Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 75
Filtrar
Filtros adicionais











Tipo de estudo
Intervalo de ano
1.
Eur J Nucl Med Mol Imaging ; 46(10): 2152-2162, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31270559

RESUMO

PURPOSE: Optic pathway glioma (OPG) is a rare neoplasm that arises predominantly during childhood. Its location in a sensitive region involving the optic pathways, onset in young patients and controversial therapy choice make the management of OPG a challenge in paediatric neuro-oncology. In this study we assessed gastrin-releasing peptide receptor (GRPR)-targeted positron emission tomography (PET) imaging in children with OPG, and the application of a PET/MRI imaging-guided surgery navigation platform. METHODS: Eight children (five boys, mean age 8.81 years, range 5-14 years) with suspicion of optic pathway glioma on MRI were recruited. Written informed consent was obtained from all patients and legal guardians. Brain PET/CT or PET/MRI acquisitions were performed 30 min after intravenous injection of 1.85 MBq/kg body weight of 68Ga-NOTA-Aca-BBN(7-14). Four patients also underwent 18F-FDG brain PET/CT for comparison. All patients underwent surgical resection within 1 week. RESULTS: All 11 lesions (100%) in the eight patients showed prominent 68Ga-NOTA-Aca-BBN(7-14) uptake with excellent contrast in relation to surrounding normal brain tissue. Tumour-to-background ratios (SUVmax and SUVmean) were significantly higher for 68Ga-NOTA-Aca-BBN(7-14) than for 18F-FDG (28.4 ± 5.59 vs. 0.47 ± 0.11 and 18.3 ± 4.99 vs. 0.35 ± 0.07, respectively). Fusion images for tumour delineation were obtained in all patients using the PET/MRI navigation platform. All lesions were pathologically confirmed as OPGs with positive GRPR expression, and 75% were pilocytic astrocytoma WHO grade I and 25% were diffuse astrocytoma WHO grade II. There was a positive correlation between the SUV of 68Ga-NOTA-Aca-BBN(7-14) and the expression level of GRPR (r2 = 0.56, P < 0.01, for SUVmax; r2 = 0.47, P < 0.05, for SUVmean). CONCLUSION: This prospective study showed the feasibility of 68Ga-NOTA-Aca-BBN(7-14) PET in children with OPG for tumour detection and localization. 68Ga-NOTA-Aca-BBN(7-14) PET/MRI may be helpful for assisting surgery planning in OPG patients with severe symptoms, GRPR-targeted PET has the potential to provide imaging guidance for further GRPR-targeted therapy in patients with OPG.

2.
Bioconjug Chem ; 30(6): 1745-1753, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31181890

RESUMO

As highly expressed in insulinomas, the glucagon-like peptide-1 receptor (GLP-1R) is believed to be an attractive target for diagnosis, localization, and treatment with radiolabeled exendin 4. However, the high and persistent radioactivity accumulation of exendin 4 in the kidneys limits accurate diagnosis and safe, as well as effective, radiotherapy in insulinomas. In this study, we intend to reduce the renal accumulation of radiolabeled exendin 4 through degradation mediated by brush border membrane enzymes. A new exendin 4 ligand NOTA-MVK-Cys40-Leu14-Exendin 4 containing Met-Val-Lys (MVK) linker between the peptide and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelator was synthesized and labeled with 68Ga. The in vitro mouse serum stability and cell binding affinity of the tracer were evaluated. Initial in vitro cleavage of the linker was determined by incubation of a model compound Boc-MVK-Dde with brush border membrane vesicles (BBMVs) with and without the inhibitor of neutral endopeptidase (NEP). Further cleavage studies were performed with the full structure of NOTA-MVK-Cys40-Leu14-Exendin 4. Kidney and urine samples were collected in the in vivo metabolism study after intravenous injection of 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4. The microPET images were acquired in INS-1 tumor model at different time points; the radioactivity uptake of 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4 in tumor and kidneys were determined and compared with the control radiotracer without MVK linker. 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4 was stable in mouse serum. The MVK modification did not affect the affinity of NOTA-MVK-Cys40-Leu14-Exendin 4 toward GLP-1R. The in vitro cleavage study and in vivo metabolism study confirmed that the MVK sequence can be recognized by BBM enzymes and cleaved at the amide bond between Met and Val, thus releasing the small fragment containing Met. MicroPET images showed that the tumor uptake of 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4 was comparable to that of the control, while the kidney uptake was significantly reduced. As a result, more favorable tumor to kidney ratios were achieved. In this study, a novel exendin 4 analogue, NOTA-MVK-Cys40-Leu14-Exendin 4, was successfully synthesized and labeled with 68Ga. With the cleavable MVK sequence, this ligand could be cleaved by the enzymes on kidneys, and releasing the fragment of 68Ga-NOTA-Met-OH, which will rapidly excrete from urine. As the high and consistent renal radioactivity accumulation could be significantly reduced, NOTA-MVK-Cys40-Leu14-Exendin 4 shows great potential in the diagnosis and radiotherapy for insulinoma.

