Publications by authors named "Zhaofei Liu"

90 Publications

Molecular PET/CT Profiling of ACE2 Expression In Vivo: Implications for Infection and Outcome from SARS-CoV-2.

Adv Sci (Weinh) 2021 Jun 26:e2100965. Epub 2021 Jun 26.

Key Laboratory of Carcinogenesis and Translational Research, NMPA Key Laboratory for Research Evaluation of Radiopharmaceuticals (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, 100142, China.

Rapid progress has been made to identify and study the causative agent leading to coronavirus disease 2019 (COVID-19) but many questions including who is most susceptible and what determines severity remain unanswered. Angiotensin-converting enzyme 2 (ACE2) is a key factor in the infection process of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In this study, molecularly specific positron emission tomography imaging agents for targeting ACE2 are first developed, and these novel agents are evaluated in vitro, in preclinical model systems, and in a first-in-human translational ACE2 imaging of healthy volunteers and a SARS-CoV-2 recovered patient (NCT04422457). ACE2 expression levels in different organs in live subjects are quantitatively delineated and observable differences are measured in the patient recovered from COVID-19. Surprising sites of uptake in the breast, reproductive system and very low uptake in pulmonary tissues are reported. This novel method can add a unique tool to facilitate SARS-CoV-2 related research and improve understanding of this enigmatic disease. Molecular imaging provides quantitative annotation of ACE2, the SARS-CoV-2 entry receptor, to noninvasively monitor organs impacted by the COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/advs.202100965DOI Listing
June 2021

Metabolic radiolabeling and in vivo PET imaging of cytotoxic T lymphocytes to guide combination adoptive cell transfer cancer therapy.

J Nanobiotechnology 2021 Jun 10;19(1):175. Epub 2021 Jun 10.

Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.

Background: Adoptive T cell transfer-based immunotherapy yields unsatisfactory results in the treatment of solid tumors, partially owing to limited tumor infiltration and the immunosuppressive microenvironment in solid tumors. Therefore, strategies for the noninvasive tracking of adoptive T cells are critical for monitoring tumor infiltration and for guiding the development of novel combination therapies.

Methods: We developed a radiolabeling method for cytotoxic T lymphocytes (CTLs) that comprises metabolically labeling the cell surface glycans with azidosugars and then covalently conjugating them with Cu-1,4,7-triazacyclononanetriacetic acid-dibenzo-cyclooctyne (Cu-NOTA-DBCO) using bioorthogonal chemistry. Cu-labeled control-CTLs and ovalbumin-specific CTLs (OVA-CTLs) were tracked using positron emission tomography (PET) in B16-OVA tumor-bearing mice. We also investigated the effects of focal adhesion kinase (FAK) inhibition on the antitumor efficacy of OVA-CTLs using a poly(lactic-co-glycolic) acid (PLGA)-encapsulated nanodrug (PLGA-FAKi).

Results: CTLs can be stably radiolabeled with Cu with a minimal effect on cell viability. PET imaging of Cu-OVA-CTLs enables noninvasive mapping of their in vivo behavior. Moreover, Cu-OVA-CTLs PET imaging revealed that PLGA-FAKi induced a significant increase in OVA-CTL infiltration into tumors, suggesting the potential for a combined therapy comprising OVA-CTLs and PLGA-FAKi. Further combination therapy studies confirmed that the PLGA-FAKi nanodrug markedly improved the antitumor effects of adoptive OVA-CTLs transfer by multiple mechanisms.

Conclusion: These findings demonstrated that metabolic radiolabeling followed by PET imaging can be used to sensitively profile the early-stage migration and tumor-targeting efficiency of adoptive T cells in vivo. This strategy presents opportunities for predicting the efficacy of cell-based adoptive therapies and for guiding combination regimens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12951-021-00924-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194184PMC
June 2021

ICAM-1 orchestrates the abscopal effect of tumor radiotherapy.

Proc Natl Acad Sci U S A 2021 Apr;118(14)

Medical Isotopes Research Center, Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China;

Compelling evidence indicates that radiotherapy (RT) has a systemic inhibitory effect on nonirradiated lesions (abscopal effect) in addition to the ablation of irradiated tumors. However, this effect occurs only in rare circumstances in clinical practice, and mechanisms underlying the abscopal effect of RT are neither fully understood nor therapeutically utilized. Here we identified that intercellular adhesion molecule-1 (ICAM-1), an inducible glycoprotein of the immunoglobulin superfamily, is up-regulated in nonirradiated tumors responsive to RT. ICAM-1 expression in preclinical animal models can be noninvasively detected by optical imaging and positron emission tomography (PET) using near-infrared fluorescence dye- and Cu-labeled imaging probes that we synthesized, respectively. Importantly, the expression levels of ICAM-1 determined by quantitative PET imaging showed a strong negative linear correlation with the growth of nonirradiated tumors. Moreover, genetic or pharmacologic up-regulation of ICAM-1 expression by either an intratumoral injection of engineered recombinant adenovirus or systemic administration of a Toll-like receptor 7 agonist-capsulated nanodrug could induce markedly increased abscopal responses to local RT in animal models. Mechanistic investigation revealed that ICAM-1 expression can enhance both the activation and tumor infiltration of CD8 T cells to improve the responses of the nonirradiated tumors to RT. Together, our findings suggest that noninvasive PET imaging of ICAM-1 expression could be a powerful means to predict the responses of nonirradiated tumors to RT, which could facilitate the exploration of new combination RT strategies for effective ablation of primary and disseminated lesions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2010333118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040592PMC
April 2021

[Expression of CDC25A in non-small cell lung cancer and its relationship with let-7 gene].

Nan Fang Yi Ke Da Xue Xue Bao 2020 Nov;40(11):1622-1627

Department of Respiratory and Critical Care Medicine, Fuyang Second People's Hospital, Fuyang 236000, China.

Objective: To investigate the expression of CDC25A in non- small cell lung cancer (NSCLC) tissues and explore its correlation with the clinicpathological features of the patients and the expressions of let-7a1 and let-7c.

Methods: We collected surgical specimens of pathologically confirmed NSCLC tissues and paired adjacent lung tissues from 44 patients and tissues of benign lung lesions from 9 patients. The expressions of CDC25A protein and mRNA in the tissues were detected by immunohistochemistry and fluorescence quantitative RT-PCR, respectively; the expressions of let-7a1 and let-7c mRNA were detected using tail-adding fluorescence quantitative RT-PCR.

