Daniel L J Thorek

Johns Hopkins Medicine, Baltimore, Maryland, United States

Are you Daniel L J Thorek?

Claim your profile

Publications (31)177.64 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate the feasibility of delivering experimental radiation therapy to tumors in the mouse pancreas. Imaging and treatment were performed using combined CT (computed tomography)/orthovoltage treatment with a rotating gantry. After intraperitoneal administration of radiopaque iodinated contrast, abdominal organ delineation was performed by x-ray CT. With this technique we delineated the pancreas and both orthotopic xenografts and genetically engineered disease. Computed tomographic imaging was validated by comparison with magnetic resonance imaging. Therapeutic radiation was delivered via a 1-cm diameter field. Selective x-ray radiation therapy of the noninvasively defined orthotopic mass was confirmed using γH2AX staining. Mice could tolerate a dose of 15 Gy when the field was centered on the pancreas tail, and treatment was delivered as a continuous 360° arc. This strategy was then used for radiation therapy planning for selective delivery of therapeutic x-ray radiation therapy to orthotopic tumors. Tumor growth delay after 15 Gy was monitored, using CT and ultrasound to determine the tumor volume at various times after treatment. Our strategy enables the use of clinical radiation oncology approaches to treat experimental tumors in the pancreas of small animals for the first time. We demonstrate that delivery of 15 Gy from a rotating gantry minimizes background healthy tissue damage and significantly retards tumor growth. This advance permits evaluation of radiation planning and dosing parameters. Accurate noninvasive longitudinal imaging and monitoring of tumor progression and therapeutic response in preclinical models is now possible and can be expected to more effectively evaluate pancreatic cancer disease and therapeutic response. Copyright © 2015 Elsevier Inc. All rights reserved.
    International journal of radiation oncology, biology, physics 06/2015; 93(2). DOI:10.1016/j.ijrobp.2015.06.001 · 4.26 Impact Factor
  • Source
    Diane Abou · David Ulmert · Robert Hobbs · Ryan Riddle · Daniel Thorek ·

    The Journal of Urology 04/2015; 193(4):e551. DOI:10.1016/j.juro.2015.02.1582 · 4.47 Impact Factor
  • Source

    The Journal of Urology 04/2015; 193(4):e441. DOI:10.1016/j.juro.2015.02.1273 · 4.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Previous studies of prostate cancer (PCa) risk and anthropometrics (ie, body measurements) were based on single measurements or obtained over limited time spans. To study the association between anthropometrics measured at multiple time points in life and their relation to later diagnosis, metastasis, or death from PCa. This case-control study includes 27 167 Swedish men enrolled in two population-based projects from 1974 to 1996. PCa diagnosis up to December 31, 2006, disease information, gestation time, and anthropometrics at birth, military conscript testing, and adulthood were collected. A total of 1355 PCa cases were matched with 5271 controls. Univariate conditional logistic regression was used to determine whether clinical diagnosis, metastasis, or PCa death was associated with low birth weight (weight <2500g); with small size for gestational age; or with weight, length, or body mass index (BMI) at birth, adolescence (aged 16-22 yr), or early middle age (aged 44-50 yr). Apart from weight at adolescence, which was associated with an increased risk of PCa diagnosis (odds ratio [OR] per 5kg: 1.05; 95% confidence interval [CI], 1.01-1.09; p=0.026), preadulthood measurements were not associated with any PCa end point. Adulthood parameters were not associated with diagnosis. In contrast, weight and BMI at early middle age were significantly associated with metastasis (OR per 5kg: 1.13; 95% CI, 1.06-1.20; p<0.0001, and OR: 1.09; 95% CI, 1.05-1.14; p<0.0001) and death (OR per 5kg: 1.11 (95% CI, 1.03-1.19; p=0.005, and OR: 1.08; 95% CI, 1.03-1.13; p=0.003), respectively. It remains unclear whether these results apply to men of nonwhite origin, to populations with active PCa screening programs, or to countries without socialized health care. The analyses of these large data sets demonstrate that significant effects of body characteristics (with links to metabolic syndrome) measured at early middle age are associated with PCa disease severity, metastatic progression, and outcome. Conversely, measurements at birth and adolescence are not associated with PCa prevalence or outcome. Increased weight and body mass index in adults is associated with a higher risk of prostate cancer metastasis and death. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