3.
Bioconjug Chem ; 30(6): 1711-1723, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31082207

RESUMO

The effectiveness of numerous molecular drugs is hampered by their poor pharmacokinetics. Different from previous approaches with limited effectiveness, most recently, emerging high-affinity albumin binding moieties (ABMs) for in vivo hitchhiking of endogenous albumin opens up an avenue to chaperone small molecules for long-acting therapeutics. Although several FDA-approved fatty acids have shown prolonged residence and therapeutic effect, an easily synthesized, water-soluble, and high-efficiency ABM with versatile drug loading ability is urgently needed to improve the therapeutic efficacy of short-lived constructs. We herein identified an ideal bivalent Evans blue derivative, denoted as N(tEB)2, as a smart ABM-delivery platform to chaperone short-lived molecules, through both computational modeling screening and efficient synthetic schemes. The optimal N(tEB)2 could reversibly link two molecules of albumin through its two binding heads with a preferable spacer, resulting in significantly extended circulation half-life of a preloaded cargo and water-soluble. Notably, this in situ dimerization of albumin was able to sandwich peptide therapeutics to protect them from proteolysis. As an application, we conjugated N(tEB)2 with exendin-4 for long-acting glucose control in a diabetic mouse model, and it was superior to both previously tested NtEB-exendin-4 (Abextide) and the newly FDA-approved semaglutide, which has been arguably the best commercial weekly formula so far. Hence, this novel albumin binder has excellent clinical potential for next-generation biomimetic drug delivery systems.

4.
Bioconjug Chem ; 30(6): 1821-1829, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31117347

RESUMO

Magnetic resonance imaging (MRI) diagnosis is better assisted by contrast agents that can augment the signal contrast in the imaging appearance. However, this technique is still limited by the inherently low sensitivity on the recorded signal changes in conventional T1 or T2 MRI in a qualitative manner. Here, we provide a new paradigm of MRI diagnosis using T1- T2 dual-modal MRI contrast agents for contrast-enhanced postimaging computations on T1 and T2 relaxation changes. An albumin-binding molecule (i.e., truncated Evans blue) chelated with paramagnetic manganese ion was developed as a novel T1- T2 dual-modal MRI contrast agent at high magnetic field (7 T). Furthermore, the postimaging computations on T1- T2 dual-modal MRI led to greatly enhanced signal-to-noise ratios (SNR) and contrast-to-noise ratios (CNR) in both subcutaneous and orthotopic brain tumor models compared with traditional MRI methods. The T1- T2 dual-modal MRI computations have great potential to eliminate suspicious artifacts and false-positive signals in mouse brain imaging. This study may open new avenues for contrast-enhanced MRI diagnosis and holds great promise for precision medicine.

5.
Theranostics ; 9(5): 1358-1368, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30867836

RESUMO

It remains a major challenge to achieve precise on-demand drug release. Here, we developed a modular nanomedicine integrated with logic-gated system enabling programmable drug release for on-demand chemotherapy. Methods: We employed two different logical AND gates consisting of four interrelated moieties to construct the nanovesicles, denoted as v-A-CED2, containing oxidation-responsive nanovesicles (v), radical generators (A), and Edman linker conjugated prodrugs (CED2). The first AND logic gate is connected in parallel by mild hyperthermia ( I ) and acidic pH ( II ), which executes NIR laser triggered prodrug-to-drug transformation through Edman degradation. Meanwhile, the mild hyperthermia effect triggers alkyl radical generation ( III ) which contributes to internal oxidation and degradation of nanovesicles ( IV ). The second AND logic gate is therefore formed by the combination of I-IV to achieve programmable drug release by a single stimulus input NIR laser. The biodistribution of the nanovesicles was monitored by positron emission tomography (PET), photoacoustic, and fluorescence imaging. Results: The developed modular nanovesicles exhibited high tumor accumulation and effective anticancer effects both in vitro and in vivo. Conclusions: This study provides a novel paradigm of logic-gated programmable drug release system by a modular nanovesicle, which may shed light on innovation of anticancer agents and strategies.