Results: The positivity rate of CDC25A protein expression was significantly higher in NSCLC tissues than in the adjacent tissues and benign pulmonary lesions ( < 0.05). CDC25A protein expression in NSCLC was not correlated with the patients' age, gender, pathological type, degree of tumor differentiation, or clinical stages ( > 0.05), and was significantly correlated with smoking and lymph node metastasis ( < 0.05). CDC25A mRNA expression was also significantly higher in NSCLC tissues than in the adjacent tissues and benign pulmonary lesions (=6.33, < 0.05), and was similar between the latter two tissues ( > 0.05). Pearson correlation analysis showed that CDC25A expression had a significant negative correlation with let-7c expression in both NSCLC tissues (=-0.42) and adjacent lung tissues (=-0.40) but was not correlated with let-7a1 expression.

Conclusions: The expression level of CDC25A is significantly increased in NSCLC with a negative correlation with Let-7c expression, which identifies CDC25A as a possible downstream target gene of Let-7c.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12122/j.issn.1673-4254.2020.11.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704372PMC
November 2020

Nuclear imaging-guided PD-L1 blockade therapy increases effectiveness of cancer immunotherapy.

J Immunother Cancer 2020 11;8(2)

Medical Isotopes Research Center and Department of Radiation Medicine, State Key Laboratory of Natural and Biomimetic Drugs, School of Basic Medical Sciences, Peking University, Beijing, China

Objectives: Strategies to improve the responsiveness of programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint blockade therapy remain an essential topic in cancer immunotherapy. In this study, we developed a new radiolabeled nanobody-based imaging probe Tc-MY1523 targeting PD-L1 for the enhanced therapeutic efficacy of PD-L1 blockade immunotherapy by the guidance of Tc-MY1523 SPECT/CT imaging.

Methods: The binding affinity and specificity of nanobody MY1523 were measured in vitro. MY1523 was radiolabeled with Tc by a site-specific transpeptidation of Sortase-A, and the biodistribution and single photon emission CT (SPECT)/CT were performed in mice bearing different tumors. We used interferon-γ (IFN-γ) as an intervention means to establish animal models with different levels of PD-L1 expression, then investigated the ability of Tc-MY1523 SPECT/CT for the in vivo non-invasive measurement of PD-L1 expression in tumors. Finally, the PD-L1 blockade immunotherapies guided by Tc-MY1523 SPECT/CT were carried out in MC-38, A20, and 4T1 tumor-bearing mouse models, followed by the testing of tumor infiltration T cells.

Results: MY1523 exhibited a high binding affinity and specificity to PD-L1 and had no competitive binding with the therapeutic antibody. Tc-MY1523 was prepared with high specific activity and radiochemical purity. It was found that tumor PD-L1 expression was dynamically upregulated by IFN-γ intervention in MC-38, A20, and 4T1 tumor-bearing mouse models, as indicated by Tc-MY1523 SPECT/CT. The PD-L1 blockade therapy initiated during the therapeutic time window determined by Tc-MY1523 SPECT/CT imaging significantly enhanced the therapeutic efficacy in all animal models, while the tumor growth was effectively suppressed, and the survival time of mice was evidently prolonged. A correlation between dynamically upregulated PD-L1 expression and improved PD-L1 blockade therapy effectiveness was revealed, and the markedly increased infiltration of effector T cells into tumors was verified after the imaging-guided therapy.

Conclusion: Our results demonstrated that Tc-MY1523 SPECT/CT allowed a real-time, quantitative and dynamic mapping of PD-L1 expression in vivo, and the imaging-guided PD-L1 blockade immunotherapy significantly enhanced the therapeutic efficacy. This strategy merits translation into clinical practice for the better management of combination therapies with radiotherapy or chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2020-001156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674096PMC
November 2020

Estimation of the Qinghai-Tibetan Plateau runoff and its contribution to large Asian rivers.

Sci Total Environ 2020 Dec 12;749:141570. Epub 2020 Aug 12.

Institute of Geographic Sciences and Natural Resources Research, Chinese Academy of Sciences, 100101 Beijing, China. Electronic address:

The Qinghai-Tibetan Plateau (QTP), named the Asian Water Towers, feeds more than 2.5 billion people in downstream regions. It is still unknown how much water outflows from this region owing to lack of observations. The main objective of this study is to clarify availability of water flowed out of this region and its contribution to large Asian rivers. The Global Land Data Assimilation System (GLDAS) products are evaluated with the help of observations of the QTP. In addition, a velocity-based routing method is embedded into the GLDAS model to route runoff products to the basin outlet in this study. The results show that the simulated dry season runoff in the GLDAS model is generally lower than the observed value, which is mainly because most hydrological models only consider the potential evapotranspiration (ET) when simulating ET, while ignoring the water constraint factor. Noah10_v2.0 has the highest precision at the QTP. For the monthly precipitation and runoff series, the relative error is within 5%, the correlation coefficient is greater than 0.90, and the Nash-Sutcliffe efficiencies are 0.95 and 0.76, respectively. Glacier melt runoff plays an important role in the QTP runoff, with a proportion of approximately 22%. It is relatively high in the Tarim River basin (83%), Syr Darya River and Amu Darya River basins (69%), and Indus River basin (60%). The contribution ratio also reaches 23% in the Yarlung Zangbo-Brahmaputra River and Ganges River basins, whereas it is the lowest in the Irrawaddy River basin (2%). According to the Noah10_v2.0 simulations, the mean annual runoff provided by the QTP exceeds 620 billion cubic metres, of which approximately 440 billion cubic metres flow out of the QTP and supply downstream regions of international rivers. The contribution ratio of the QTP runoff to the total runoff of its affected basins is approximately 16%.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.scitotenv.2020.141570DOI Listing
December 2020

Clinical Translation of a Ga-Labeled Integrin αβ-Targeting Cyclic Radiotracer for PET Imaging of Pancreatic Cancer.

J Nucl Med 2020 10 21;61(10):1461-1467. Epub 2020 Feb 21.

Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; and

The overexpression of integrin αβ in pancreatic cancer makes it a promising target for noninvasive PET imaging. However, currently, most integrin αβ-targeting radiotracers are based on linear peptides, which are quickly degraded in the serum by proteinases. Herein, we aimed to develop and assess a Ga-labeled integrin αβ-targeting cyclic peptide (Ga-cycratide) for PET imaging of pancreatic cancer. Ga-cycratide was prepared, and its PET imaging profile was compared with that of the linear peptide (Ga-linear-pep) in an integrin αβ-positive BxPC-3 human pancreatic cancer mouse model. Five healthy volunteers (2 women and 3 men) underwent whole-body PET/CT imaging after injection of Ga-cycratide, and biodistribution and dosimetry were calculated. PET/CT imaging of 2 patients was performed to investigate the potential role of Ga-cycratide in pancreatic cancer diagnosis and treatment monitoring. Ga-cycratide exhibited significantly higher tumor uptake than did Ga-linear-pep in BxPC-3 tumor-bearing mice, owing-at least in part-to markedly improved in vivo stability. Ga-cycratide could sensitively detect the pancreatic cancer lesions in an orthotopic mouse model and was well tolerated in all healthy volunteers. Preliminary PET/CT imaging in patients with pancreatic cancer demonstrated that Ga-cycratide was comparable to F-FDG for diagnostic imaging and postsurgery tumor relapse monitoring. Ga-cycratide is an integrin αβ-specific PET radiotracer with favorable pharmacokinetics and a favorable dosimetry profile. Ga-cycratide is expected to provide an effective noninvasive PET strategy for pancreatic cancer lesion detection and therapy response monitoring.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.119.237347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539652PMC
October 2020

Evaluation of Cu radiolabeled anti-hPD-L1 Nb6 for positron emission tomography imaging in lung cancer tumor mice model.

Bioorg Med Chem Lett 2020 02 24;30(4):126915. Epub 2019 Dec 24.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, PR China. Electronic address:

Recently, we selected a novel anti-hPD-L1-specific HCAb named Nb6 with high affinity (EC = 0.65 ng/mL) for potential hPD-L1 targeted non-invasive PET imaging. In this research, Nb6 was conjugated with the bifunctional chelator NCS-Bz-NOTA ((2-[(4-Isothiocyanophenyl) methyl]-1,4,7-triazacy-clononane-1,4,7-triacetic acid)) and further labeled with radio-nuclide Cu. Cu-NOTA-Nb6 was prepared with over 95% labeling yield, over 99% radiochemical purity and 14-16 GBq/μmol specific activity after PD-10 column purification. It shows good stability in 0.01 M PBS and 5% HSA solutions. Cu-NOTA-Nb6 has a high binding affinity to 3.60 nM which was tested by humanlungadenocarcinoma A549 cell lines. Tumor lesion can be clearly observed from 20 h to 38 h by Micro-PET equipment after Cu-NOTA-Nb6 administration. The study revealed that Cu-NOTA-Nb6 has good lesion detection ability, high ratios between tumor and non-tumor signal and can specifically target A549 xenografted tumor model. Taken together of good stability, high binding affinity, and tumor detection ability, Cu labeled Nb6 is a promising radio-tracer in diagnosing of hPD-L1 overexpression tumor, supposed to monitor PD-L1overexpression tumor progression and guide targeted therapy with PET molecular imaging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2019.126915DOI Listing
February 2020

Noninvasive PET tracking of post-transplant gut microbiota in living mice.

Eur J Nucl Med Mol Imaging 2020 04 2;47(4):991-1002. Epub 2020 Jan 2.

Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.

Purpose: The role that gut microbiota plays in determining the efficacy of the anti-tumor effect of immune checkpoint inhibitors is gaining increasing attention, and fecal bacterial transplantation has been recognized as a promising strategy for improving or rescuing the effect of immune checkpoint inhibition. However, techniques for the precise monitoring of in vivo bacterial behaviors after transplantation are limited. In this study, we aimed to use metabolic labeling and subsequent positron emission tomography (PET) imaging to track the in vivo behaviors of gut bacteria that are responsible for the efficacy of anti-PD-1 therapy in living mice.

Methods: The antitumor effect of anti-PD-1 blockade was tested in a low-response 4T1 syngeneic mouse model with or without fecal transplantation and with or without broad-spectrum antibiotic imipenem treatment. High-throughput sequencing analyses of 16S rRNA gene amplicons in feces of 4T1 tumor-bearing mice pre- and post-anti-PD-1 treatment were performed. The identified bacteria, Bacteroides fragilis (B. fragilis), were labeled with Cu and fluorescence dye by the metabolic labeling of N followed by click chemistry. In vivo PET and optical imaging of B. fragilis were performed in mice after oral gavage.

Results: The disturbance of gut microbiota reduced the efficacy of anti-PD-1 treatment, and the combination of B. fragilis gavage and PD-1 blockade was beneficial in rescuing the antitumor effect of anti-PD-1 therapy. Metabolic oligosaccharide engineering and biorthogonal click chemistry resulted in successful B. fragilis labeling with Cu and fluorescence dye with high in vitro and in vivo stability and no effect on viability. PET imaging successfully detected the in vivo behaviors of B. fragilis after transplantation.

Conclusion: PET tracking by metabolic labeling is a powerful, noninvasive tool for the real-time tracking and quantitative imaging of gut microbiota. This strategy is clinically translatable and may also be extended to the PET tracking of other functional cells to guide cell-based adoptive therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00259-019-04639-3DOI Listing
April 2020

Ceria Nanoparticles Meet Hepatic Ischemia-Reperfusion Injury: The Perfect Imperfection.

Adv Mater 2019 Oct 16;31(40):e1902956. Epub 2019 Aug 16.

Departments of Radiology and Medical Physics, University of Wisconsin-Madison, Madison, WI, 53705, USA.

The mononuclear phagocyte system (MPS, e.g., liver, spleen) is often treated as a "blackbox" by nanoresearchers in translating nanomedicines. Often, most of the injected nanomaterials are sequestered by the MPS, preventing their delivery to the desired disease areas. Here, this imperfection is exploited by applying nano-antioxidants with preferential liver uptake to directly prevent hepatic ischemia-reperfusion injury (IRI), which is a reactive oxygen species (ROS)-related disease. Ceria nanoparticles (NPs) are selected as a representative nano-antioxidant and the detailed mechanism of preventing IRI is investigated. It is found that ceria NPs effectively alleviate the clinical symptoms of hepatic IRI by scavenging ROS, inhibiting activation of Kupffer cells and monocyte/macrophage cells. The released pro-inflammatory cytokines are then significantly reduced and the recruitment and infiltration of neutrophils are minimized, which suppress subsequent inflammatory reaction involved in the liver. The protective effect of nano-antioxidants against hepatic IRI in living animals and the revealed mechanism herein suggests their future use for the treatment of hepatic IRI in the clinic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/adma.201902956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773480PMC
October 2019

The deubiquitylase OTUD3 stabilizes GRP78 and promotes lung tumorigenesis.

Nat Commun 2019 07 2;10(1):2914. Epub 2019 Jul 2.

State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, 100850, Beijing, China.

