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1.
Nat Biomed Eng ; 4(3): 272-285, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32165735

RESUMO

For oral, oropharyngeal and oesophageal cancer, the early detection of tumours and of residual tumour after surgery are prognostic factors of recurrence rates and patient survival. Here, we report the validation, in animal models and a human, of the use of a previously described fluorescently labelled small-molecule inhibitor of the DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP1) for the detection of cancers of the oral cavity, pharynx and oesophagus. We show that the fluorescent contrast agent can be used to quantify the expression levels of PARP1 and to detect oral, oropharyngeal and oesophageal tumours in mice, pigs and fresh human biospecimens when delivered topically or intravenously. The fluorescent PARP1 inhibitor can also detect oral carcinoma in a patient when applied as a mouthwash, and discriminate between fresh biopsied samples of the oral tumour and the surgical resection margin with more than 95% sensitivity and specificity. The PARP1 inhibitor could serve as the basis of a rapid and sensitive assay for the early detection and for the surgical-margin assessment of epithelial cancers of the upper intestinal tract.


Assuntos
Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Orofaríngeas/diagnóstico por imagem , Poli(ADP-Ribose) Polimerase-1/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/isolamento & purificação , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Animais , Biomarcadores Tumorais/isolamento & purificação , Biomarcadores Tumorais/metabolismo , Modelos Animais de Doenças , Neoplasias Esofágicas/patologia , Feminino , Xenoenxertos/diagnóstico por imagem , Humanos , Masculino , Camundongos , Neoplasias Orofaríngeas/patologia , Suínos
2.
Sci Rep ; 10(1): 5587, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32221347

RESUMO

The inner clock of biological organisms plays a pivotal role and has strong effects on metabolic processes such as glucose consumption. Since the commonly used positron emission tomography (PET) tracer 18F-flourodeoxygucose (FDG) is a glucose analogue, it is not surprising that the FDG distribution in mice and humans has been shown to succumb to daily rhythms. In preclinical studies, the circadian rhythm of animals is often not considered, and studies are performed at different times of day. Only a few studies have analyzed the effect of the circadian rhythm on FDG uptake in mice, and none of these studies included human tumor xenografts. Therefore, it is not known how strongly a preclinical tumor study is influenced by the time of day. In this work, the effect of the circadian rhythm on FDG uptake in human tumor xenografts and other organs was analyzed. CD1 nu/nu mice were kept for three weeks under a 12 h light/12 h dark rhythm and then injected s.c. with PC3 or A431 tumor cells. When the tumors had reached an appropriate volume, FDG-PET scans were performed on different animal groups (n = 4-5) every 4 h over a time period from 8 A.M. to 8 P.M. Tracer uptake in the tumors and in other organs was determined based on the PET scans and biodistribution studies. The standardized uptake value and %injected dose/cc of the tumors remained constant over the whole observed time period, and no statistically significant differences were determined according to the PET analysis. In the brain, we found a small but statistically significant increase from noon to 4 P.M., which led to a decrease in the tumor-to-brain ratio. No evidence for an effect of the circadian rhythm on FDG uptake could be found in subcutaneous tumors, however, in brain studies the circadian rhythm needs to be considered.


Assuntos
Química Encefálica , Ritmo Circadiano , Xenoenxertos/metabolismo , Tomografia por Emissão de Pósitrons , Animais , Glicemia/análise , Glicemia/fisiologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Química Encefálica/fisiologia , Feminino , Fluordesoxiglucose F18 , Xenoenxertos/diagnóstico por imagem , Humanos , Camundongos , Músculo Esquelético/diagnóstico por imagem , Transplante de Neoplasias/diagnóstico por imagem , Neuroimagem , Células PC-3
3.
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
4.
Macromol Biosci ; 19(12): e1900260, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31743618

RESUMO

The development of tumor targeted probes with strong signal and high contrast is always challenging in cancer imaging. Here, a unique multilayered activatable nanoprobe (MAN) is prepared to fulfill this long-standing goal. MAN adopts a versatile layer-by-layer fabrication technique that sequentially assembles multifunctional polyelectrolytes onto nanoparticles via charge-charge interaction. Unlike the common one-probe-one-fluorochrome construct, MAN offers a dramatic fluorescence enhancement by transporting a large quantity of quenched fluorochromes for maximal signal and contrast. Excellent signal amplification and retention with negligible cytotoxicity is observed in cell study. Upon systemic injection into mice, MAN quickly accumulates in tumor and its fluorescent signal is turned on by proteases overexpressed in tumors, resulting in >700% tumor-to-normal-tissue contrast. This multilayered fabrication provides a simple and powerful universal platform to design sensitive tumor imaging probes.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Carbocianinas/química , Xenoenxertos/diagnóstico por imagem , Imagem Molecular/métodos , Sondas Moleculares/química , Polilisina/química , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Xenoenxertos/patologia , Humanos , Injeções Intravenosas , Luz , Camundongos , Camundongos Nus , Nanopartículas/administração & dosagem , Nanopartículas/química , Proteínas de Neoplasias/metabolismo , Peptídeo Hidrolases/metabolismo , Polieletrólitos/química , Razão Sinal-Ruído , Eletricidade Estática
5.
Tomography ; 5(3): 320-331, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31572793