6.
Adv Healthc Mater ; : e1800686, 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30300471

RESUMO

Abextide, synthesized by conjugating an albumin-binding moiety-truncated Evans blue-to glucagon-like peptide 1 receptor (GLP-1R) agonist exendin-4, shows extended drug release and enhanced hypoglycemic effect in diabetic mice. The aim of this study is to evaluate the pharmacodynamics of Abextide in nonhuman primates. Two batches of elderly cynomolgus monkeys with naturally occurring diabetes are used for this study. During the whole experiment period, no abnormalities such as swelling at the injection site, lethargy, or hypoglycemia are observed in all animals. The monkeys in the Abextide group lose appetite after drug administration and then recover over time. In the single dose treatment, at day 1 and day 3 after treatment, decreased plasma glucose level is observed in the Abextide-treated group but not in placebo or Albiglutide-treated group. For monkeys that receive two doses of drug, the blood glucose level in all subjects in Abextide group decreases rapidly upon drug administration and return to a plateau by day 3. A similar pattern of response is seen after the second dose administration. The delayed drug release and hypoglycemic effect of Abextide make it potentially useful as an antidiabetic drug for weekly subcutaneous administration.

7.
Bioconjug Chem ; 29(9): 3213-3221, 2018 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-30105912

RESUMO

Prostate cancer is the most frequently diagnosed malignant tumor in men worldwide. Prostate-specific membrane antigen (PSMA) is a surface molecule specifically expressed by prostate tumors that has been shown to be a valid target for internal radionuclide therapy in both preclinical and clinical settings. The most common radiotherapeutic agent is the small molecule 177Lu-PSMA-617, which is under clinical evaluation in multiple countries. Nevertheless, its efficacy in causing tumor regression is still suboptimal, even when administered in several cycles per patient, perhaps due to poor pharmacokinetics (PK), which limits uptake by the tumor cells. We postulated that the addition of the Evans blue (EB) moiety to PSMA-617 would improve the PK by extending circulation half-life, which would increase tumor uptake and improve radiotherapeutic efficacy. PSMA-617 was modified by conjugation of a 2-thiol acetate group onto the primary amine and thereafter reacted with a maleimide functional group of an EB derivative, to give EB-PSMA-617. The PK and radiotherapeutic efficacy of 90Y- or 177Lu-EB-PSMA-617 was compared to the clinically used radiopharmaceutical 90Y- or 177Lu- PSMA-617 in PC3-PIP tumor-bearing mice. EB-PSMA-617 retained binding to serum albumin as well as a high internalization rate by tumor cells. Upon injection, metal-labeled EB-PSMA-617 demonstrated an extended blood half-life compared to PSMA-617 and, thereby, prolonged the time window for binding to PSMA. The improved PK of EB-PSMA-617 resulted in significantly higher accumulation in PSMA+ tumors and highly effective radiotherapeutic efficacy. Remarkably, a single dose of 1.85 MBq of 90Y- or 177Lu-EB-PSMA-617 was sufficient to eradicate established PMSA+ tumors in mice. No significant body weight loss was observed, suggesting little to no gross toxicity. The construct described here, EB-PSMA-617, may improve the radiotherapeutic efficacy for patients with PSMA-positive tumors by reducing both the amount of activity needed for therapy as well as the frequency of administration, as compared to PSMA-617.

8.
Clin Nucl Med ; 43(9): 648-654, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30052597

RESUMO

OBJECTIVES: Uncommon pathological subtypes of meningioma may present with severe peritumoral brain edema and mimic high-grade glioma (HGG). In a prospective cohort study of Ga-NOTA-PRGD2 PET/CT to evaluate glioma, we occasionally observed that a combination of Ga-NOTA-PRGD2 and F-FDG was able to differentiate these 2 lesion types. METHODS: From 2013 to 2016, 21 patients suspected of HGG by MRI were recruited for evaluation using Ga-NOTA-PRGD2 PET/CT. Brain F-FDG PET/CT was performed within 3 days for comparison, and the tumor was surgically removed. The PET results were compared with integrin αvß3 expression and microvascular density quantification of tumor samples. RESULTS: Of the 21 recruited patients, 5 patients were finally pathologically diagnosed as uncommon meningioma with severe peritumoral brain edema, including chordoid meningioma (n = 1), angiomatous meningioma (n = 1), and mixed angiomatous and microcystic meningioma (n = 3). Sixteen were diagnosed as HGG. All the meningioma lesions (n = 5) exhibited intense and homogeneous Ga-NOTA-PRGD2 uptake with higher SUVmax on Ga-NOTA-PRGD2 PET (1.64-7.86; mean ± SD, 4.23 ± 2.48) than the HGG lesions (0.81-2.99; mean ± SD, 1.57 ± 0.33; P = 0.0047). Moreover, the uptake ratios of Ga-NOTA-PRGD2 over F-FDG, normalized as lg100 * SUVmax (RGD / FDG), in the uncommon meningiomas were significantly higher than those in HGG (1.87 ± 1.36 vs 1.04 ± 0.87, P = 0.0001). A cutoff value of 1.58 was able to discriminate between these lesion types. There were positive correlations among the expression level of integrin αvß3, microvascular density, and the tumor-to-background ratio derived from Ga-NOTA-PRGD2 PET (P < 0.05). CONCLUSIONS: This study reveals a specific imaging pattern of uncommon meningioma mimicking HGG, in which Ga-NOTA-PRGD2 PET provided added value to F-FDG PET.