The deubiquitylase OTUD3 plays a suppressive role in breast tumorigenesis through stabilizing PTEN protein, but its role in lung cancer remains unclear. Here, we demonstrate that in vivo deletion of OTUD3 indeed promotes breast cancer development in mice, but by contrast, it slows down Kras-driven lung adenocarcinoma (ADC) initiation and progression and markedly increases survival in mice. Moreover, OTUD3 is highly expressed in human lung cancer tissues and its higher expression correlates with poorer survival of patients. Further mechanistic studies reveal that OTUD3 interacts with, deubiquitylates and stabilizes the glucose-regulated protein GRP78. Knockdown of OTUD3 results in a decrease in the level of GRP78 protein, suppression of cell growth and migration, and tumorigenesis in lung cancer. Collectively, our results reveal a previously unappreciated pro-oncogenic role of OTUD3 in lung cancer and indicate that deubiquitylases could elicit tumor-suppressing or tumor-promoting activities in a cell- and tissue-dependent context.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-10824-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606649PMC
July 2019

HOXB13 networking with ABCG1/EZH2/Slug mediates metastasis and confers resistance to cisplatin in lung adenocarcinoma patients.

Theranostics 2019 6;9(7):2084-2099. Epub 2019 Apr 6.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), and State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China.

Distant metastasis and chemoresistance are the major causes of short survival after initial chemotherapy in lung adenocarcinoma patients. However, the underlying mechanisms remain elusive. Our pilot study identified high expression of the homeodomain transcription factor HOXB13 in chemoresistant lung adenocarcinomas. We aimed to investigate the role of HOXB13 in mediating lung adenocarcinoma chemoresistance. Immunohistochemistry assays were employed to assess HOXB13 protein levels in 148 non-small cell lung cancer patients. The role of HOXB13 in lung adenocarcinoma progression and resistance to cisplatin therapy was analyzed in cells, xenografted mice, and patient-derived xenografts. Needle biopsies from 15 lung adenocarcinoma patients who were resistant to cisplatin and paclitaxel therapies were analyzed for HOXB13 and EZH2 protein levels using immunohistochemistry. High expression of HOXB13 observed in 17.8% of the lung adenocarcinoma patients in this study promoted cancer progression and predicted poor prognosis. HOXB13 upregulated an array of metastasis- and drug-resistance-related genes, including ABCG1, EZH2, and Slug, by directly binding to their promoters. Cisplatin induced HOXB13 expression in lung adenocarcinoma cells, and patient-derived xenografts and depletion of ABCG1 enhanced the sensitivity of lung adenocarcinoma cells to cisplatin therapy. Our results suggest that determining the combined expression of HOXB13 and its target genes can predict patient outcomes. A cisplatin-HOXB13-ABCG1/EZH2/Slug network may account for a novel mechanism underlying cisplatin resistance and metastasis after chemotherapy. Determining the levels of HOXB13 and its target genes from needle biopsy specimens may help predict the sensitivity of lung adenocarcinoma patients to platinum-based chemotherapy and patient outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.29463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485289PMC
April 2020

Molybdenum-based nanoclusters act as antioxidants and ameliorate acute kidney injury in mice.

Nat Commun 2018 12 21;9(1):5421. Epub 2018 Dec 21.

Departments of Radiology and Medical Physics, University of Wisconsin, Madison, WI, 53705, USA.

Acute kidney injury (AKI) is a common reactive oxygen species (ROS)-related renal disease that causes numerous deaths annually, yet only supportive treatment is currently available in the clinics. Development of antioxidants with high accumulation rates in kidneys is highly desired to help prevent AKI. Here we report molybdenum-based polyoxometalate (POM) nanoclusters with preferential renal uptake as novel nano-antioxidants for kidney protection. These POM nanoclusters, with a readily variable valence state of molybdenum ions, possess the capability to scavenge detrimental ROS. Our results demonstrate that POM nanoclusters can efficiently alleviate clinical symptoms in mice subjected to AKI, as verified by dynamic PET imaging with Ga-EDTA, serum tests, kidney tissue staining, and biomarkers detection in the kidneys. The protective effect of POM nanoclusters against AKI in living animals suggests exploring their use for the treatment of AKI patients, as well as patients with other ROS-related diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-07890-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303396PMC
December 2018

Small-animal SPECT/CT imaging of cancer xenografts and pulmonary fibrosis using a Tc-labeled integrin αvβ6-targeting cyclic peptide with improved stability.

Biophys Rep 2018 2;4(5):254-264. Epub 2018 Nov 2.

1Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191 China.

Abstract: Integrin αvβ6 is expressed at an undetectable level in normal tissues, but is remarkably upregulated during many pathological processes, especially in cancer and fibrosis. Noninvasive imaging of integrin αvβ6 expression using a radiotracer with favorable pharmacokinetics would facilitate disease diagnosis and therapy monitoring. Through disulfide-cyclized method, we synthesized in this study, a new integrin αvβ6-targeted cyclic peptide (denoted as cHK), and radiolabeled it with Tc. The ability of the resulting radiotracer Tc-HYNIC-cHK to detect integrin αvβ6 expression in pancreatic cancer xenografts and idiopathic pulmonary fibrosis was evaluated using small-animal single-photon emission computed tomography (SPECT)/computed tomography (CT). Tc-HYNIC-cHK showed significantly improved metabolic stability compared to the linear peptide-based radiotracer Tc-HYNIC-HK. Tc-HYNIC-cHK exhibited similar biodistribution properties to Tc-HYNIC-HK, but the tumor-to-muscle ratio was significantly increased (2.99 ± 0.87 vs. 1.82 ± 0.27, < 0.05). High-contrast images of integrin αvβ6-positive tumors and bleomycin-induced fibrotic lungs were obtained by SPECT/CT imaging using Tc-HYNIC-cHK. Overall, our studies demonstrate that Tc-HYNIC-cHK is a promising SPECT radiotracer for the noninvasive imaging of integrin αvβ6 in living subjects.

Graphical Abstract:
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s41048-018-0071-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245143PMC
November 2018

Molecular imaging of diabetes and diabetic complications: Beyond pancreatic β-cell targeting.

Adv Drug Deliv Rev 2019 01 5;139:32-50. Epub 2018 Dec 5.

Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China. Electronic address:

Diabetes is a chronic non-communicable disease affecting over 400 million people worldwide. Diabetic patients are at a high risk of various complications, such as cardiovascular, renal, and other diseases. The pathogenesis of diabetes (both type 1 and type 2 diabetes) is associated with a functional impairment of pancreatic β-cells. Consequently, most efforts to manage and prevent diabetes have focused on preserving β-cells and their function. Advances in imaging techniques, such as magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography, and single-photon-emission computed tomography, have enabled noninvasive and quantitative detection and characterization of the population and function of β-cells in vivo. These advantages aid in defining and monitoring the progress of diabetes and determining the efficacy of anti-diabetic therapies. Beyond β-cell targeting, molecular imaging of biomarkers associated with the development of diabetes, e.g., lymphocyte infiltration, insulitis, and metabolic changes, may also be a promising strategy for early detection of diabetes, monitoring its progression, and occurrence of complications, as well as facilitating exploration of new therapeutic interventions. Moreover, molecular imaging of glucose uptake, production and excretion in specified tissues is critical for understanding the pathogenesis of diabetes. In the current review, we summarize and discuss recent advances in noninvasive imaging technologies for imaging of biomarkers beyond β-cells for early diagnosis of diabetes, investigation of glucose metabolism, and precise diagnosis and monitoring of diabetic complications for better management of diabetic patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.addr.2018.11.007DOI Listing
January 2019

Synergistic enzymatic and bioorthogonal reactions for selective prodrug activation in living systems.

Nat Commun 2018 11 28;9(1):5032. Epub 2018 Nov 28.

CAS Center for Excellence in Nanoscience, CAS Key Laboratory of Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing, 100190, China.

Adverse drug reactions (ADRs) restrict the maximum doses applicable in chemotherapy, which leads to failure in cancer treatment. Various approaches, including nano-drug and prodrug strategies aimed at reducing ADRs, have been developed, but these strategies have their own pitfalls. A renovated strategy for ADR reduction is urgently needed. Here, we employ an enzymatic supramolecular self-assembly process to accumulate a bioorthogonal decaging reaction trigger inside targeted cancer cells, enabling spatiotemporally controlled, synergistic prodrug activation. The bioorthogonally activated prodrug exhibits significantly enhanced potency against cancer cells compared with normal cells. This prodrug activation strategy further demonstrates high tumour inhibition efficacy with satisfactory biocompatibility, pharmacokinetics, and safety in vivo. We envision that integration of enzymatic and bioorthogonal reactions will serve as a general small-molecule-based strategy for alleviation of ADRs in chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-07490-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261997PMC
November 2018

Enhancing Anti-PD-1/PD-L1 Immune Checkpoint Inhibitory Cancer Therapy by CD276-Targeted Photodynamic Ablation of Tumor Cells and Tumor Vasculature.

Mol Pharm 2019 01 30;16(1):339-348. Epub 2018 Nov 30.

Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences , Peking University Health Science Center , Beijing 100191 , China.

Antiangiogenic therapies have been demonstrated to improve the efficacy of immune checkpoint inhibition by overcoming the immunosuppressive status of the tumor microenvironment. However, most of the current antiangiogenic agents cannot discriminate tumor angiogenesis from physiological angiogenesis. The aim of this study was to investigate whether a photodynamic therapy (PDT) agent that targets CD276, a receptor overexpressed in various tumor cells and tumor vasculature but with limited expression in normal tissue vasculature, could improve the tumor inhibitory efficacy of a PD-1/PD-L1 blockade. A CD276-targeting agent (IRD-αCD276/Fab) was synthesized by conjugating the Fab fragment of an anti-CD276 antibody with a photosensitizer IRDye700. The in vivo tumor-targeting efficacy and therapeutic effects of IRD-αCD276/Fab with or without an anti-PD-1/PD-L1 blockade were tested in subcutaneous and lung metastatic tumor models. PDT using IRD-αCD276/Fab significantly suppressed the growth of subcutaneous 4T1 tumor and inhibited its lung metastasis. Moreover, it triggered in vivo antitumor immunity by increasing the activation and maturation of dendritic cells. Tumor PD-L1 levels were also markedly increased after PDT using IRD-αCD276/Fab, as evidenced by noninvasive PD-L1-targeted small-animal PET imaging. In combination with an anti-PD-1/PD-L1 blockade, IRD-αCD276/Fab PDT markedly suppressed the growth of tumors and prevented their metastasis to the lung by recruiting the tumor infiltration of CD8 T cells. Our data provide evidence for the role of CD276-targeted PDT for local immune modulation, and its combination with PD-L1/PD-1 axis inhibition is a promising strategy for eliminating primary tumors as well as disseminated metastases, by generating local and systemic antitumor responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.molpharmaceut.8b00997DOI Listing
January 2019

Radon emission from soil gases in the active fault zones in the Capital of China and its environmental effects.

Sci Rep 2018 11 13;8(1):16772. Epub 2018 Nov 13.

CEA Key Laboratory of Earthquake Prediction (Institute of Earthquake Forecasting), China Earthquake Administration, Beijing, 100036, China.

The release of radon in active fault zones is a sustained radioactive pollution source of the atmospheric environment. The species, concentration and flux of radon emitted in soil gas in active fault zones in the Capital of China were investigated by in-situ field measurements. Two main species of radon discharging from soil gas in active fault zones were identified, including radon diffused and dispersed from permeable soil, and upwelling from faults. Higher concentrations and flux of radon from faults were observed in the Bohai Bay Basin due to the accumulated uranium in the sandstone reservoirs and higher permeability of the strata and bed rocks. Increased radon released by strong earthquakes persists, with the max flux of 334.56 mBq m s observed in FN (Fengnan district) located at the epicenter of the 28 July, 1976 Tangshan M 7.8 earthquake. The level of radon released in 8 of 22 locations within the Basin and Range Province (to the west of Taihangshan piedmont fault Zone) reached level 2, and 13 of 14 locations within the Bohai Bay Basin reached levels 2-4, according to the Chinese Code (GB 50325-2001, 2006). Corresponding protective and safety measures should be in place to protect the health of nearby residents, due to their exposure to radon emitted from the faults. Also, the concentration of radon in active fault zones should be investigated to assess the possible risk, before land-use is planned.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-35262-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233208PMC
November 2018

Noninvasive small-animal imaging of galectin-1 upregulation for predicting tumor resistance to radiotherapy.

Biomaterials 2018 03 15;158:1-9. Epub 2017 Dec 15.

Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China. Electronic address:

Increasing evidence indicates that the overexpression of galectin-1, a member of the galectin family, is related to tumor progression and invasion, as well as tumor resistance to therapies (e.g., radiotherapy). Herein, we investigated whether near-infrared fluorescence (NIRF) imaging and positron-emission tomography (PET) were sensitive approaches for detecting and quantitating galectin-1 upregulation in vivo. An anti-galectin-1 antibody was labeled with either an NIRF dye or Cu, and NIRF and PET imaging using the resulting probes (Dye-αGal-1 and Cu- 1,4,7-triazacyclononane-1,4,7-triacetic acid [NOTA]-αGal-1) were performed in 4T1 breast cancer-bearing mice treated with several rounds of sorafenib. Radiotherapy was performed in vitro and in vivo to identify the role of galectin-1 in radioresistance. NIRF and PET imaging both revealed significantly increased upregulation of galectin-1 in the hypoxic tumors after sorafenib treatment, which was verified by ex vivo biodistribution, western blotting, and enzyme-linked immunosorbent assays. Galectin-1 specific inhibition by thiodigalactoside dramatically improved the efficacy of radiotherapy, and overcame sorafenib-induced radiotherapy resistance. Taken together, galectin-1 is a key mediator of tumor resistance to radiotherapy. Targeted molecular imaging allows for real-time, noninvasive, and quantitative detection of the dynamic changes in galectin-1 levels in vivo; this introduces the possibility of early detection of tumor resistance to therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biomaterials.2017.12.012DOI Listing
March 2018

Noninvasive Imaging of CD206-Positive M2 Macrophages as an Early Biomarker for Post-Chemotherapy Tumor Relapse and Lymph Node Metastasis.

Theranostics 2017 26;7(17):4276-4288. Epub 2017 Sep 26.

Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.

Tumor relapse after initial regression post-chemotherapy is a major challenge in cancer treatment, as it usually leads to local-regional recurrence or inoperable distant metastasis. M2 macrophages diminish the tumor-inhibitory effect of chemotherapy and correlate with distant metastasis and poor prognosis. In this study, we investigated whether molecular imaging of M2 macrophages could serve as an early biomarker for tumor relapse after chemotherapy and tumor lymph node metastasis in preclinical mouse models. We developed M2 macrophage-targeted probes for near-infrared fluorescence (NIRF) imaging and single-photon emission computed tomography (SPECT) using an anti-CD206 monoclonal antibody. The specific targeting capacity and potential applications of the NIRF and SPECT probes were investigated in subcutaneous tumor and lymph node metastasis models of 4T1 murine breast cancer. M2 macrophage infiltration was significantly increased in the 4T1 tumors that later underwent relapse but not in non-relapsing 4T1 tumors after cyclophosphamide treatment. Through NIRF imaging and SPECT using our synthesized probes, the infiltration of M2 macrophages in relapsing tumors and tumor lymph node metastasis could be sensitively detected. Importantly, early prediction of tumor relapse by molecular imaging of M2 macrophages resulted in an effective eradication of tumors upon combination with additional radiotherapy. Our findings demonstrate that M2 macrophage-targeted imaging allows for noninvasively predicting post-chemotherapy tumor relapse and sensitively detecting the metastatic lymph nodes . This imaging strategy could provide a better understanding of cancer progression, enable early prediction of tumor resistance, and have implications on the rational design of cancer therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.20999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695012PMC
July 2018

Chemotherapy-Induced Macrophage Infiltration into Tumors Enhances Nanographene-Based Photodynamic Therapy.

Cancer Res 2017 11 15;77(21):6021-6032. Epub 2017 Sep 15.

Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.

Increased recruitment of tumor-associated macrophages (TAM) to tumors following chemotherapy promotes tumor resistance and recurrence and correlates with poor prognosis. TAM depletion suppresses tumor growth, but is not highly effective due to the effects of tumorigenic mediators from other stromal sources. Here, we report that adoptive macrophage transfer led to a dramatically enhanced photodynamic therapy (PDT) effect of 2-(1-hexyloxyethyl)-2-devinyl pyropheophor-bide-alpha (HPPH)-coated polyethylene glycosylated nanographene oxide [GO(HPPH)-PEG] by increasing its tumor accumulation. Moreover, tumor treatment with commonly used chemotherapeutic drugs induced an increase in macrophage infiltration into tumors, which also enhanced tumor uptake and the PDT effects of GO(HPPH)-PEG, resulting in tumor eradication. Macrophage recruitment to tumors after chemotherapy was visualized noninvasively by near-infrared fluorescence and single-photon emission CT imaging using F4/80-specific imaging probes. Our results demonstrate that chemotherapy combined with GO(HPPH)-PEG PDT is a promising strategy for the treatment of tumors, especially those resistant to chemotherapy. Furthermore, TAM-targeted molecular imaging could potentially be used to predict the efficacy of combination therapy and select patients who would most benefit from this treatment approach. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-17-1655DOI Listing
November 2017

Inhibiting Metastasis and Preventing Tumor Relapse by Triggering Host Immunity with Tumor-Targeted Photodynamic Therapy Using Photosensitizer-Loaded Functional Nanographenes.

ACS Nano 2017 10 18;11(10):10147-10158. Epub 2017 Sep 18.

Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center , Beijing 100191, China.

Effective cancer therapy depends not only on destroying the primary tumor but also on conditioning the host immune system to recognize and eliminate residual tumor cells and prevent metastasis. In this study, a tumor integrin αvβ6-targeting peptide (the HK peptide)-functionalized graphene oxide (GO) was coated with a photosensitizer (HPPH). The resulting GO conjugate, GO(HPPH)-PEG-HK, was investigated whether it could destroy primary tumors and boost host antitumor immunity. We found that GO(HPPH)-PEG-HK exhibited significantly higher tumor uptake than GO(HPPH)-PEG and HPPH. Photodynamic therapy (PDT) using GO(HPPH)-PEG suppressed tumor growth in both subcutaneous and lung metastatic mouse models. Necrotic tumor cells caused by GO(HPPH)-PEG-HK PDT activated dendritic cells and significantly prevented tumor growth and lung metastasis by increasing the infiltration of cytotoxic CD8 T lymphocytes within tumors as evidenced by in vivo optical and single-photon emission computed tomography (SPECT)/CT imaging. These results demonstrate that tumor-targeted PDT using GO(HPPH)-PEG-HK could effectively ablate primary tumors and destroy residual tumor cells, thereby preventing distant metastasis by activating host antitumor immunity and suppressing tumor relapse by stimulation of immunological memory.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsnano.7b04736DOI Listing
October 2017

Author Correction: Nanoparticle-mediated local depletion of tumour-associated platelets disrupts vascular barriers and augments drug accumulation in tumours.

Nat Biomed Eng 2017 08;1(8):680

Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China.

In the version of the Supplementary Information originally published, in Supplementary Fig. 8a, in the bottom row, the left-most image ('Control') was not the correct image; this has now been replaced.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41551-017-0125-6DOI Listing
August 2017

Nanoparticle-mediated local depletion of tumour-associated platelets disrupts vascular barriers and augments drug accumulation in tumours.