    European Urology 03/2015; 86. DOI:10.1016/j.eururo.2015.03.017 · 13.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Peritoneal carcinomatosis (PC) is a terminal progression of colorectal cancer (CRC). Poor response to cytoreductive operation and chemotherapy coupled with the inability to reliably track disease progression by the use of established diagnostic methods, make this a deadly disease. We examined the effectiveness of the oncolytic vaccinia virus GLV-1h153 as a therapeutic and diagnostic vehicle. We believe that viral expression of the human sodium iodide transporter (hNIS) provides both real-time monitoring of viral therapy and effective treatment of colorectal peritoneal carcinomatosis (CRPC). Infectivity and cytotoxic effect of GLV-1h153 on CRC cell lines was assayed in vitro. Viral replication was examined by standard viral plaque assays. Orthotopic CRPC xenografts were generated in athymic nude mice and subsequently administered GLV-1h153 intraperitoneally. A decrease in tumor burden was assessed by mass. Orthotopic tumors were visualized by single-photon emission computed tomography/computed tomography after Iodine ((131)I) administration and by fluorescence optical imaging. GLV-1h153 infected and killed CRC cells in a time- and concentration-dependent manner. Viral replication demonstrated greater than a 2.35 log increase in titer over 4 days. Intraperitoneal treatment of orthotopic CRPC xenografts resulted in a substantial decrease in tumor burden. Infection of orthotopic xenografts was therapeutic and facilitated monitoring by (131)I-single-photon emission computed tomography/computed tomography via expression of hNIS in infected tissue. GLV-1h153 kills CRC in vitro effectively and decreases tumor burden in vivo. We demonstrate that GLV-1h153 can be used as an agent to provide accurate delineation of tumor burden in vivo. These findings indicate that GLV-1h153 has potential for use as a therapeutic and diagnostic agent in the treatment of CRPC. Copyright © 2015 Elsevier Inc. All rights reserved.
    Surgery 02/2015; 157(2):331-7. DOI:10.1016/j.surg.2014.09.008 · 3.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: Human tumors xenografted in immunodeficient mice are crucial models in nuclear medicine to evaluate the effectiveness of candidate diagnostic and therapeutic compounds. However, little attention has been focused on the biological profile of the host model and its potential effects on the bio-distribution and tumor targeting of the tracer compound under study. We specifically investigated the dissimilarity in bio-distribution of (111)In-DTPA-5A10, which targets free prostate specific antigen (fPSA), in two animal models. Methods: In vivo bio-distribution studies of (111)In-DTPA-5A10 were performed in immunodeficient BALB/c-nu or NMRI-nu mice with subcutaneous (s.c.) LNCaP tumors. Targeting-specificity of the tracer was assessed by quantifying the uptake in (a) mice with s.c. xenografts of PSA-negative DU145 cells as well as (b) BALB/c-nu or NMRI-nu mice co-injected with an excess of non-labeled 5A10. Finally, the effect of neonatal Fc-receptor (FcRn) inhibition on the bio-distribution of the conjugate was studied by saturating FcRn-binding capacity with nonspecific IgG1. Results: The inherent biological attributes of the mouse model substantially influenced the bio-distribution and pharmacokinetics of (111)In-DTPA-5A10. With LNCaP xenografts in BALB/c-nu mice (with intact B and NK cells but with deficient T cells) versus NMRI-nu mice (with intact B cells, increased NK cells and absent T cells), we observed a significantly higher hepatic accumulation (26 ± 3.9 versus 3.5 ± 0.4%IA/g respectively), and concomitantly lower tumor uptake (25 ± 11 versus 52 ± 10%IA/g respectively) in BALB/c-nu mice. Inhibiting FcRn by administration of nonspecific IgG1 just prior to (111)In-DTPA-5A10 did not change tumor accumulation significantly. Conclusions: We demonstrated that the choice of immunodeficient mouse model importantly influence the bio-distribution of (111)In-DTPA-5A10. This study further highlighted important considerations in the evaluation of preclinical tracers, with respect to gaining information on their performance in the translational setting. Investigators utilizing xenograft models need to assess not only radiolabeling strategies, but also the host immunological status.