Assuntos
Glioma/diagnóstico por imagem , Neoplasias Meníngeas/diagnóstico por imagem , Meningioma/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Adulto , Complexos de Coordenação , Diagnóstico Diferencial , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos Cíclicos , Compostos Radiofarmacêuticos
9.
Clin Nucl Med ; 43(9): 663-669, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30036253

RESUMO

BACKGROUND: This prospective pilot study investigated the value of Ga-NOTA-RM26, an antagonist targeting gastrin-releasing peptide receptor, in evaluation of breast cancer. METHODS: Thirty-five women in suspicion of breast cancer based on mammography or ultrasonography were recruited with informed consent. They underwent PET/CT scans 30 minutes after intravenous injection of Ga-NOTA-RM26 in a dose of 1.85 MBq (0.05 mCi) per kilogram body weight within 1 week before surgery. The Ga-NOTA-RM26 uptake was correlated with the pathological and immunohistochemical findings. RESULTS: Ga-NOTA-RM26 positivity was found correlated with estrogen receptor (ER) expression (P = 0.006) and menstrual status (P = 0.019). In 34 patients diagnosed with breast cancer, the SUVmax was found significantly higher in the ER-positive breast cancer (4.97 ± 1.89) than in the ER-negative breast cancer (2.78 ± 0.65, P < 0.001). Ga-NOTA-RM26 was also found accumulated in normal breast tissue, with the SUVmax significantly higher in patients at the secretory phase of menstrual cycle (2.27 ± 0.71) than in those at the nonsecretory phase (1.59 ± 0.49, P = 0.017) and postmenopause (1.43 ± 0.44, P = 0.002). If the secretory phase patients were excluded, the sensitivity, specificity, and accuracy for differentiation of breast cancer from breast tissue increased from 85.3%, 86.8%, and 86.1% to 100%, 90.9%, and 95.5%, respectively. CONCLUSIONS: This pilot study indicates that the diagnostic accuracy of Ga-NOTA-RM26 PET/CT in breast cancer may correlate with ER expression and menstrual status of the patient. It may be better to avoid performing this examination during the menstrual secretory phase to reduce physiological uptake in normal breast tissue.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Compostos Organometálicos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Receptores da Bombesina/metabolismo , Sensibilidade e Especificidade
10.
Theranostics ; 8(9): 2508-2520, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29721096

RESUMO

Purpose: Despite the use of fluorescence-guided surgery (FGS), maximum safe resection of glioblastoma multiforme (GBM) remains a major challenge. It has restricted surgeons between preoperative diagnosis and intraoperative treatment. Currently, an integrated approach combining preoperative assessment with intraoperative guidance would be a significant step in this direction. Experimental design: We developed a novel 68Ga-IRDye800CW-BBN PET/near-infrared fluorescence (NIRF) dual-modality imaging probe targeting gastrin-releasing peptide receptor (GRPR) in GBM. The preclinical in vivo tumor imaging and FGS were first evaluated using an orthotopic U87MG glioma xenograft model. Subsequently, the first-in-human prospective cohort study (NCT 02910804) of GBM patients were conducted with preoperative PET assessment and intraoperative FGS. Results: The orthotopic tumors in mice could be precisely resected using the near-infrared intraoperative system. Translational cohort research in 14 GBM patients demonstrated an excellent correlation between preoperative positive PET uptake and intraoperative NIRF signal. The tumor fluorescence signals were significantly higher than those from adjacent brain tissue in vivo and ex vivo (p < 0.0001). Compared with pathology, the sensitivity and specificity of fluorescence using 42 loci of fluorescence-guided sampling were 93.9% (95% CI 79.8%-99.3%) and 100% (95% CI 66.4%-100%), respectively. The tracer was safe and the extent of resection was satisfactory without newly developed neurologic deficits. Progression-free survival (PFS) at 6 months was 80% and two newly diagnosed patients achieved long PFS. Conclusions: This initial study has demonstrated that the novel dual-modality imaging technique is feasible for integrated pre- and intraoperative targeted imaging via the same molecular receptor and improved intraoperative GBM visualization and maximum safe resection.