Nat Biomed Eng 2017 Aug 24;1(8):667-679. Epub 2017 Jul 24.

Chinese Academy of Sciences Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China.

Limited intratumoural perfusion and nanoparticle retention remain major bottlenecks for the delivery of nanoparticle therapeutics into tumours. Here, we show that polymer-lipid-peptide nanoparticles delivering the antiplatelet antibody R300 and the chemotherapeutic agent doxorubicin can locally deplete tumour-associated platelets, thereby enhancing vascular permeability and augmenting the accumulation of the nanoparticles in tumours. R300 is specifically released in the tumour on cleavage of the lipid-peptide shell of the nanoparticles by matrix metalloprotease 2, which is commonly overexpressed in tumour vascular endothelia and stroma, thus facilitating vascular breaches that enhance tumour permeability. We also show that this strategy leads to substantial tumour regression and metastasis inhibition in mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41551-017-0115-8DOI Listing
August 2017

Radiolabeled novel mAb 4G1 for immunoSPECT imaging of EGFRvIII expression in preclinical glioblastoma xenografts.

Oncotarget 2017 Jan;8(4):6364-6375

Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China.

Epidermal growth factor receptor mutant III (EGFRvIII) is exclusively expressed in tumors, such as glioblastoma, breast cancer and hepatocellular carcinoma, but never in normal organs. Increasing evidence suggests that EGFRvIII has clinical significance in glioblastoma prognosis due to its enhanced tumorigenicity and chemo/radio resistance, thus the development of an imaging approach to early detect EGFRvIII expression with high specificity is urgently needed. To illustrate this point, we developed a novel anti-EGFRvIII monoclonal antibody 4G1 through mouse immunization, cell fusion and hybridoma screening and then confirmed its specificity and affinity by a serial of assays. Following biodistribution and small animal single-photon emission computed tomography (SPECT/CT) imaging of 125I-4G1 in EGFRvIII positive/negative tumor-bearing mice were performed and evaluated to verify the tumor accumulation of this radiotracer. The biodistribution indicated that 125I-4G1 showed prominent tumor accumulation at 24 h post-injection, which reached maximums of 11.20 ± 0.75% ID/g and 13.98 ± 0.57% ID/g in F98npEGFRvIII and U87vIII xenografts, respectively. In contrast, 125I-4G1 had lower tumor accumulation in F98npEGFR and U87MG xenografts. Small animal SPECT/CT imaging revealed that 125I-4G1 had a higher tumor uptake in EGFRvIII-positive tumors than that in EGFRvIII-negative tumors. This study demonstrates that radiolabeled 4G1 can serve as a valid probe for the imaging of EGFRvIII expression, and would be valuable into the clinical translation for the diagnosis, prognosis, guiding therapy, and therapeutic efficacy evaluation of tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.14088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351638PMC
January 2017

Integrin Imaging with Tc-3PRGD2 SPECT/CT Shows High Specificity in the Diagnosis of Lymph Node Metastasis from Non-Small Cell Lung Cancer.

Radiology 2016 Dec 29;281(3):958-966. Epub 2016 Jul 29.

From the Departments of Nuclear Medicine (X.J., X.S., Y.L., K.Z., F.L., Z.Z.), Thoracic Surgery (N.L., S.L.), Respiratory Medicine (M.W., J.L.), and Pathology (Y.M., Q.C.), Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Dongcheng District, Beijing 100730, China; Medical Isotopes Research Center, Peking University, Beijing, China (B.J., Z.L., J.S., F.W.); and Interdisciplinary Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (F.W.).

Purpose To evaluate an integrin imaging approach based on single photon emission computed tomography (SPECT)/computed tomography (CT) by using technetium 99m (Tc)-dimeric cyclic arginine-glycine-aspartic acid (RGD) peptides with three polyethylene glycol spacers (3PRGD2) as the tracer to target the integrin αβ expression in lung cancer and lymph node metastasis. Materials and Methods With ethics committee approval and written informed consent, 65 patients (41 male, 24 female; mean age, 60 years ± 11 [standard deviation]) with suspicious lung lesions were recruited with informed consent. The patients underwent both Tc-3PRGD2 SPECT/CT and fluorine 18 (F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT within 1 week. Finally, 65 lung lesions in 53 patients were pathologically diagnosed as non-small cell lung cancer (NSCLC) and 14 lung lesions in 12 patients were benign. Per-region analysis of lymph nodes included 248 regions with metastasis and 56 negative regions. Twenty specimens from the removed lung lesions or lymph nodes were stained with integrin αβ, CD34, and Ki-67 to correlate with the image findings. Receiver operating characteristic curve, z statistics, McNemar test, and χ analysis were used to compare the diagnostic performance of the two imaging methods. Results Tc-3PRGD2 SPECT/CT was found to be more specific than F-FDG PET/CT in the per-region diagnosis of lymph node metastasis (specificity, 94.6% vs 75.0%; P = .008) when the sensitivity of the two methods was comparable (88.3% vs 90.7%; P = .557). There was no significant difference between the two methods in the per-lesion diagnosis of lung tumor (z = 0.82, P = .410). The accumulation level of Tc-3PRGD2 was found in positive correlation with the integrin αβ expression (r = 0.84, P = .001) and microvessel density (r = 0.63, P = .011) in the tumors. Conclusion Tc-3PRGD2 SPECT/CT shows high specificity in the diagnosis of lymph node metastasis from NSCLC, which may benefit surgical decision making for the patients. RSNA, 2016.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1148/radiol.2016150813DOI Listing
December 2016

Enhanced Anti-Tumor Efficacy through a Combination of Integrin αvβ6-Targeted Photodynamic Therapy and Immune Checkpoint Inhibition.

Theranostics 2016 3;6(5):627-37. Epub 2016 Mar 3.

1. Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China;

"Training" the host immune system to recognize and systemically eliminate residual tumor lesions and micrometastases is a promising strategy for cancer therapy. In this study, we investigated whether integrin αvβ6-targeted photodynamic therapy (PDT) of tumors using a phthalocyanine dye-labeled probe (termed DSAB-HK) could trigger the host immune response, and whether PDT in combination with anti-PD-1 immune checkpoint inhibition could be used for the effective therapy of primary tumors and metastases. By near-infrared fluorescence imaging, DSAB-HK was demonstrated to specifically target either subcutaneous tumors in a 4T1 mouse breast cancer model or firefly luciferase stably transfected 4T1 (4T1-fLuc) lung metastatic tumors. Upon light irradiation, PDT by DSAB-HK significantly inhibited the growth of subcutaneous 4T1 tumors, and in addition promoted the maturation of dendritic cells and their production of cytokines, which subsequently stimulated the tumor recruitment of CD8(+) cytotoxic T lymphocytes. Furthermore, DSAB-HK PDT of the first tumor followed by PD-1 blockade markedly suppressed the growth of a second subcutaneous tumor, and also slowed the growth of 4T1-fLuc lung metastasis as demonstrated by serial bioluminescence imaging. Together, our results demonstrated the synergistic effect of tumor-targeted PDT and immune checkpoint inhibition for improving anti-tumor immunity and suppressing tumor growth/metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.14792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4805658PMC
December 2016

99mTc-Glu-c(RGDyK)-Bombesin SPECT Can Reduce Unnecessary Biopsy of Masses That Are BI-RADS Category 4 on Ultrasonography.

J Nucl Med 2016 Aug 24;57(8):1196-200. Epub 2016 Mar 24.

Department of Nuclear Medicine, China-Japan Union Hospital of Jilin University, Changchun, China

Unlabelled: Masses that, on ultrasonography, are category 4 according to the Breast Imaging Reporting and Data System (BI-RADS) represent possible malignancy, and a biopsy is recommended. This study explored the value of (99m)Tc-Glu-c(RGDyK)-bombesin ((99m)Tc-RGD-bombesin) in reducing unnecessary biopsy of these masses.

Methods: Ninety women with a BI-RADS 4 mass on ultrasonography were enrolled in this study to undergo breast SPECT using (99m)Tc-RGD-bombesin. The images were independently interpreted using qualitative visual and semiquantitative analyses. The final diagnosis was based on histopathologic examination of surgically excised or percutaneous biopsy specimens. Fractions of the samples were immunohistochemically analyzed to evaluate expression of integrin αvβ3 and gastrin-releasing peptide receptor (GRPR). The receptor-positive group was further divided into 3 subgroups (GRPR(+)/αvβ3 (+), GRPR(+)/αvβ3 (-), and αvβ3 (+)/GRPR(-)).

Results: Ninety-four masses (22 malignant and 72 benign) were confirmed by histopathologic examination. On qualitative analysis, 20 of the malignant masses showed high (99m)Tc-RGD-bombesin accumulation and 48 of the benign masses showed no (99m)Tc-RGD-bombesin accumulation. The optimal cutoff for qualitative analysis was a score of 2. Semiquantitative analysis revealed that 20 of the malignant masses and 16 of the benign masses had a relatively high tumor-to-normal-tissue ratio (T/N). The optimal cutoff was a T/N of 2.26. The mean T/N was higher for malignant masses than for benign masses (3.17 ± 0.86 vs. 1.89 ± 0.71, P < 0.05). T/Ns did not differ among the 3 subgroups (P > 0.05). The areas under the receiver-operating-characteristic curves for the qualitative and semiquantitative analyses were 0.788 and 0.865, respectively, and the overall diagnostic performance did not significantly differ between these analyses (P > 0.05).

Conclusion: (99m)Tc-RGD-bombesin SPECT can differentiate benign from malignant BI-RADS 4 masses with high specificity. Further study of the application of this test to clinical breast cancer appears warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.115.168773DOI Listing
August 2016

Comparison of surface water chemistry and weathering effects of two lake basins in the Changtang Nature Reserve, China.

J Environ Sci (China) 2016 Mar 13;41:183-194. Epub 2015 Jun 13.

Institute of Tibetan Plateau Research, Chinese Academy of Sciences, Beijing 100085, China.

The geochemistry of natural waters in the Changtang Nature Reserve, northern Tibet, can help us understand the geology of catchments, and provide additional insight in surface processes that influence water chemistry such as rock weathering on the Qinghai-Tibet Plateau. However, severe natural conditions are responsible for a lack of scientific data for this area. This study represents the first investigation of the chemical composition of surface waters and weathering effects in two lake basins in the reserve (Lake Dogaicoring Qiangco and Lake Longwei Co). The results indicate that total dissolved solids (TDS) in the two lakes are significantly higher than in other gauged lakes on the Qinghai-Tibet Plateau, reaching 20-40g/L, and that TDS of the tectonic lake (Lake Dogaicoring Qiangco) is significantly higher than that of the barrier lake (Lake Longwei Co). Na(+) and Cl(-) are the dominant ions in the lake waters as well as in the glacier-fed lake inflows, with chemical compositions mainly affected by halite weathering. In contrast, ion contents of inflowing rivers fed by nearby runoff are lower and concentrations of dominant ions are not significant. Evaporite, silicate, and carbonate weathering has relatively equal effects on these rivers. Due to their limited scope, small streams near the lakes are less affected by carbonate than by silicate weathering.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jes.2015.03.016DOI Listing
March 2016

Inhibition of tumor growth and metastasis by photoimmunotherapy targeting tumor-associated macrophage in a sorafenib-resistant tumor model.

Biomaterials 2016 Apr 13;84:1-12. Epub 2016 Jan 13.

Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China. Electronic address:

Tumor-associated macrophages (TAMs) play essential roles in tumor invasion and metastasis, and contribute to drug resistance. Clinical evidence suggests that TAM levels are correlated with local tumor relapse, distant metastasis, and poor prognosis in patients. In this study, we synthesized a TAM-targeted probe (IRD-αCD206) by conjugating a monoclonal anti-CD206 antibody with a near-infrared phthalocyanine dye. We then investigated the potential application of the IRD-αCD206 probe to near-infrared fluorescence (NIRF) imaging and photoimmunotherapy (PIT) of tumors resistant to treatment with the kinase inhibitor sorafenib. Sorafenib treatment had no effect on tumor growth in a 4T1 mouse model of breast cancer, but induced M2 macrophage polarization in tumors. M2 macrophage recruitment by sorafenib-treated 4T1 tumors was noninvasively visualized by in vivo NIRF imaging of IRD-αCD206. Small-animal single-photon emission computed tomography (SPECT)/CT and intratumoral microdistribution analysis indicated TAM-specific localization of the IRD-αCD206 probe in 4T1 tumors after several rounds of sorafenib treatment. Upon light irradiation, IRD-αCD206 suppressed the growth of sorafenib-resistant tumors. In vivo CT imaging and ex vivo histological analysis confirmed the inhibition of lung metastasis in mice by IRD-αCD206 PIT. These results demonstrate the utility of the IRD-αCD206 probe for TAM-targeted diagnostic imaging and treatment of tumors that are resistant to conventional therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biomaterials.2016.01.027DOI Listing
April 2016
-->