    Nuclear Medicine and Biology 12/2014; 42(4). DOI:10.1016/j.nucmedbio.2014.12.012 · 2.41 Impact Factor
  • Sudeep Das · Jan Grimm · Daniel L.J. Thorek ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Cerenkov luminescence (CL) has been used recently in a plethora of medical applications like imaging and therapy with clinically relevant medical isotopes. The range of medical isotopes used is fairly large and expanding. The generation of in vivo light is useful since it circumvents depth limitations for excitation light. Cerenkov luminescence imaging (CLI) is much cheaper in terms of infrastructure than positron emission tomography (PET) and is particularly useful for imaging of superficial structures. Imaging can basically be done using a sensitive camera optimized for low-light conditions, and it has a better resolution than any other nuclear imaging modality. CLI has been shown to effectively diagnose disease with regularly used PET isotope ((18)F-FDG) in clinical setting. Cerenkov luminescence tomography, Cerenkov luminescence endoscopy, and intraoperative Cerenkov imaging have also been explored with positive conclusions expanding the current range of applications. Cerenkov has also been used to improve PET imaging resolution since the source of both is the radioisotope being used. Smart imaging agents have been designed based on modulation of the Cerenkov signal using small molecules and nanoparticles giving better insight of the tumor biology.
    Advances in Cancer Research 10/2014; 124:213-34. DOI:10.1016/B978-0-12-411638-2.00006-9 · 5.32 Impact Factor
  • Charalambos Kaittanis · Travis M Shaffer · Daniel L J Thorek · Jan Grimm ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Nanotechnology plays an increasingly important role not only in our everyday life (with all its benefits and dangers) but also in medicine. Nanoparticles are to date the most intriguing option to deliver high concentrations of agents specifically and directly to cancer cells; therefore, a wide variety of these nanomaterials has been developed and explored. These span the range from simple nanoagents to sophisticated smart devices for drug delivery or imaging. Nanomaterials usually provide a large surface area, allowing for decoration with a large amount of moieties on the surface for either additional functionalities or targeting. Besides using particles solely for imaging purposes, they can also carry as a payload a therapeutic agent. If both are combined within the same particle, a theranostic agent is created. The sophistication of highly developed nanotechnology targeting approaches provides a promising means for many clinical implementations and can provide improved applications for otherwise suboptimal formulations. In this review we will explore nanotechnology both for imaging and therapy to provide a general overview of the field and its impact on cancer imaging and therapy.
    Critical reviews in oncogenesis 10/2014; 19(3-4):143-176. DOI:10.1615/CritRevOncog.2014011601
  • Daniel L. J. Thorek · Sudeep Das · Jan Grimm ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Cerenkov luminescence (CL) imaging is an emerging technique that collects the visible photons produced by radioisotopes. Here, molecular imaging strategies are investigated that switch the CL signal off. The noninvasive molecularly specific detection of cancer is demonstrated utilizing a combination of clinically approved agents, and their analogues. CL is modulated in vitro in a dose dependent manner using approved small molecules (Lymphazurin), as well as the clinically approved Feraheme and other preclinical superparamagnetic iron oxide nanoparticles (SPIO). To evaluate the quenching of CL in vivo, two strategies are pursued. [18F]-FDG is imaged by PET and CL in tumors prior to and following accumulation of nanoparticles. Initially, non-targeted particles are administered to mice bearing tumors in order to attenuate CL. For targeted imaging, a dual tumor model (expressing the human somatostatin receptor subtype-2 (hSSTr2) and a control negative cell line) is used. Targeting hSSTr2 with octreotate-conjugated SPIO, quenched CL enabling non-invasive distinction between tumors' molecular expression profiles is demonstrated. In this work, the quenching of Cerenkov emissions is demonstrated in several proof of principle models using a combination of approved agents and nanoparticle platforms to provide disease relevant information including tumor vascularity and specific antigen expression.