11.
Stat Med ; 37(14): 2187-2207, 2018 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-29664214

RESUMO

In clinical research and development, interim monitoring is critical for better decision-making and minimizing the risk of exposing patients to possible ineffective therapies. For interim futility or efficacy monitoring, predictive probability methods are widely adopted in practice. Those methods have been well studied for univariate variables. However, for longitudinal studies, predictive probability methods using univariate information from only completers may not be most efficient, and data from on-going subjects can be utilized to improve efficiency. On the other hand, leveraging information from on-going subjects could allow an interim analysis to be potentially conducted once a sufficient number of subjects reach an earlier time point. For longitudinal outcomes, we derive closed-form formulas for predictive probabilities, including Bayesian predictive probability, predictive power, and conditional power and also give closed-form solutions for predictive probability of success in a future trial and the predictive probability of success of the best dose. When predictive probabilities are used for interim monitoring, we study their distributions and discuss their analytical cutoff values or stopping boundaries that have desired operating characteristics. We show that predictive probabilities utilizing all longitudinal information are more efficient for interim monitoring than that using information from completers only. To illustrate their practical application for longitudinal data, we analyze 2 real data examples from clinical trials.

12.
Theranostics ; 8(4): 1121-1130, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29464003

RESUMO

Purpose: This study was to assess a gastrin-releasing peptide receptor (GRPR) and integrin αvß3 dual targeting tracer 68Ga-BBN-RGD for positron emission tomography (PET)/computed tomography (CT) imaging of breast cancer and metastasis. Materials and Methods: Twenty-two female patients were recruited either with suspected breast cancer on screening mammography (n = 16) or underwent breast cancer radical mastectomy (n = 6). All the 22 patients underwent PET/CT at 30-45 min after intravenous injection of 68Ga-BBN-RGD. Eleven out of 22 patients also accepted 68Ga-BBN PET/CT within 2 weeks for comparison. A final diagnosis was made based on the histopathologic examination of surgical excision or biopsy. Results: Both the primary cancer and metastases showed positive 68Ga-BBN-RGD accumulation. The T/B ratios of 68Ga-BBN-RGD accumulation were 2.10 to 9.44 in primary cancer and 1.10 to 3.71 in axillary lymph node metastasis, 3.80 to 10.7 in distant lymph nodes, 2.70 to 5.35 in lung metastasis and 3.17 to 22.8 in bone metastasis, respectively. For primary lesions, the SUVmax from 68Ga-BBN-RGD PET in ER positive group was higher than that in ER negative group (P < 0.01). For both primary and metastatic lesions, SUVmean quantified from 68Ga-BBN-RGD PET correlated well with both GRPR expression and integrin αvß3 expression. Conclusion: This study demonstrated significant uptake of a new type of dual integrin αvß3 and GRPR targeting radiotracer in both the primary lesion and the metastases of breast cancer. 68Ga-BBN-RGD PET/CT may be of great value in discerning both primary breast cancers, axillary lymph node metastasis and distant metastases.

13.
J Nucl Med ; 59(6): 922-928, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29123014

RESUMO

This study was designed to analyze the safety, biodistribution, and radiation dosimetry of a gastrin-releasing peptide receptor (GRPR) antagonist PET tracer, 68Ga-RM26; to assess its clinical diagnostic value in prostate cancer patients; and to perform a direct comparison between GRPR antagonist 68Ga-RM26 and agonist 68Ga-BBN. Methods: Five healthy volunteers were enrolled to validate the safety of 68Ga-RM26 and calculate dosimetry. A total of 28 patients with prostate cancer (17 newly diagnosed and 11 posttherapy) were recruited and provided written informed consent. All the cancer patients underwent PET/CT at 15-30 min after intravenous injection of 1.85 MBq (0.05 mCi) per kilogram of body weight of 68Ga-RM26. Among them, 22 patients (11 newly diagnosed and 11 posttherapy) underwent 68Ga-BBN PET/CT for comparison within 1 wk. 99mTc-MDP (methylene diphosphonate) bone scans were obtained within 2 wk for comparison. GRPR immunohistochemical staining of tumor samples was performed. Results: The administration of 68Ga-M26 was well tolerated by all subjects, with no adverse symptoms being noticed or reported during the procedure and at 2-wk follow-up. The total effective dose equivalent and effective dose were 0.0912 ± 0.0140 and 0.0657 ± 0.0124 mSv/MBq, respectively. In the 17 patients with newly diagnosed prostate cancer, 68Ga-RM26 PET/CT showed positive prostate-confined findings in 15 tumors with an SUVmax of 6.49 ± 2.37. In the 11 patients who underwent prostatectomy or brachytherapy with or without androgen deprivation therapy, 68Ga-RM26 PET/CT detected 8 metastatic lymph nodes in 3 patients with an SUVmax of 4.28 ± 1.25 and 21 bone lesions in 8 patients with an SUVmax of 3.90 ± 3.07. Compared with 68Ga-RM26 PET/CT, GRPR agonist 68Ga-BBN PET/CT detected fewer primary lesions and lymph node metastases as well as demonstrated lower tracer accumulation. There was a significant positive correlation between SUV derived from 68Ga-RM26 PET and the expression level of GRPR (P < 0.001). Conclusion: This study indicates the safety and significant efficiency of GRPR antagonist 68Ga-RM26. 68Ga-RM26 PET/CT would have remarkable value in detecting both primary prostate cancer and metastasis. 68Ga-RM26 is also expected to be better than GRPR agonist as an imaging marker to evaluate GRPR expression in prostate cancer.