RESUMO

Preclinical imaging is critical in the development of translational strategies to detect diseases and monitor response to therapy. The National Cancer Institute Co-Clinical Imaging Resource Program was launched, in part, to develop best practices in preclinical imaging. In this context, the objective of this work was to develop a 1-hour, multiparametric magnetic resonance image-acquisition pipeline with triple-negative breast cancer patient-derived xenografts (PDXs). The 1-hour, image-acquisition pipeline includes T1- and T2-weighted scans, quantitative T1, T2, and apparent diffusion coefficient (ADC) parameter maps, and dynamic contrast-enhanced (DCE) time-course images. Quality-control measures used phantoms. The triple-negative breast cancer PDXs used for this study averaged 174 ± 73 µL in volume, with region of interest-averaged T1, T2, and ADC values of 1.9 ± 0.2 seconds, 62 ± 3 milliseconds, and 0.71 ± 0.06 µm2/ms (mean ± SD), respectively. Specific focus was on assessing the within-subject test-retest coefficient-of-variation (CVWS) for each of the magnetic resonance imaging metrics. Determination of PDX volume via manually drawn regions of interest is highly robust, with ∼1% CVWS. Determination of T2 is also robust with a ∼3% CVWS. Measurements of T1 and ADC are less robust with CVWS values in the 6%-11% range. Preliminary DCE test-retest time-course determinations, as quantified by area under the curve and Ktrans from 2-compartment exchange (extended Tofts) modeling, suggest that DCE is the least robust protocol, with ∼30%-40% CVWS.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Meios de Contraste , Imageamento por Ressonância Magnética Multiparamétrica/métodos , Intensificação de Imagem Radiográfica/métodos , Neoplasias de Mama Triplo Negativas/diagnóstico por imagem , Animais , Neoplasias da Mama/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Modelos Animais de Doenças , Feminino , Xenoenxertos/diagnóstico por imagem , Xenoenxertos/patologia , Humanos , Camundongos , Camundongos Endogâmicos , Imagens de Fantasmas , Distribuição Aleatória , Análise e Desempenho de Tarefas , Neoplasias de Mama Triplo Negativas/patologia
6.
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
7.
Magn Reson Med ; 82(2): 763-774, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30957300

RESUMO

PURPOSE: The purpose of this study was to investigate the feasibility of in vivo imaging of human pancreatic ductal cells by OATP1B3 reporter gene under MRI. METHODS: A human cell line (PANC-1) derived from the pancreatic ductal epithelium was used in this study. After transduction of OATP1B3, the cellular physiological functions and the ability of intracellular uptake of the MRI contrast medium (Gd-EOB-DTPA) were examined. Induced differentiation of the PANC-1 cells into hormone-secreting cells were performed to simulate pancreatic ß-like cells. The hormone-secreting cells were implanted into rats and in vivo MRI was evaluated. RESULTS: The mRNA and proteins of OATP1B3 were highly expressed. No significant change of cellular physiological functions was found after the expression. After induced differentiation, the hormone secretion capacities of the OATP1B3-expressing PANC-1 cells were confirmed. Intra-cellular uptake of Gd-EOB-DTPA was determined in vitro by inductively coupled plasma mass spectrometry and MRI. In vivo MRI of the OATP1B3-expressing xenograft revealed an increased signal intensity after contrast enhancement. CONCLUSION: OATP1B3 can be used as a safe and feasible in vivo MRI gene reporter for human pancreatic ductal cells.