    Small 09/2014; 10(18). DOI:10.1002/smll.201400733 · 8.37 Impact Factor
  • Daniel L J Thorek · Christopher C Riedl · Jan Grimm ·

    Journal of Nuclear Medicine 01/2014; 55(3). DOI:10.2967/jnumed.113.135533 · 6.16 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The invasion status of tumour-draining lymph nodes (LNs) is a critical indicator of cancer stage and is important for treatment planning. Clinicians currently use planar scintigraphy and single-photon emission computed tomography (SPECT) with (99m)Tc-radiocolloid to guide biopsy and resection of LNs. However, emerging multimodality approaches such as positron emission tomography combined with magnetic resonance imaging (PET/MRI) detect sites of disease with higher sensitivity and accuracy. Here we present a multimodal nanoparticle, (89)Zr-ferumoxytol, for the enhanced detection of LNs with PET/MRI. For genuine translational potential, we leverage a clinical iron oxide formulation, altered with minimal modification for radiolabelling. Axillary drainage in naive mice and from healthy and tumour-bearing prostates was investigated. We demonstrate that (89)Zr-ferumoxytol can be used for high-resolution tomographic studies of lymphatic drainage in preclinical disease models. This nanoparticle platform has significant translational potential to improve preoperative planning for nodal resection and tumour staging.
    Nature Communications 01/2014; 5:3097. DOI:10.1038/ncomms4097 · 11.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Both (131)I- and (123)I-labeled meta-iodobenzylguanidine (MIBG) have been widely used in the clinic for targeted imaging of the norepinephrine transporter (NET). The human NET (hNET) gene has been imaged successfully with (124)I-MIBG positron emission tomography (PET) at time points of >24 h post-injection (p.i.). (18)F-labeled MIBG analogs may be ideal to image hNET expression at time points of <8 h p.i. We developed improved methods for the synthesis of known MIBG analogs, [(18)F]MFBG and [(18)F]PFBG and evaluated them in hNET reporter gene-transduced C6 rat glioma cells and xenografts. [(18)F]MFBG and [(18)F]PFBG were synthesized manually using a three-step synthetic scheme. Wild-type and hNET reporter gene-transduced C6 rat glioma cells and xenografts were used to comparatively evaluate the (18)F-labeled analogs with [(123)I]/[(124)I]MIBG. The fluorination efficacy on benzonitrile was predominantly determined by the position of the trimethylammonium group. The para-isomer afforded higher yields (75 ± 7 %) than meta-isomer (21 ± 5 %). The reaction of [(18)F]fluorobenzylamine with 1H-pyrazole-1-carboximidamide was more efficient than with 2-methyl-2-thiopseudourea. The overall radiochemical yields (decay-corrected) were 11 ± 2 % (n = 12) for [(18)F]MFBG and 41 ± 12 % (n = 5) for [(18)F]PFBG, respectively. The specific uptakes of [(18)F]MFBG and [(18)F]PFBG were similar in C6-hNET cells, but 4-fold less than that of [(123)I]/[(124)I]MIBG. However, in vivo [(18)F]MFBG accumulation in C6-hNET tumors was 1.6-fold higher than that of [(18)F]PFBG at 1 h p.i., whereas their uptakes were similar at 4 h. Despite [(18)F]MFBG having a 2.8-fold lower affinity to hNET and approximately 4-fold lower cell uptake in vitro compared to [(123)I]/[(124)I]MIBG, PET imaging demonstrated that [(18)F]MFBG was able to visualize C6-hNET xenografts better than [(124)I]MIBG. Biodistribution studies showed [(18)F]MFBG and (123)I-MIBG had a similar tumor accumulation, which was lower than that of no-carrier-added [(124)I]MIBG, but [(18)F]MFBG showed a significantly more rapid body clearance and lower uptake in most non-targeting organs. [(18)F]MFBG and [(18)F]PFBG were synthesized in reasonable radiochemical yields under milder conditions. [(18)F]MFBG is a better PET ligand to image hNET expression in vivo at 1-4 h p.i. than both [(18)F]PFBG and [(123)I]/[(124)I]MIBG.
    European Journal of Nuclear Medicine 10/2013; 41(2). DOI:10.1007/s00259-013-2558-9 · 5.38 Impact Factor
  • Daniel L J Thorek · Christopher C. Riedl · Jan Grimm ·
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to determine the feasibility of Cerenkov luminescence (CL) imaging of patients undergoing diagnostic (18)F-FDG scans to detect nodal disease. Patients undergoing routine (18)F-FDG PET/CT for various malignancies consented to being scanned for CL. White-light and Cerenkov images (5-min acquisition) of the surface of the patient contralateral to and at the site of nodal (18)F-FDG uptake were acquired using a cooled, intensified charge-coupled-device camera. The camera demonstrated linear correlation between activity and counts into the low nanocurie range using (18)F-FDG. Imaging of patients revealed the presence of (18)F-FDG uptake in nodes that demonstrated uptake on PET. A correlation between maximum standardized uptake value from PET and counting rate per area on the CL imaging was established. CL imaging with diagnostic doses of (18)F-FDG is feasible and can aid in detecting disease in the clinical setting.
    Journal of Nuclear Medicine 09/2013; 55(1). DOI:10.2967/jnumed.113.127266 · 6.16 Impact Factor
  • Source
    Daniel L J Thorek · Anuja Ogirala · Bradley J Beattie · Jan Grimm ·
    [Show abstract] [Hide abstract]
    ABSTRACT: In the era of personalized medicine, there is an urgent need for in vivo techniques able to sensitively detect and quantify molecular activities. Sensitive imaging of gamma rays is widely used; however, radioactive decay is a physical constant, and its signal is independent of biological interactions. Here, we introduce a framework of previously uncharacterized targeted and activatable probes that are excited by a nuclear decay-derived signal to identify and measure molecular signatures of disease. We accomplished this by using Cerenkov luminescence, the light produced by β-particle-emitting radionuclides such as clinical positron emission tomography (PET) tracers. Disease markers were detected using nanoparticles to produce secondary Cerenkov-induced fluorescence. This approach reduces background signal compared to conventional fluorescence imaging. In addition to tumor identification from a conventional PET scan, we demonstrate the medical utility of our approach by quantitatively determining prognostically relevant enzymatic activity. This technique can be applied to monitor other markers and represents a shift toward activatable nuclear medicine agents.
    Nature medicine 09/2013; 19(10). DOI:10.1038/nm.3323 · 27.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Obesity is a major cause of morbidity and mortality resulting in pathologic changes in virtually every organ system. Although the cardiovascular system has been a focus of intense study, the effects of obesity on the lymphatic system remain essentially unknown. The purpose of this study was to identify the pathologic consequences of diet induced obesity (DIO) on the lymphatic system. Adult male wild-type or RAG C57B6-6J mice were fed a high fat (60%) or normal chow diet for 8-10 weeks followed by analysis of lymphatic transport capacity. In addition, we assessed migration of dendritic cells (DCs) to local lymph nodes, lymph node architecture, and lymph node cellular make up. High fat diet resulted in obesity in both wild-type and RAG mice and significantly impaired lymphatic fluid transport and lymph node uptake; interestingly, obese wild-type but not obese RAG mice had significantly impaired migration of DCs to the peripheral lymph nodes. Obesity also resulted in significant changes in the macro and microscopic anatomy of lymph nodes as reflected by a marked decrease in size of inguinal lymph nodes (3.4-fold), decreased number of lymph node lymphatics (1.6-fold), loss of follicular pattern of B cells, and dysregulation of CCL21 expression gradients. Finally, obesity resulted in a significant decrease in the number of lymph node T cells and increased number of B cells and macrophages. Obesity has significant negative effects on lymphatic transport, DC cell migration, and lymph node architecture. Loss of T and B cell inflammatory reactions does not protect from impaired lymphatic fluid transport but preserves DC migration capacity. Future studies are needed to determine how the interplay between diet, obesity, and the lymphatic system modulate systemic complications of obesity.
    PLoS ONE 08/2013; 8(8):e70703. DOI:10.1371/journal.pone.0070703 · 3.23 Impact Factor
  • D L J Thorek · M J Evans · S V Carlsson · D Ulmert · H Lilja ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Kallikreins are a family of serine proteases with a range of tissue-specific and essential proteolytic functions. Among the best studied are the prostate tissue-specific KLK2 and KLK3 genes and their secreted protease products, human kallikrein 2, hk2, and prostate-specific antigen (PSA). Members of the so-called classic kallikreins, these highly active trypsin-like serine proteases play established roles in human reproduction. Both hK2 and PSA expression is regulated by the androgen receptor which has a fundamental role in prostate tissue development and progression of disease. This feature, combined with the ability to sensitively detect different forms of these proteins in blood and biopsies, result in a crucially important biomarker for the presence and recurrence of cancer. Emerging evidence has begun to suggest a role for these kallikreins in critical vascular events. This review discusses the established and developing biological roles of hK2 and PSA, as well as the historical and advanced use of their detection to accurately and non-invasively detect and guide treatment of prostatic disease.
    Thrombosis and Haemostasis 08/2013; 110(3). DOI:10.1160/TH13-04-0275 · 4.98 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: Dual-modality PET/MR platforms add a new dimension to patient diagnosis with high resolution, functional, and anatomical imaging. The full potential of this emerging hybrid modality could be realized by using a corresponding dual-modality probe. Here, we report pegylated liposome (LP) formulations, housing a MR T(1) contrast agent (Gd) and the positron-emitting (89)Zr (half-life: 3.27 days), for simultaneous PET and MR tumor imaging capabilities. Methods: (89)Zr oxophilicity was unexpectedly found advantageous for direct radiolabeling of preformed paramagnetic LPs. LPs were conjugated with octreotide to selectively target neuroendocrine tumors via human somatostatin receptor subtype 2 (SSTr2). (89)Zr-Gd-LPs and octreotide-conjugated homolog were physically, chemically and biologically characterized. Results: (89)Zr-LPs showed reasonable stability over serum proteins and chelator challenges for proof-of-concept in vitro and in vivo investigations. Nuclear and paramagnetic tracking quantified superior SSTr2-recognition of octreotide-LP compared to controls. Conclusions: This study demonstrated SSTr2-targeting specificity along with direct chelator-free (89)Zr-labeling of LPs and dual PET/MR imaging properties.
    Pharmaceutical Research 12/2012; 30(3). DOI:10.1007/s11095-012-0929-8 · 3.42 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bombesin receptors are under intense investigation as molecular targets since they are overexpressed in several prevalent solid tumors. We rationally designed and synthesized a series of modified bombesin (BN) peptide analogs to study the influence of charge and spacers at the N-terminus, as well as amino acid substitutions, on both receptor binding affinity and pharmacokinetics. This enabled development of a novel (64/67)Cu-labeled BN peptide for PET imaging and targeted radiotherapy of BN receptor-positive tumors. Our results show that N-terminally positively charged peptide ligands had significantly higher affinity to human gastrin releasing peptide receptor (GRPr) than negatively charged or uncharged ligands (IC(50): 3.2±0.5 vs 26.3±3.5 vs 41.5±2.5 nM). The replacement of Nle(14) by Met, and deletion of D-Tyr(6), further resulted in 8-fold higher affinity. Contrary to significant changes to human GRPr binding, modifications at the N-terminal and at the 6(th), 11(th), and 14(th) position of BN induced only slight influences on affinity to mouse GRPr. [Cu(II)]-CPTA-[βAla(11)] BN(7-14) ([Cu(II)]-BZH7) showed the highest internalization rate into PC-3 cells with relatively slow efflux because of its subnanomolar affinity to GRPr. Interestingly, [(64/67)Cu]-BZH7 also displayed similar affinities to the other 2 human BN receptor subtypes. In vivo studies showed that [(64/67)Cu]-BZH7 had a high accumulation in PC-3 xenografts and allowed for clear-cut visualization of the tumor in PET imaging. In addition, a CPTA-glycine derivative, forming a hippurane-type spacer, enhanced kidney clearance of the radiotracer. These data indicate that the species variation of BN receptor plays an important role in screening radiolabeled BN. As well, the positive charge from the metallated complex at the N-terminal significantly increases affinity to human GRPr. Application of these observations enabled the novel ligand [(64/67)Cu]-BZH7 to clearly visualize PC-3 tumors in vivo. This study provides a strong starting point for optimizing radiopeptides for targeting carcinomas that express any of the BN receptor subtypes.
    PLoS ONE 09/2012; 7(9):e44046. DOI:10.1371/journal.pone.0044046 · 3.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The lymphatic system plays a critical role in the maintenance of healthy tissues. Its function is an important indicator of the presence and extent of disease. In oncology, metastatic spread to local lymph nodes (LNs) is a strong predictor of poor outcome. Clinical methods for the visualization of LNs involve regional injection and tracking of (99m)Tc-sulfur colloid ((99m)Tc-SC) along with absorbent dyes. Intraoperatively, these techniques suffer from the requirement of administration of multiple contrast media ((99m)Tc-SC and isosulfan blue), unwieldy γ-probes, and a short effective surgical window for dyes. Preclinically, imaging of transport through the lymphatics is further hindered by the resolution of lymphoscintigraphy and SPECT. We investigated multimodal imaging in animal models using intradermal administration of (18)F-FDG for combined diagnostic and intraoperative use. PET visualizes LNs with high sensitivity and resolution and low background. Cerenkov radiation (CR) from (18)F-FDG was evaluated to optically guide surgical resection of LNs. Imaging of (18)F-FDG uptake used PET and sensitive luminescent imaging equipment (for CR). Dynamic PET was performed in both sexes and multiple strains (NCr Nude, C57BL/6, and Nu/Nu) of mice. Biodistribution confirmed the uptake of (18)F-FDG and was compared with that of (99m)Tc-SC. Verification of uptake and the ability to use (18)F-FDG CR to guide nodal removal were confirmed histologically. Intradermal injection of (18)F-FDG clearly revealed lymphatic vessels and LNs by PET. Dynamic imaging revealed rapid and sustained labeling of these structures. Biodistribution of the radiotracer confirmed the active transport of radioglucose in the lymphatics to the local LNs and over time into the general circulation. (18)F-FDG also enabled visualization of LNs through CR, even before surgically revealing the site, and guided LN resection. Intradermal (18)F-FDG can enhance the preclinical investigation of the lymphatics through dynamic, high-resolution, and quantitative tomographic imaging. Clinically, combined PET/Cerenkov imaging has significant potential as a single-dose, dual-modality tracer for diagnostics (PET/CT) and guided resection of LNs (Cerenkov optical).
    Journal of Nuclear Medicine 08/2012; 53(9):1438-45. DOI:10.2967/jnumed.112.104349 · 6.16 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: There has been recent and growing interest in applying Cerenkov radiation (CR) for biological applications. Knowledge of the production efficiency and other characteristics of the CR produced by various radionuclides would help in accessing the feasibility of proposed applications and guide the choice of radionuclides. To generate this information we developed models of CR production efficiency based on the Frank-Tamm equation and models of CR distribution based on Monte-Carlo simulations of photon and β particle transport. All models were validated against direct measurements using multiple radionuclides and then applied to a number of radionuclides commonly used in biomedical applications. We show that two radionuclides, Ac-225 and In-111, which have been reported to produce CR in water, do not in fact produce CR directly. We also propose a simple means of using this information to calibrate high sensitivity luminescence imaging systems and show evidence suggesting that this calibration may be more accurate than methods in routine current use.
    PLoS ONE 02/2012; 7(2):e31402. DOI:10.1371/journal.pone.0031402 · 3.23 Impact Factor

Publication Stats

977 Citations
177.64 Total Impact Points


  • 2014-2015
    • Johns Hopkins Medicine
      • Department of Radiology and Radiological Science
      Baltimore, Maryland, United States
    • Johns Hopkins University
      • Division of Nuclear Medicine
      Baltimore, Maryland, United States
  • 2011-2014
    • Memorial Sloan-Kettering Cancer Center
      • • Department of Radiology
      • • Department of Medical Physics
      New York, New York, United States
  • 2006-2010
    • University of Pennsylvania
      • Department of Bioengineering
      Filadelfia, Pennsylvania, United States