14.
Bioconjug Chem ; 29(2): 410-419, 2018 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-29254329

RESUMO

Radiolabeled bombesin (BBN) analogs have long been used for developing gastrin-releasing peptide receptor (GRPR) targeted imaging probes, and tracers with excellent in vivo performance including high tumor uptake, high contrast, and favorable pharmacokinetics are highly desired. In this study, we compared the 68Ga-labeled GRPR agonist (Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2, BBN7-14) and antagonist (d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, RM26) for the positron emission tomography (PET) imaging of prostate cancer. The in vitro stabilities, receptor binding, cell uptake, internalization, and efflux properties of the probes 68Ga-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-Aca-BBN7-14 and 68Ga-NOTA-poly(ethylene glycol)3 (PEG3)-RM26 were studied in PC-3 cells, and the in vivo GRPR targeting abilities and kinetics were investigated using PC-3 tumor xenografted mice. BBN7-14, PEG3-RM26, NOTA-Aca-BBN7-14, and NOTA-PEG3-RM26 showed similar binding affinity to GRPR. In PC-3 tumor-bearing mice, the tumor uptake of 68Ga-NOTA-PEG3-RM26 remained at around 3.00 percentage of injected dose per gram of tissue within 1 h after injection, in contrast with 68Ga-NOTA-Aca-BBN7-14, which demonstrated rapid elimination and high background signal. Additionally, the majority of the 68Ga-NOTA-PEG3-RM26 remained intact in mouse serum at 5 min after injection, while almost all of the 68Ga-NOTA-Aca-BBN7-14 was degraded under the same conditions, demonstrating more-favorable in vivo pharmacokinetic properties and metabolic stabilities of the antagonist probe relative to its agonist counterpart. Overall, the antagonistic GRPR targeted probe 68Ga-NOTA-PEG3-RM26 is a more-promising candidate than the agonist 68Ga-NOTA-Aca-BBN7-14 for the PET imaging of prostate cancer patients.


Assuntos
Radioisótopos de Gálio/química , Peptídeos/química , Tomografia por Emissão de Pósitrons/métodos , Próstata/diagnóstico por imagem , Neoplasias da Próstata/diagnóstico por imagem , Receptores da Bombesina/agonistas , Receptores da Bombesina/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Feminino , Radioisótopos de Gálio/farmacocinética , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacocinética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Peptídeos/farmacocinética
15.
Nat Commun ; 8(1): 1954, 2017 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-29203865

RESUMO

Subunit vaccines have been investigated in over 1000 clinical trials of cancer immunotherapy, but have shown limited efficacy. Nanovaccines may improve efficacy but have rarely been clinically translated. By conjugating molecular vaccines with Evans blue (EB) into albumin-binding vaccines (AlbiVax), here we develop clinically promising albumin/AlbiVax nanocomplexes that self-assemble in vivo from AlbiVax and endogenous albumin for efficient vaccine delivery and potent cancer immunotherapy. PET pharmacoimaging, super-resolution microscopies, and flow cytometry reveal almost 100-fold more efficient co-delivery of CpG and antigens (Ags) to lymph nodes (LNs) by albumin/AlbiVax than benchmark incomplete Freund's adjuvant (IFA). Albumin/AlbiVax elicits ~10 times more frequent peripheral antigen-specific CD8+ cytotoxic T lymphocytes with immune memory than IFA-emulsifying vaccines. Albumin/AlbiVax specifically inhibits progression of established primary or metastatic EG7.OVA, B16F10, and MC38 tumors; combination with anti-PD-1 and/or Abraxane further potentiates immunotherapy and eradicates most MC38 tumors. Albumin/AlbiVax nanocomplexes are thus a robust platform for combination cancer immunotherapy.


