aumento do Rebordo Alveolar/métodos , Transplante Ósseo/métodos , Xenoenxertos/transplante , Mandíbula/cirurgia , Retalhos Cirúrgicos/cirurgia , Animais , Densidade Óssea/fisiologia , Substitutos Ósseos/uso terapêutico , Tecido Conjuntivo/patologia , Cães , Xenoenxertos/diagnóstico por imagem , Xenoenxertos/patologia , Processamento de Imagem Assistida por Computador/métodos , Arcada Parcialmente Edêntula/cirurgia , Mandíbula/diagnóstico por imagem , Mandíbula/patologia , Minerais/uso terapêutico , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Modelos Animais , Osteogênese/fisiologia , Periósteo/cirurgia , Radiografia , Distribuição Aleatória
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