Assuntos
Genes Reporter/genética , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Imagem por Ressonância Magnética/métodos , Animais , Linhagem Celular , Meios de Contraste , Estudos de Viabilidade , Feminino , Gadolínio DTPA , Xenoenxertos/química , Xenoenxertos/diagnóstico por imagem , Xenoenxertos/metabolismo , Humanos , Células Secretoras de Insulina/química , Camundongos , Camundongos SCID , Imagem Molecular , Ratos , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/química , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo
8.
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
9.
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
10.
Mol Imaging Biol ; 21(3): 426-435, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30151646

RESUMO

PURPOSE: Fluorescence of co-enzyme reduced nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins (Fp) provides a sensitive measure of the mitochondrial redox state and cellular metabolism. By imaging NADH and Fp, we investigated the utility of optical redox imaging (ORI) to monitor cellular metabolism and detect early metabolic response to cancer drugs. PROCEDURES: We performed ORI of human melanoma DB-1 cells in culture and DB-1 mouse xenografts to detect the redox response to lonidamine (LND) treatment. RESULTS: For cultured cells, LND treatment for 45 min significantly lowered NADH levels with no significant change in Fp, resulting in a significant increase in the Fp redox ratio (Fp/(NADH+Fp)); 3-h prolonged treatment led to a decrease in NADH and an increase in Fp and a more oxidized redox state compared to control. Significant decrease in the mitochondrial redox capacity of LND-treated cells was observed for the first time. For xenografts, 45-min LND treatment resulted in a significant reduction of NADH content, no significant changes in Fp content, and a trend of increase in the Fp redox ratio. Intratumor redox heterogeneity was observed in both control and LND-treated groups. CONCLUSION: Our results support the utility of ORI for evaluating cellular metabolism and monitoring early metabolic response to cancer drugs.


Assuntos
Xenoenxertos/diagnóstico por imagem , Indazóis/uso terapêutico , Melanoma/diagnóstico por imagem , Melanoma/tratamento farmacológico , Imagem Óptica , Animais , Linhagem Celular Tumoral , Transporte de Elétrons/efeitos dos fármacos , Xenoenxertos/efeitos dos fármacos , Humanos , Indazóis/farmacologia , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas de Desacoplamento Mitocondrial/metabolismo , Oxirredução/efeitos dos fármacos
11.
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
12.
Cancer Biother Radiopharm ; 33(10): 445-459, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30133308

RESUMO

Background: To study the distribution and imaging of 99mTc-nGO-PEG-FA in human pancreatic cancer Patu8988 tumor-bearing nude mice, and to explore its usefulness as an imaging reagent for pancreatic cancer. Materials and Methods: Natural graphite powder was used as raw material to prepare the nanosized graphene oxide (nGO) by using the modified Hummers method, and then was covalently modified by polyethylene glycol (PEG) on the surface of nGO. The nGO was further optimized by in vitro cell experiment, and then conjugated with the targeting molecule folic acid (FA) to form nGO-PEG-FA system. The nGO-PEG-FA was finally labeled by radioactive nuclide 99mTc by direct labeling method to form the 99mTc-nGO-PEG-FA molecular imaging probe. Nude mice bearing patu8988 pancreatic cancer xenografts were intravenous injection (I.V.) injected with 99mTc-nGO-PEG-FA, and the distribution of 99mTc-nGO-PEG-FA in nude mice at different time course was investigated by determination of tissue uptake of radioactivity (%ID/g), as well as the single photon emission computed tomography (SPECT) imaging at different time course. Results: The labeling rate of nGO-PEG-FA with 99mTc was (90.08 ± 2.34)%, and the highest binding rate of 99mTc-nGO-PEG-FA with Patu8988 cells was (3.15 ± 0.31)%. The radioactive uptake in tumor reached (5.11 ± 1.23)%ID/g at 6 h after I.V. injection of 99mTc-nGO-PEG-FA in nude mice. Meanwhile, the radioactive uptake in liver, spleen, and lung was also high and reached (10.33 ± 1.22)%ID/g, (5.86 ± 0.59)%ID/g, and (3.55 ± 0.93)%ID/g, respectively, whereas less radioactivity uptake was observed in the heart (1.12 ± 0.33)%ID/g and blood (2.76 ± 0.39)%ID/g, respectively. The tumors can be clearly imaged at 4.0-6.0 h after 99mTc-nGO-PEG-FA injection. Conclusions: 99mTc-nGO-PEG-FA can efficiently target pancreatic cancer, which may be developed as an imaging agent for pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico por imagem , Xenoenxertos/diagnóstico por imagem , Transplante de Neoplasias/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Compostos Radiofarmacêuticos/análise , Tomografia Computadorizada de Emissão de Fóton Único , Animais , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Estabilidade de Medicamentos , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Especificidade de Órgãos , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/toxicidade , Distribuição Aleatória , Soro , Espectrofotometria Ultravioleta , Distribuição Tecidual
13.
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
14.
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
15.
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
16.
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
17.
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
18.
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
19.
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
20.
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
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