Assuntos
Vacinas Anticâncer/farmacologia , Linfonodos/efeitos dos fármacos , Melanoma Experimental/patologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Adjuvantes Imunológicos/farmacologia , Paclitaxel Ligado a Albumina/farmacologia , Albuminas , Animais , Antígenos de Neoplasias/imunologia , Antineoplásicos/farmacologia , Antineoplásicos Imunológicos/farmacologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Adjuvante de Freund/farmacologia , Imunoterapia , Lipídeos/farmacologia , Linfonodos/patologia , Camundongos , Simulação de Acoplamento Molecular , Nanoestruturas , Tomografia por Emissão de Pósitrons
16.
Theranostics ; 7(9): 2363-2376, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28744320

RESUMO

Purpose: Evans Blue (EB) is an azo dye that binds quantitatively with serum albumin. With an albumin binding, NOTA conjugated truncated Evan's blue (NEB) dye derived PET tracer, we aimed to establish a strategy for evaluating vascular permeability in malignant tumors via non-invasive PET. Experimental design: Sixty-minute dynamic PET using [18F]FAl-NEB was performed in three xenograft tumor models including INS-1 rat insulinoma, UM-SCC-22B human head and neck carcinoma and U-87 MG human glioblastoma. Tumor vascular permeability was quantified by the difference of the slopes between tumor and blood time-activity curve (TACs, expressed as Ps ). The method was further substantiated by EB extraction and colorimetric assay and correlates with that calculated from dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). The changes in tumor vasculature at different time points were assessed with NEB PET in U-87 MG and UM-SCC-22B tumor models after treatment with bevacizumab or doxorubicin. Result: The Ps values calculated from tumor and blood TACs from multiple time-point static images are consistent with those from dynamic images. Moreover, the Ps showed a positive and significant correlation with extracted EB concentration and KPS-MRI generated from DCE-MRI, which further confirmed the soundness of this methodology. The antiangiogenic effect of bevacizumab could be revealed by NEB PET in U-87 MG tumors as early as 8 hrs after therapy, demonstrated by a substantial decrease of Ps. On the contrary, there was no significant change of Ps in bevacizumab treated UM-SCC-22B tumors, compared with control group. However, the significant changes of Ps were overestimated in doxorubicin treated UM-SCC-22B tumors. Conclusions: We successfully developed a relatively convenient and novel strategy to evaluate vascular permeability and blood volume using NEB PET. This method will be advantageous in evaluating vascular permeability, promoting drug delivery, and monitoring tumor response to therapeutics that affect tumor angiogenesis.


Assuntos
Volume Sanguíneo , Permeabilidade Capilar , Carcinoma/diagnóstico por imagem , Azul Evans/administração & dosagem , Glioblastoma/diagnóstico por imagem , Insulinoma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Animais , Antineoplásicos/administração & dosagem , Bevacizumab/administração & dosagem , Carcinoma/tratamento farmacológico , Carcinoma/patologia , Modelos Animais de Doenças , Radioisótopos de Flúor/administração & dosagem , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Compostos Heterocíclicos/administração & dosagem , Humanos , Insulinoma/tratamento farmacológico , Insulinoma/patologia , Ratos
17.
Eur J Nucl Med Mol Imaging ; 44(9): 1501-1510, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28382512

RESUMO

OBJECTIVE: The popularity of contemporary microsurgical techniques in treatment of lower-limb lymphedema calls for better visualization of the lymphatic system, both preoperatively and intra-operatively. The aim of this prospective study was to investigate the feasibility of a novel combination of 68Ga-NEB positron emission tomography (PET) with magnetic resonance lymphography (MRL) in evaluating lymphedema and guiding surgical intervention. METHODS: A total of 11 patients (F 9, M 2, age range 29-69 y) with lower-limb lymphedema classified into stage I to III were recruited. PET acquisition was performed at 30, 60 and 90 min after subcutaneous injection of the albumin-binding radiotracer 68Ga-NEB into the bilateral first web spaces of the feet. All the patients were also subjected to 99mTc-sulfur colloid (SC) lymphoscintigraphy for comparison. Gd-DTPA-enhanced magnetic resonance imaging (MRI) was performed using sequences specialized for lymphatic vessel scans. All the patients underwent surgical interventions within a week. The surgical approach includes the use of a linear marker for edema localization and indocyanine green (ICG) lymphography with a near-infrared surgical navigation system intra-operatively. RESULTS: Lymph transport in lymphatic channels was clearly observed by visualization of 68Ga-NEB activity in the lymphatic vessels and within lymph nodes for all 11 patients as well as the visualization of the edema section plane with dermal backflow (DB), abnormally increased and disconnected uptake along the lymphatic channels. Preoperative 68Ga-NEB PET combined with MRL provides advantageous three-dimensional images, higher temporal resolution, significantly shorter time lapse before image acquisition after tracer injection and more accurate pathological lymphatic vessel distribution than 99mTc-SC lymphoscintigraphy combined with MRI. CONCLUSION: This study documented an effective imaging pattern to combine 68Ga-NEB PET and MRL in patients with lower-limb lymphedema. This strategy demonstrated significant advantage over 99mTc-SC lymphoscintigraphy/MRL in the evaluation of lymphedema severity, staging and pathological location of lymph vessels to make an individualized treatment plan. Dual 68Ga-NEB PET/MRL is thus recommended before the operation for staging and therapy planning.


