Daniel L J Thorek

Johns Hopkins Medicine, Baltimore, Maryland, United States

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Publications (24)136.66 Total impact

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    ABSTRACT: 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 111In-DTPA-5A10, which targets free Prostate Specific Antigen (fPSA), in two animal models.
    Nuclear Medicine and Biology 12/2014; · 2.41 Impact Factor
  • Daniel L. J. Thorek, Sudeep Das, Jan Grimm
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    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 05/2014; · 7.51 Impact Factor
  • Daniel L J Thorek, Christopher C Riedl, Jan Grimm
    Journal of Nuclear Medicine 01/2014; · 5.56 Impact Factor
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    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. · 10.74 Impact Factor
  • Sudeep Das, Jan Grimm, Daniel L J Thorek
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    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. 01/2014; 124:213-34.
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    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 01/2014; 19(3-4):143-176.
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    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; · 4.53 Impact Factor
  • Daniel L J Thorek, Christopher Riedl, Jan Grimm
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    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). · 5.56 Impact Factor
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    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; · 28.05 Impact Factor
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    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. · 3.53 Impact Factor
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    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; · 4.74 Impact Factor
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    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. · 3.53 Impact Factor
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    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. · 5.56 Impact Factor
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    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. · 3.53 Impact Factor
  • D L J Thorek, J Grimm
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    ABSTRACT: Molecular imaging of disease development, progression and treatment is seen as key to further advancement in the understanding and triumph over illness. The role of enzymes is to catalyze the biochemical reactions that help regulate health, and when dysregulated in complex organisms lead to or indicate disease. The ability to image the action of these proteins for diagnostic purposes opens a window for the researcher and clinician to witness specifc molecular events in vitro and in vivo. Such probes have been developed and deployed for the optical, radionuclide and magnetic resonance modalities and offer significant benefits over conventional agents. The signal of enzymatically-activated probes is regulated by the specific activity of the desired enzyme. This allows for a higher signal to background ratio over non-specific and targeted agents. It also enables the modulation of contrast agent distribution (and even cellular accumulation) following enzymatic activity. This review summarizes the strategies and probes in development and use in this emergent field of molecular imaging, with a particular focus on the research and medical relevance of these advances.
    Current pharmaceutical biotechnology 01/2012; 13(4):523-36. · 3.40 Impact Factor
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    ABSTRACT: Stem cell therapies hold the great promise and interest for cardiac regeneration among scientists, clinicians and patients. However, advancement and distillation of a standard treatment regimen are not yet finalised. Into this breach step recent developments in the imaging biosciences. Thus far, these technical and protocol refinements have played a critical role not only in the evaluation of the recovery of cardiac function but also in providing important insights into the mechanism of action of stem cells. Molecular imaging, in its many forms, has rapidly become a necessary tool for the validation and optimisation of stem cell engrafting strategies in preclinical studies. These include a suite of radionuclide, magnetic resonance and optical imaging strategies to evaluate non-invasively the fate of transplanted cells. In this review, we highlight the state-of-the-art of the various imaging techniques for cardiac stem cell presenting the strengths and limitations of each approach, with a particular focus on clinical applicability.
    European Radiology 07/2011; 22(1):189-204. · 4.34 Impact Factor
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    ABSTRACT: In many clinical cases of radicular pain, no noticeable neuropathology is detected by conventional medical imaging strategies. Superparamagnetic iron oxide (SPIO) nanoparticles were evaluated as magnetic resonance contrast agents to specifically detect neuroinflammation at sites of painful injury in a rat model of cervical nerve root compression. Two separate groups of rats were used: an injury group that underwent controlled transient compression of the dorsal root and a sham group that received the same surgical procedures but no injury. Precontrast magnetic resonance imaging (MRI) was performed 6 days after surgery, followed by administration of SPIO via tail vein injection. After 24 hours, T2*-weighted imaging at the site of root injury revealed a postcontrast enhancement of 72.9 ± 31%. This was significantly greater than that of injured animals prior to SPIO administration (5.3 ± 12.9%). SPIO did not generate any significant postcontrast enhancement in the nerve roots of the sham group. Histology confirmed colocalization of SPIO with macrophage at the injury site. These findings suggest that SPIO-enhanced MRI may be a valuable tool to identify otherwise undetectable nerve root compression and enable improved patient management.
    Molecular Imaging 06/2011; 10(3):206-14. · 3.41 Impact Factor
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    ABSTRACT: B cell depletion immunotherapy has been successfully employed to treat non-Hodgkin's lymphoma. In recent years, increasing attention has been directed towards also using B-cell depletion therapy as a treatment option in autoimmune disorders. However, it appears that the further development of these approaches will depend on a methodology to determine the relation of B-cell depletion to clinical response and how individual patients should be dosed. Thus far, patients have generally been followed by quantification of peripheral blood B cells, but it is not apparent that this measurement accurately reflects systemic B cell dynamics. Cellular imaging of the targeted population in vivo may provide significant insight towards effective therapy and a greater understanding of underlying disease mechanics. Superparamagnetic iron oxide (SPIO) nanoparticles in concert with near infrared (NIR) fluorescent dyes were used to label and track primary C57BL/6 B cells. Following antibody mediated B cell depletion (anti-CD79), NIR-only labeled cells were expeditiously cleared from the circulation and spleen. Interestingly, B cells labeled with both SPIO and NIR were not depleted in the spleen. Whole body fluorescent tracking of B cells enabled noninvasive, longitudinal imaging of both the distribution and subsequent depletion of B lymphocytes in the spleen. Quantification of depletion revealed a greater than 40% decrease in splenic fluorescent signal-to-background ratio in antibody treated versus control mice. These data suggest that in vivo imaging can be used to follow B cell dynamics, but that the labeling method will need to be carefully chosen. SPIO labeling for tracking purposes, generally thought to be benign, appears to interfere with B cell functions and requires further examination.
    PLoS ONE 05/2010; 5(5):e10655. · 3.53 Impact Factor
  • Zhiliang Cheng, Daniel L J Thorek, Andrew Tsourkas
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    ABSTRACT: The use of nanovesicles with encapsulated Gd as MR contrast agents has largely been ignored due to the detrimental effects of the slow water exchange rate through the vesicle bilayer on the relaxivity of encapsulated Gd. Here, we describe the facile synthesis of a composite MR contrast platform, consisting of dendrimer conjugates encapsulated in porous polymersomes. These nanoparticles exhibit improved permeability to water flux and a large capacity to store chelated Gd within the aqueous lumen, resulting in enhanced longitudinal relaxivity. The porous polymersomes, ~130 nm in diameter, were produced through the aqueous assembly of the polymers, polyethylene oxide-b-polybutadiene (PBdEO), and polyethylene oxide-b-polycaprolactone (PEOCL). Subsequent hydrolysis of the caprolactone (CL) block resulted in a highly permeable outer membrane. To prevent the leakage of small Gd-chelate through the pores, Gd was conjugated to PAMAM dendrimer via diethylenetriaminepentaacetic acid dianhydride (DTPA dianhydride) prior to encapsulation. As a result of the slower rotational correlation time of Gd-labeled dendrimers, the porous outer membrane of the nanovesicle, and the high Gd payload, these functional nanoparticles were found to exhibit a relaxivity (R1) of 292,109 mM(-1) s(-1) per particle. The polymersomes were also found to exhibit unique pharmacokinetics with a circulation half-life of >3.5 hrs and predominantly renal clearance.
    Advanced Functional Materials 12/2009; 19(23):3753-3759. · 10.44 Impact Factor
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    Zhiliang Cheng, Daniel L J Thorek, Andrew Tsourkas
    Angewandte Chemie International Edition 12/2009; 49(2):346-50. · 11.34 Impact Factor

Publication Stats

600 Citations
136.66 Total Impact Points


  • 2014
    • Johns Hopkins Medicine
      • Department of Radiology and Radiological Science
      Baltimore, Maryland, United States
  • 2011–2014
    • Memorial Sloan-Kettering Cancer Center
      • Department of Radiology
      New York City, New York, United States
  • 2006–2011
    • University of Pennsylvania
      • Department of Bioengineering
      Philadelphia, PA, United States