Assuntos
Complexos de Coordenação , Extremidade Inferior/diagnóstico por imagem , Linfedema/cirurgia , Microcirurgia , Imagem Multimodal , Período Pré-Operatório , Cirurgia Assistida por Computador , Adulto , Idoso , Feminino , Humanos , Extremidade Inferior/cirurgia , Linfedema/diagnóstico por imagem , Linfografia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons
18.
Lancet ; 389(10088): 2492-2502, 2017 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-28434648

RESUMO

BACKGROUND: For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis. METHODS: We did a phase 1/2, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (≥18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0·1-10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with ClinicalTrials.gov, number NCT01658878. FINDINGS: Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15-26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6-28) in the dose-escalation phase. INTERPRETATION: Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma. FUNDING: Bristol-Myers Squibb.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Idoso , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Neoplasias Hepáticas/patologia , Masculino , Nivolumabe , Critérios de Avaliação de Resposta em Tumores Sólidos , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral
19.
J Nucl Med ; 58(2): 228-234, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27493267

RESUMO

This study aimed to document the first-in-human application of a 68Ga-labeled heterodimeric peptide BBN-RGD (bombesin-RGD) that targets both integrin αvß3 and gastrin-releasing peptide receptor (GRPR). We evaluated the safety and assessed the clinical diagnostic value of 68Ga-BBN-RGD PET/CT in prostate cancer patients in comparison with 68Ga-BBN. METHODS: Five healthy volunteers (4 men and 1 woman; age range, 28-53 y) were enrolled to validate the safety of 68Ga-BBN-RGD. Dosimetry was calculated using the OLINDA/EXM software. Thirteen patients with prostate cancer (4 newly diagnosed and 9 posttherapy) were enrolled. All the patients underwent PET/CT scans 15-30 min after intravenous injection of 1.85 MBq (0.05 mCi) per kilogram of body weight of 68Ga-BBN-RGD and also accepted 68Ga-BBN PET/CT within 2 wk for comparison. RESULTS: With a mean injected dose of 107.3 ± 14.8 MBq per patient, no side effect was found during the whole procedure and 2 wk follow-up, demonstrating the safety of 68Ga-BBN-RGD. A patient would be exposed to a radiation dose of 2.90 mSv with an injected dose of 129.5 MBq (3.5 mCi), which is much lower than the dose limit set by the Food and Drug Administration. In 13 patients with prostate cancer diagnosed by biopsy, 68Ga-BBN-RGD PET/CT detected 3 of 4 primary tumors, 14 metastatic lymph nodes, and 20 bone lesions with an SUVmax of 4.46 ± 0.50, 6.26 ± 2.95, and 4.84 ± 1.57, respectively. Only 2 of 4 primary tumors, 5 lymph nodes, and 12 bone lesions were positive on 68Ga-BBN PET/CT, with the SUVmax of 2.98 ± 1.24, 4.17 ± 1.89, and 3.61 ± 1.85, respectively. CONCLUSION: This study indicates the safety and efficiency of a new type of dual integrin αvß3- and GRPR-targeting PET radiotracer in prostate cancer diagnosis and staging.


Assuntos
Bombesina/farmacocinética , Integrina alfaVbeta3/metabolismo , Oligopeptídeos/farmacocinética , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/metabolismo , Receptores da Bombesina/metabolismo , Adulto , Idoso , Feminino , Radioisótopos de Gálio/farmacocinética , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Imagem Molecular , Especificidade de Órgãos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Distribuição Tecidual
20.
Nanoscale ; 8(20): 10553-7, 2016 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-27149392

RESUMO

A new type of photothermally responsive nanoprobe based on Edman degradation has been synthesized and characterized. Under irradiation by an 808 nm laser, the heat generated by the gold nanorod core breaks the thiocarbamide structure and releases the fluorescent dye Cy5.5 with increased near-infrared (NIR) fluorescence under mild acidic conditions. This RGD modified nanoprobe is capable of fluorescence imaging of ανß3 over-expressing U87MG cells in vitro and in vivo. This Edman degradation-based nanoprobe provides a novel strategy to design activatable probes for biomedical imaging and drug/gene delivery.


Assuntos
Corantes Fluorescentes , Ouro , Nanotubos , Neoplasias/diagnóstico por imagem , Ressonância de Plasmônio de Superfície , Animais , Linhagem Celular Tumoral , Técnicas de Transferência de Genes , Humanos , Camundongos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA