All Publications

  • Positron emission tomography imaging of novel AAV capsids maps rapid brain accumulation. Nature communications Seo, J. W., Ingham, E. S., Mahakian, L. n., Tumbale, S. n., Wu, B. n., Aghevlian, S. n., Shams, S. n., Baikoghli, M. n., Jain, P. n., Ding, X. n., Goeden, N. n., Dobreva, T. n., Flytzanis, N. C., Chavez, M. n., Singhal, K. n., Leib, R. n., James, M. L., Segal, D. J., Cheng, R. H., Silva, E. A., Gradinaru, V. n., Ferrara, K. W. 2020; 11 (1): 2102


    Adeno-associated viruses (AAVs) are typically single-stranded deoxyribonucleic acid (ssDNA) encapsulated within 25-nm protein capsids. Recently, tissue-specific AAV capsids (e.g. PHP.eB) have been shown to enhance brain delivery in rodents via the LY6A receptor on brain endothelial cells. Here, we create a non-invasive positron emission tomography (PET) methodology to track viruses. To provide the sensitivity required to track AAVs injected at picomolar levels, a unique multichelator construct labeled with a positron emitter (Cu-64, t1/2?=?12.7?h) is coupled to the viral capsid. We find that brain accumulation of the PHP.eB capsid 1) exceeds that reported in any previous PET study of brain uptake of targeted therapies and 2) is correlated with optical reporter gene transduction of the brain. The PHP.eB capsid brain endothelial receptor affinity is nearly 20-fold greater than that of AAV9. The results suggest that novel PET imaging techniques can be applied to inform and optimize capsid design.

    View details for DOI 10.1038/s41467-020-15818-4

    View details for PubMedID 32355221

  • CD8+ T-cell density imaging with 64Cu-labeled cys-diabody informs immunotherapy protocols. Clinical cancer research : an official journal of the American Association for Cancer Research Seo, J. W., Tavare, R., Mahakian, L. M., Silvestrini, M. T., Tam, S., Ingham, E. S., Salazar, F. B., Borowsky, A. D., Wu, A. M., Ferrara, K. W. 2018


    PURPOSE: Noninvasive and quantitative tracking of CD8+ T-cells by positron emission tomography (PET) has emerged as a potential technique to gauge response to immunotherapy. We apply an anti-CD8 cys-diabody, labeled with 64Cu, to assess the sensitivity of PET imaging of normal and diseased tissue. Experimental Design Radiolabeling of an anti-CD8 cys-diabody (169cDb) with 64Cu was developed. The accumulation of 64Cu-169cDb was evaluated with PET/CT imaging (0, 5, and 24 hours) and biodistribution (24 hours) in wild-type mouse strains (n = 8 per group studied with imaging and immunohistochemistry or flow cytometry) after intravenous administration. Tumor-infiltrating CD8+ T-cells in tumor bearing mice treated with CpG and aPD-1 were quantified and mapped (n = 6-8 per group studied with imaging and immunohistochemistry or flow cytometry). Results We demonstrate the ability of immunoPET to detect small differences in CD8+ T-cell distribution between mouse strains and across lymphoid tissues, including the intestinal tract of normal mice. In FVB mice bearing a syngeneic HER2-driven model of mammary adenocarcinoma (NDL), 64Cu-169cDb PET imaging accurately visualized and quantified changes in tumor-infiltrating CD8+ T-cells in response to immunotherapy. A reduction in the circulation time of the imaging probe followed the development of treatment-related liver and splenic hypertrophy and provided an indication of off-target effects associated with immunotherapy protocols. Conclusion 64Cu-169cDb imaging can spatially map the distribution of CD8+ T-cells in normal organs and tumors. ImmunoPET imaging of tumor-infiltrating cytotoxic CD8+ T-cells detected changes in T-cell density resulting from adjuvant and checkpoint immunotherapy protocols in our pre-clinical evaluation.

    View details for PubMedID 29967252

  • Self-assembled 20-nm Cu-64-micelles enhance accumulation in rat glioblastoma JOURNAL OF CONTROLLED RELEASE Seo, J., Ang, J., Mahakian, L. M., Tam, S., Fite, B., Ingham, E. S., Beyer, J., Forsayeth, J., Bankiewicz, K. S., Xu, T., Ferrara, K. W. 2015; 220: 51?60


    There is an urgent need to develop nanocarriers for the treatment of glioblastoma multiforme (GBM). Using co-registered positron emission tomography (PET) and magnetic resonance (MR) images, here we performed systematic studies to investigate how a nanocarrier's size affects the pharmacokinetics and biodistribution in rodents with a GBM xenograft. In particular, highly stable, long-circulating three-helix micelles (3HM), based on a coiled-coil protein tertiary structure, were evaluated as an alternative to larger nanocarriers. While the circulation half-life of the 3HM was similar to 110-nm PEGylated liposomes (t1/2=15.5 and 16.5h, respectively), the 20-nm micelles greatly enhanced accumulation within a U87MG xenograft in nu/nu rats after intravenous injection. After accounting for tumor blood volume, the extravasated nanoparticles were quantified from the PET images, yielding ~0.77%ID/cm(3) for the micelles and 0.45%ID/cm(3) for the liposomes. For GBM lesions with a volume greater than 100mm(3), 3HM accumulation was enhanced both within the detectable tumor and in the surrounding brain parenchyma. Further, the nanoparticle accumulation was shown to extend to the margins of the GBM xenograft. In summary, 3HM provides an attractive nanovehicle for carrying treatment to GBM.

    View details for PubMedID 26437259

    View details for PubMedCentralID PMC4688122

  • The pharmacokinetics of Zr-89 labeled liposomes over extended periods in a murine tumor model NUCLEAR MEDICINE AND BIOLOGY Seo, J., Mahakian, L. M., Tam, S., Qin, S., Ingham, E. S., Meares, C. F., Ferrara, K. W. 2015; 42 (2): 155?63


    (89)Zr (t1/2=78.4h), a positron-emitting metal, has been exploited for PET studies of antibodies because of its relatively long decay time and facile labeling procedures. Here, we used (89)Zr to evaluate the pharmacokinetics of long-circulating liposomes over 168h (1week). We first developed a liposomal-labeling method using p-isothiocyanatobenzyl-desferrioxamine (df-Bz-NCS) and df-PEG1k-DSPE. Df-Bz-NCS was conjugated to 1mol% amino- and amino-PEG2k-DSPE, where the 1mol% df-PEG1k-DSPE was incorporated when the liposomes were formulated. Incubation of (89)Zr with df, df-PEG1k, and df-PEG2k liposomes for one hour resulted in greater than 68% decay-corrected yield. The loss of the (89)Zr label from liposomes after incubation in 50% human serum for 48h ranged from ~1 to 3% across the three formulations. Tail vein administration of the three liposomal formulations in NDL tumor-bearing mice showed that the (89)Zr label at the end of the PEG2k brush was retained in the tumor, liver, spleen and whole body for a longer time interval than (89)Zr labels located under the PEG2k brush. The blood clearance rate of all three liposomal formulations was similar. Overall, the results indicate that the location of the (89)Zr label altered the clearance rate of intracellularly-trapped radioactivity and that df-PEG1k-DSPE provides a stable chelation site for liposomal or lipid-based particle studies over extended periods of time.

    View details for PubMedID 25451215

    View details for PubMedCentralID PMC4281498

  • Cu-64-Labeled LyP-1-Dendrimer for PET-CT Imaging of Atherosclerotic Plaque BIOCONJUGATE CHEMISTRY Seo, J., Baek, H., Mahakian, L. M., Kusunose, J., Hamzah, J., Ruoslahti, E., Ferrara, K. W. 2014; 25 (2): 231?39


    The ability to detect and quantify macrophage accumulation can provide important diagnostic and prognostic information for atherosclerotic plaque. We have previously shown that LyP-1, a cyclic 9-amino acid peptide, binds to p32 proteins on activated macrophages, facilitating the visualization of atherosclerotic plaque with PET. Yet, the in vivo plaque accumulation of monomeric [(18)F]FBA-LyP-1 was low (0.31 0.05%ID/g). To increase the avidity of LyP-1 constructs to p32, we synthesized a dendritic form of LyP-1 on solid phase using lysine as the core structural element. Imaging probes (FAM or 6-BAT) were conjugated to a lysine or cysteine on the dendrimer for optical and PET studies. The N-terminus of the dendrimer was further modified with an aminooxy group in order to conjugate LyP-1 and ARAL peptides bearing a ketone. Oxime ligation of peptides to both dendrimers resulted in (LyP-1)4- and (ARAL)4-dendrimers with optical (FAM) and PET probes (6-BAT). For PET-CT studies, (LyP-1)4- and (ARAL)4-dendrimer-6-BAT were labeled with (64)Cu (t1/2 = 12.7 h) and intravenously injected into the atherosclerotic (ApoE(-/-)) mice. After two hours of circulation, PET-CT coregistered images demonstrated greater uptake of the (LyP-1)4-dendrimer-(64)Cu than the (ARAL)4-dendrimer-(64)Cu in the aortic root and descending aorta. Ex vivo images and the biodistribution acquired at three hours after injection also demonstrated a significantly higher uptake of the (LyP-1)4-dendrimer-(64)Cu (1.1 0.26%ID/g) than the (ARAL)4-dendrimer-(64)Cu (0.22 0.05%ID/g) in the aorta. Similarly, subcutaneous injection of the LyP-1-dendrimeric carriers resulted in preferential accumulation in plaque-containing regions over 24 h. In the same model system, ex vivo fluorescence images within aortic plaque depict an increased accumulation and penetration of the (LyP-1)4-dendrimer-FAM as compared to the (ARAL)4-dendrimer-FAM. Taken together, the results suggest that the (LyP-1)4-dendrimer can be applied for in vivo PET imaging of plaque and that LyP-1 could be further exploited for the delivery of therapeutics with multivalent carriers or nanoparticles.

    View details for PubMedID 24433095

  • Liposomal Cu-64 Labeling Method Using Bifunctional Chelators: Poly(ethylene glycol) Spacer and Chelator Effects BIOCONJUGATE CHEMISTRY Seo, J., Mahakian, L. M., Kheirolomoom, A., Zhang, H., Meares, C. F., Ferdani, R., Anderson, C. J., Ferrara, K. W. 2010; 21 (7): 1206?15


    Two bifunctional Cu-64 chelators (BFCs), (6-(6-(3-(2-pyridyldithio)propionamido)hexanamido)benzyl)-1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA-PDP) and 4-(2-(2-pyridyldithioethyl)ethanamido)-11-carboxymethyl-1,4,8,11-tetraazabicyclo(6.6.2)hexadecane (CB-TE2A-PDEA), were synthesized and conjugated to long-circulating liposomes (LCLs) via attachment to a maleimide lipid. An in vitro stability assay of (64)Cu-TETA, (64)Cu-TETA-PEG2k, and (64)Cu-CB-TE2A-PEG2k liposomes showed that more than 86% of the radioactivity remains associated with the liposomal fraction after 48 h of incubation with mouse serum. The in vivo time activity curves (TAC) for the three liposomal formulations showed that approximately 50% of the radioactivity cleared from the blood pool in 16-18 h. As expected, the in vivo biodistribution and TAC data obtained at 48 h demonstrate that the clearance of radioactivity from the liver slows with the incorporation of a poly(ethylene glycol)-2k (PEG2k) brush. Our data suggest that (64)Cu-TETA and (64)Cu-CB-TE2A are similarly stable in the blood pool and accumulation of radioactivity in the liver and spleen is not related to the stability of Cu-64 chelator complex; however, clearance of Cu-64 from the liver and spleen are faster when injected as (64)Cu-TETA-chelated liposomes rather than (64)Cu-CB-TE2A-chelated liposomes.

    View details for PubMedID 20568726

  • A Novel Method to Label Preformed Liposomes with (CU)-C-64 for Positron Emission Tomography (PET) Imaging BIOCONJUGATE CHEMISTRY Seo, J., Zhang, H., Kukis, D. L., Meares, C. F., Ferrara, K. W. 2008; 19 (12): 2577?84


    Radiolabeling of liposomes with 64Cu (t(1/2)=12.7 h) is attractive for molecular imaging and monitoring drug delivery. A simple chelation procedure, performed at a low temperature and under mild conditions, is required to radiolabel preloaded liposomes without lipid hydrolysis or the release of the encapsulated contents. Here, we report a 64Cu postlabeling method for liposomes. A 64Cu-specific chelator, 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (BAT), was conjugated with an artificial lipid to form a BAT-PEG-lipid. After incorporation of 0.5% (mol/mol) BAT-PEG-lipid during liposome formulation, liposomes were successfully labeled with 64Cu in 0.1 M NH4OAc pH 5 buffer at 35 degrees C for 30-40 min with an incorporation yield as high as 95%. After 48 h of incubation of 64Cu-liposomes in 50/50 serum/PBS solution, more than 88% of the 64Cu label was still associated with liposomes. After injection of liposomal 64Cu in a mouse model, 44+/-6.9, 21+/-2.7, 15+/-2.5, and 7.4+/-1.1 (n=4) % of the injected dose per cubic centimeter remained within the blood pool at 30 min, 18, 28, and 48 h, respectively. The biodistribution at 48 h after injection verified that 7.0+/-0.47 (n=4) and 1.4+/-0.58 (n=3) % of the injected dose per gram of liposomal 64Cu and free 64Cu remained in the blood pool, respectively. Our results suggest that this fast and easy 64Cu labeling of liposomes could be exploited in tracking liposomes in vivo for medical imaging and targeted delivery.

    View details for PubMedID 18991368

  • Positron emission tomography imaging of adeno-associated virus serotype 9-tetracystein (AAV9-TC) labeled with a multichelator Seo, J., Mahakian, L., Ingham, E., Tumbale, S., Shams, S., Silva, E., Ferrara, K. WILEY. 2019: S40?S41
  • Enhanced delivery of AAV-like nanoparticles after blood-brain barrier disruption in a mouse model Foiret, J., Seo, J., Zhang, H., Kakwere, H., Mahakian, L. M., Tam, S., Ferrara, K. W., IEEE IEEE. 2019: 884?87
  • A Scalable Method for Squalenoylation and Assembly of Multifunctional 64Cu-Labeled Squalenoylated Gemcitabine Nanoparticles. Nanotheranostics Tucci, S. T., Seo, J. W., Kakwere, H., Kheirolomoom, A., Ingham, E. S., Mahakian, L. M., Tam, S., Tumbale, S., Baikoghli, M., Cheng, R. H., Ferrara, K. W. 2018; 2 (4): 387?402


    Squalenoylation of gemcitabine, a front-line therapy for pancreatic cancer, allows for improved cellular-level and system-wide drug delivery. The established methods to conjugate squalene to gemcitabine and to form nanoparticles (NPs) with the squalenoylated gemcitabine (SqGem) conjugate are cumbersome, time-consuming and can be difficult to reliably replicate. Further, the creation of multi-functional SqGem-based NP theranostics would facilitate characterization of in vivo pharmacokinetics and efficacy. Methods: Squalenoylation conjugation chemistry was enhanced to improve reliability and scalability using tert-butyldimethylsilyl (TBDMS) protecting groups. We then optimized a scalable microfluidic mixing platform to produce SqGem-based NPs and evaluated the stability and morphology of select NP formulations using dynamic light scattering (DLS) and transmission electron microscopy (TEM). Cytotoxicity was evaluated in both PANC-1 and KPC (KrasLSL-G12D/+; Trp53LSL-R172H/+; Pdx-Cre) pancreatic cancer cell lines. A 64Cu chelator (2-S-(4-aminobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid, NOTA) was squalenoylated and used with positron emission tomography (PET) imaging to monitor the in vivo fate of SqGem-based NPs. Results: Squalenoylation yields of gemcitabine increased from 15% to 63%. Cholesterol-PEG-2k inclusion was required to form SqGem-based NPs using our technique, and additional cholesterol inclusion increased particle stability at room temperature; after 1 week the PDI of SqGem NPs with cholesterol was ~ 0.2 while the PDI of SqGem NPs lacking cholesterol was ~ 0.5. Similar or superior cytotoxicity was achieved for SqGem-based NPs compared to gemcitabine or Abraxane when evaluated at a concentration of 10 M. Squalenoylation of NOTA enabled in vivo monitoring of SqGem-based NP pharmacokinetics and biodistribution. Conclusion: We present a scalable technique for fabricating efficacious squalenoylated-gemcitabine nanoparticles and confirm their pharmacokinetic profile using a novel multifunctional 64Cu-SqNOTA-SqGem NP.

    View details for PubMedID 30324084

  • Dynamic contrast enhanced MRI detects changes in vascular transport rate constants following treatment with thermally-sensitive liposomal doxorubicin JOURNAL OF CONTROLLED RELEASE Fite, B. Z., Kheirolomoom, A., Foiret, J. L., Seo, J. W., Mahakian, L. M., Ingham, E. S., Tam, S. M., Borowsky, A. D., Curry, F. E., Ferrara, K. W. 2017; 256: 203?13


    Temperature-sensitive liposomal formulations of chemotherapeutics, such as doxorubicin, can achieve locally high drug concentrations within a tumor and tumor vasculature while maintaining low systemic toxicity. Further, doxorubicin delivery by temperature-sensitive liposomes can reliably cure local cancer in mouse models. Histological sections of treated tumors have detected red blood cell extravasation within tumors treated with temperature-sensitive doxorubicin and ultrasound hyperthermia. We hypothesize that the local release of drug into the tumor vasculature and resulting high drug concentration can alter vascular transport rate constants along with having direct tumoricidal effects. Dynamic contrast enhanced MRI (DCE-MRI) coupled with a pharmacokinetic model can detect and quantify changes in such vascular transport rate constants. Here, we set out to determine whether changes in rate constants resulting from intravascular drug release were detectable by MRI. We found that the accumulation of gadoteridol was enhanced in tumors treated with temperature-sensitive liposomal doxorubicin and ultrasound hyperthermia. While the initial uptake rate of the small molecule tracer was slower (k1=0.04780.011s-1 versus 0.1160.047s-1) in treated compared to untreated tumors, the tracer was retained after treatment due to a larger reduction in the rate of clearance (k2=0.2910.030s-1 versus 0.7470.24s-1). While DCE-MRI assesses a combination of blood flow and permeability, ultrasound imaging of microvascular flow rate is sensitive only to changes in vascular flow rate; based on this technique, blood flow was not significantly altered 30min after treatment. In summary, DCE-MRI provides a means to detect changes that are associated with treatment by thermally-activated particles and such changes can be exploited to enhance local delivery.

    View details for PubMedID 28395970

    View details for PubMedCentralID PMC5545100

  • 2-Acetyl-7-hydroxy-6-methoxy-1-methyl-1,2,3,4,-tetrahydroisoquinoline exhibits anti-inflammatory properties and protects the nigral dopaminergic neurons EUROPEAN JOURNAL OF PHARMACOLOGY Son, H., Han, S., Lee, J., Lee, C., Seo, J., Chi, D., Hwang, O. 2016; 771: 152?61


    Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopamine(DA)ergic neurons. Neuroinflammation caused by microglial activation is believed to be involved in the pathogenesis of neurodegenerative diseases including PD. In the present study, we tested the effects of a novel compound 2-acetyl-7-hydroxy-6-methoxy-1-methyl-1,2,3,4,-tetarhydroisoquinoline (AMTIQ) on neuroinflammatory response and DAergic neurodegeneration. In lipopolysaccharide-activated BV-2 microglial cells, AMTIQ lowered nitric oxide and tetrahydrobiopterin levels and downregulated gene expression of inducible nitric oxide synthase and GTP cyclohydrolase I. AMTIQ also repressed gene expression of the proinflammatory cytokines IL-1? and TNF-?, and attenuated nuclear translocation of NF-?B. AMTIQ was stable against liver microsomal enzymes from human and mouse and did not interfere with activities of the cytochrome p450 enzymes 1A2, 2D6, 2C9, 2C19 and 3A4. Pharmacokinetic studies revealed the brain to plasma ratio of AMTIQ to be 45%, suggesting it can penetrate the blood brain barrier. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mouse PD model, AMTIQ led to decreased microglial activation, increased survival of DAergic neurons and their fibers, and improved behavioral scores on rotarod and vertical grid tests. Taken together, these results suggest that AMTIQ might serve as a candidate preventive-therapeutic agent for neurodegenerative diseases such as PD.

    View details for DOI 10.1016/j.ejphar.2015.12.009

    View details for Web of Science ID 000368105100019

    View details for PubMedID 26687634

  • Multifunctional Nanoparticles Facilitate Molecular Targeting and miRNA Delivery to Inhibit Atherosclerosis in ApoE(-/-) Mice ACS NANO Kheirolomoom, A., Kim, C., Seo, J., Kumar, S., Son, D., Gagnon, M. J., Ingham, E. S., Ferrara, K. W., Jo, H. 2015; 9 (9): 8885?97


    The current study presents an effective and selective multifunctional nanoparticle used to deliver antiatherogenic therapeutics to inflamed pro-atherogenic regions without off-target changes in gene expression or particle-induced toxicities. MicroRNAs (miRNAs) regulate gene expression, playing a critical role in biology and disease including atherosclerosis. While anti-miRNA are emerging as therapeutics, numerous challenges remain due to their potential off-target effects, and therefore the development of carriers for selective delivery to diseased sites is important. Yet, co-optimization of multifunctional nanoparticles with high loading efficiency, a hidden cationic domain to facilitate lysosomal escape and a dense, stable incorporation of targeting moieties is challenging. Here, we create coated, cationic lipoparticles (CCLs), containing anti-miR-712 (?1400 molecules, >95% loading efficiency) within the core and with a neutral coating, decorated with 5 mol % of peptide (VHPK) to target vascular cell adhesion molecule 1 (VCAM1). Optical imaging validated disease-specific accumulation as anti-miR-712 was efficiently delivered to inflamed mouse aortic endothelial cells in vitro and in vivo. As with the naked anti-miR-712, the delivery of VHPK-CCL-anti-miR-712 effectively downregulated the d-flow induced expression of miR-712 and also rescued the expression of its target genes tissue inhibitor of metalloproteinase 3 (TIMP3) and reversion-inducing-cysteine-rich protein with kazal motifs (RECK) in the endothelium, resulting in inhibition of metalloproteinase activity. Moreover, an 80% lower dose of VHPK-CCL-anti-miR-712 (1 mg/kg dose given twice a week), as compared with naked anti-miR-712, prevented atheroma formation in a mouse model of atherosclerosis. While delivery of naked anti-miR-712 alters expression in multiple organs, miR-712 expression in nontargeted organs was unchanged following VHPK-CCL-anti-miR-712 delivery.

    View details for PubMedID 26308181

    View details for PubMedCentralID PMC4581466

  • Comparison of PET Imaging with Cu-64-Liposomes and F-18-FDG in the 7,12-Dimethylbenz[a]anthracene (DMBA)-Induced Hamster Buccal Pouch Model of Oral Dysplasia and Squamous Cell Carcinoma MOLECULAR IMAGING AND BIOLOGY Mahakian, L. M., Farwell, D., Zhang, H., Seo, J., Poirier, B., Tinling, S. P., Afify, A. M., Haynam, E. M., Shaye, D., Ferrara, K. W. 2014; 16 (2): 284?92


    Currently, 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) is the gold standard radiotracer for staging of head and neck cancer; however, the low sensitivity of this tracer can impede detection of early lesions. (64)Cu-liposomes accumulate in various cancers and provide both a sensitive tracer and an indication of the biodistribution of nanotherapeutics. Here, the accumulation of (64)Cu-liposomes in early and established cancers is assessed and compared with (18)F-FDG in a head and neck cancer model.Lesions ranging from mild dysplasia to squamous cell carcinoma were induced in a hamster model of head and neck cancer by topical application of 7,12-dimethylbenz[a]anthracene to the buccal pouch. The hamsters were imaged with micro-positron emission tomography using (18)F-FDG and (64)Cu-liposomes.At 24 h postinjection, (64)Cu-liposome accumulation exceeded the accumulation of (18)F-FDG in every pathologic grade. The lesion-to-cheek pouch (background) ratio and lesion-to-brain ratio were also higher for (64)Cu-liposomes than for (18)F-FDG.Imaging of a nanotracer such as (64)Cu-liposomes can improve the visualization of head and neck tumors. Accumulation of liposomal particles in head and neck tumors over various pathologic grades averaged 3.5%ID/cc demonstrating the potential for liposomal therapy with targeted chemotherapeutic agents.

    View details for PubMedID 24019092

    View details for PubMedCentralID PMC3984137

  • A Physiological Perspective on the Use of Imaging to Assess the In Vivo Delivery of Therapeutics ANNALS OF BIOMEDICAL ENGINEERING Qin, S., Fite, B. Z., Gagnon, M. J., Seo, J. W., Curry, F., Thorsen, F., Ferrara, K. W. 2014; 42 (2): 280?98


    Our goal is to provide a physiological perspective on the use of imaging to optimize and monitor the accumulation of nanotherapeutics within target tissues, with an emphasis on evaluating the pharmacokinetics of organic particles. Positron emission tomography (PET), magnetic resonance imaging (MRI) and ultrasound technologies, as well as methods to label nanotherapeutic constructs, have created tremendous opportunities for preclinical optimization of therapeutics and for personalized treatments in challenging disease states. Within the methodology summarized here, the accumulation of the construct is estimated directly from the image intensity. Particle extravasation is then estimated based on classical physiological measures. Specifically, the transport of nanotherapeutics is described using the concept of apparent permeability, which is defined as the net flux of solute across a blood vessel wall per unit surface area of the blood vessel and per unit solute concentration difference across the blood vessel wall. The apparent permeability to small molecule MRI constructs is accurately shown to be far larger than that estimated for proteins such as albumin or nanoconstructs such as liposomes. Further, the quantitative measurements of vascular permeability are shown to facilitate detection of the transition from a pre-malignant to a malignant cancer and to quantify the delivery enhancement resulting from interventions such as ultrasound. While PET-based estimates facilitate quantitative comparisons of many constructs, high field MRI proves useful in the visualization of model drugs within small lesions and in the evaluation of the release and intracellular trafficking of nanoparticles and cargo.

    View details for PubMedID 24018607

    View details for PubMedCentralID PMC3943857

  • The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis NATURE COMMUNICATIONS Son, D., Kumar, S., Takabe, W., Kim, C., Ni, C., Alberts-Grill, N., Jang, I., Kim, S., Kim, W., Kang, S., Baker, A. H., Seo, J., Ferrara, K. W., Jo, H. 2013; 4: 3000


    MicroRNAs (miRNAs) regulate cardiovascular biology and disease, but the role of flow-sensitive microRNAs in atherosclerosis is still unclear. Here we identify miRNA-712 (miR-712) as a mechanosensitive miRNA upregulated by disturbed flow (d-flow) in endothelial cells, in vitro and in vivo. We also show that miR-712 is derived from an unexpected source, pre-ribosomal RNA, in an exoribonuclease-dependent but DiGeorge syndrome critical region 8 (DGCR8)-independent manner, suggesting that it is an atypical miRNA. Mechanistically, d-flow-induced miR-712 downregulates tissue inhibitor of metalloproteinase 3 (TIMP3) expression, which in turn activates the downstream matrix metalloproteinases (MMPs) and a disintegrin and metalloproteases (ADAMs) and stimulate pro-atherogenic responses, endothelial inflammation and permeability. Furthermore, silencing miR-712 by anti-miR-712 rescues TIMP3 expression and prevents atherosclerosis in murine models of atherosclerosis. Finally, we report that human miR-205 shares the same 'seed sequence' as murine-specific miR-712 and also targets TIMP3 in a flow-dependent manner. Targeting these mechanosensitive 'athero-miRs' may provide a new treatment paradigm in atherosclerosis.

    View details for PubMedID 24346612

  • A comparison of image contrast with Cu-64-labeled long circulating liposomes and F-18-FDG in a murine model of mammary carcinoma AMERICAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING Ormsby, A., Zhang, H., Seo, J., Mahakian, L. M., Caskey, C. F., Ferrara, K. W. 2013; 3 (1): 32?43


    Conjugation of the (64)Cu PET radioisotope (t(1/2) = 12.7 hours) to long circulating liposomes enables long term liposome tracking. To evaluate the potential clinical utility of this radiotracer in diagnosis and therapeutic guidance, we compare image contrast, tumor volume, and biodistribution of (64)Cu-liposomes to metrics obtained with the dominant clinical tracer, (18)F-FDG. Twenty four female FVB mice with MET1 mammary carcinoma tumor grafts were examined. First, serial PET images were obtained with the (18)F-FDG radiotracer at 0.5 hours after injection and with the (64)Cu-liposome radiotracer at 6, 18, 24, and 48 hours after injection (n = 8). Next, paired imaging and histology were obtained at four time points: 0.5 hours after (18)F-FDG injection and 6, 24, and 48 hours after (64)Cu-liposome injection (n = 16). Tissue biodistribution was assessed with gamma counting following necropsy and tumors were paraffin embedded, sectioned, and stained with hematoxylin and eosin. The contrast ratio of images obtained using (18)F-FDG was 0.88 0.01 (0.5 hours after injection), whereas with the (64)Cu-liposome radiotracer the contrast ratio was 0.78 0.01, 0.89 0.01, 0.88 0.01, and 0.94 0.01 at 6, 18, 24, and 48 hours, respectively. Estimates of tumor diameter were comparable between (64)Cu-liposomes and (18)F-FDG, (64)Cu-liposomes and necropsy, and (64)Cu-liposomes and ultrasound with Pearson's r-squared values of 0.79, 0.79, and 0.80, respectively. Heterogeneity of tumor tracer uptake was observed with both tracers, correlating with regions of necrosis on histology. The average tumor volume of 0.41 0.05 cc measured with (64)Cu-liposomes was larger than that estimated with (18)F-FDG (0.28 0.04 cc), with this difference apparently resulting primarily from accumulation of the radiolabeled particles in the pro-angiogenic tumor rim. The imaging of radiolabeled nanoparticles can facilitate tumor detection, identification of tumor margins, therapeutic evaluation and interventional guidance.

    View details for PubMedID 23342299

  • New synthetic method for benzofurans from 2-(cyanomethyl)phenyl derivatives TETRAHEDRON Kim, H., Seo, J., Lee, M., Shin, D., Kim, H., Cho, H., Lee, B., Chi, D. 2012; 68 (21): 3942?47
  • A novel compound PTIQ protects the nigral dopaminergic neurones in an animal model of Parkinson's disease induced by MPTP BRITISH JOURNAL OF PHARMACOLOGY Son, H., Lee, J., Shin, N., Choi, J., Seo, J., Chi, D., Lee, C., Kim, E., Choe, H., Hwang, O. 2012; 165 (7): 2213?27


    In Parkinson's disease, the dopaminergic neurones in the substantia nigra undergo degeneration. While the exact mechanism for the degeneration is not completely understood, neuronal apoptosis and neuroinflammation are thought to be key contributors. We have recently established that MMP-3 plays crucial roles in dopaminergic cell death and microglial activation.We tested the effects of 7-hydroxy-6-methoxy-2-propionyl-1,2,3,4-tetrahydroisoquinoline (PTIQ) on expression of MMP-3 and inflammatory molecules and dopaminergic cell death in vitro and in an animal model of Parkinson's disease, and Parkinson's disease-related motor deficits. The pharmacokinetic profile of PTIQ was also evaluated.PTIQ effectively suppressed the production of MMP-3 induced in response to cellular stress in the dopaminergic CATH.a cell line and prevented the resulting cell death. In BV-2 microglial cells activated with lipopolysaccharide, PTIQ down-regulated expression of MMP-3 along with IL-1?, TNF-? and cyclooxygenase-2 and blocked nuclear translocation of NF-?B. In the mouse model of Parkinson's disease ,induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), PTIQ attenuated the associated motor deficits, prevented neurodegeneration and suppressed microglial activation in the substantia nigra. Pharmacokinetic analysis showed it was relatively stable against liver microsomal enzymes, did not inhibit the cytochrome p450 isozymes or the hERG ion channel, exhibited no cytotoxicity on liver cells or lethality when administered at 1000 mg?kg(-1) and entered the brain rather rapidly yielding a 28% brain:plasma ratio after i.p. injection.These results suggest PTIQ has potential as a candidate drug for disease-modifying therapy for Parkinson's disease.

    View details for DOI 10.1111/j.1476-5381.2011.01692.x

    View details for Web of Science ID 000301281700020

    View details for PubMedID 21951056

    View details for PubMedCentralID PMC3413858

  • Ultrasound Increases Nanoparticle Delivery by Reducing Intratumoral Pressure and Increasing Transport in Epithelial and Epithelial-Mesenchymal Transition Tumors CANCER RESEARCH Watson, K. D., Lai, C., Qin, S., Kruse, D. E., Lin, Y., Seo, J., Cardiff, R. D., Mahakian, L. M., Beegle, J., Inghanm, E. S., Curry, F., Reed, R. K., Ferrara, K. W. 2012; 72 (6): 1485?93


    Acquisition of the epithelial-mesenchymal transition (EMT) tumor phenotype is associated with impaired chemotherapeutic delivery and a poor prognosis. In this study, we investigated the application of therapeutic ultrasound methods available in the clinic to increase nanotherapeutic particle accumulation in epithelial and EMT tumors by labeling particles with a positron emission tomography tracer. Epithelial tumors were highly vascularized with tight cell-cell junctions, compared with EMT tumors where cells displayed an irregular, elongated shape with loosened cell-cell adhesions and a reduction in E-cadherin and cytokeratins 8/18 and 19. Without ultrasound, the accumulation of liposomal nanoparticles administered to tumors in vivo was approximately 1.5 times greater in epithelial tumors than EMT tumors. When ultrasound was applied, both nanoaccumulation and apparent tumor permeability were increased in both settings. Notably, ultrasound effects differed with thermal and mechanical indices, such that increasing the thermal ultrasound dose increased nanoaccumulation in EMT tumors. Taken together, our results illustrate how ultrasound can be used to enhance nanoparticle accumulation in tumors by reducing their intratumoral pressure and increasing their vascular permeability.

    View details for PubMedID 22282664

  • Positron emission tomography imaging of the stability of Cu-64 labeled dipalmitoyl and distearoyl lipids in liposomes JOURNAL OF CONTROLLED RELEASE Seo, J., Qin, S., Mahakian, L. M., Watson, K. D., Kheirolomoom, A., Ferrara, K. W. 2011; 151 (1): 28?34


    Changes in lipid acyl chain length can result in desorption of lipid from the liposomal anchorage and interaction with blood components. PET studies of the stability of such lipids have not been performed previously although such studies can map the pharmacokinetics of unstable lipids non-invasively in vivo. The purpose of this study was to characterize the in vivo clearance of (64)Cu-labeled distearoyl- and dipalmitoyl lipid included within long circulating liposomes. Distearoyl and dipalmitoyl maleimide lipids (1mol%) in liposomes were labeled with a (64)Cu-incorporated bifunctional chelator (TETA-PDP) after the activation of pyridine disulfide to thiol by TCEP. Long circulating liposomes containing HSPC:DSPE-PEG2k-OMe:cholesterol: x (55:5:39:1), where x was (64)Cu-DSPE or (64)Cu-DPPE, or HSPC:DSPE-PEG2k-OMe:cholesterol:(64)Cu-DSPE:DPPC (54:5:39:1:1) were evaluated in serum (in vitro) and via intravenous injection to FVB mice. The time-activity curves for the blood, liver, and kidney were measured from PET images and the biodistribution was performed at 48h. In vitro assays showed that (64)Cu-DPPE transferred from liposomes to serum with a 7.9h half-life but (64)Cu-DSPE remained associated with the liposomes. The half clearance of radioactivity from the blood pool was 18 and 5h for (64)Cu-DSPE- and (64)Cu-DPPE liposome-injected mice, respectively. The clearance of radioactivity from the liver and kidney was significantly greater following the injection of (64)Cu-DPPE-labeled liposomes than (64)Cu-DSPE-labeled liposomes at 6, 18 and 28h. Forty eight hours after injection, the whole body radioactivity was 57 and 17% ID/cc for (64)Cu-DSPE and (64)Cu-DPPE, respectively. These findings suggest that the acyl chain length of the radiolabel should be considered for liposomal PET studies and that PET is an effective tool for evaluating the stability of nanoformulations in vivo.

    View details for PubMedID 21241753

  • Novel Method to Label Solid Lipid Nanoparticles with Cu-64 for Positron Emission Tomography Imaging BIOCONJUGATE CHEMISTRY Andreozzi, E., Seo, J., Ferrara, K., Louie, A. 2011; 22 (4): 808?18


    Solid lipid nanoparticles (SLNs) are submicrometer (1-1000 nm) colloidal carriers developed in the past decade as an alternative system to traditional carriers (emulsions, liposomes, and polymeric nanoparticles) for intravenous applications. Because of their potential as drug carriers, there is much interest in understanding the in vivo biodistribution of SLNs following intravenous (i.v.) injection. Positron emission tomography (PET) is an attractive method for investigating biodistribution but requires a radiolabeled compound. In this work, we describe a method to radiolabel SLN for in vivo PET studies. A copper specific chelator, 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (BAT), conjugated with a synthetic lipid, was incorporated into the SLN. Following incubation with (64)CuCl(2) for 1 h at 25 C in 0.1 M NH(4)OAc buffer (pH 5.5), the SLNs (?150 nm) were successfully radiolabeled with (64)Cu (66.5% radiolabeling yield), exhibiting >95% radiolabeled particles following purification. The (64)Cu-SLNs were delivered intravenously to mice and imaged with PET at 0.5, 3, 20, and 48 h post injection. Gamma counting was utilized post imaging to confirm organ distributions. Tissue radioactivity (% injected dose/gram, %ID/g), obtained by quantitative analysis of the images, suggests that the (64)Cu-SLNs are circulating in the bloodstream after 3 h (blood half-life ?1.4 h), but are almost entirely cleared by 48 h. PET and gamma counting demonstrate that approximately 5-7%ID/g (64)Cu-SLNs remain in the liver at 48 h post injection. Stability assays confirm that copper remains associated with the SLN over the 48 h time period and that the biodistribution patterns observed are not from free, dissociated copper. Our results indicate that SLNs can be radiolabeled with (64)Cu, and their biodistribution can be quantitatively evaluated by in vivo PET imaging and ex vivo gamma counting.

    View details for PubMedID 21388194

  • Longitudinal Investigation of Permeability and Distribution of Macromolecules in Mouse Malignant Transformation Using PET CLINICAL CANCER RESEARCH Rygh, C. B., Qin, S., Seo, J. W., Mahakian, L. M., Zhang, H., Adamson, R., Chen, J. Q., Borowsky, A. D., Cardiff, R. D., Reed, R. K., Curry, F. E., Ferrara, K. W. 2011; 17 (3): 550?59


    We apply positron emission tomography (PET) to elucidate changes in nanocarrier extravasation during the transition from premalignant to malignant cancer, providing insight into the use of imaging to characterize early cancerous lesions and the utility of nanoparticles in early disease.Albumin and liposomes were labeled with (64)Cu (half-life 12.7 hours), and longitudinal PET and CT imaging studies were conducted in a mouse model of ductal carcinoma in situ. A pharmacokinetic model was applied to estimate the tumor vascular volume and permeability.From early time points characterized by disseminated hyperproliferation, the enhanced vascular permeability facilitated lesion detection. During disease progression, the vascular volume fraction increased 1.6-fold and the apparent vascular permeability to albumin and liposomes increased ?2.5-fold to 6.6 10(-8) and 1.3 10(-8) cm/s, respectively, with the accumulation of albumin increasing earlier in the disease process. In the malignant tumor, both tracers reached similar mean intratumoral concentrations of ?6% ID/cc but the distribution of liposomes was more heterogeneous, ranging from 1% to 18% ID/cc compared with 1% to 9% ID/cc for albumin. The tumor-to-muscle ratio was 17.9 8.1 and 7.1 0.5 for liposomes and albumin, respectively, indicating a more specific delivery of liposomes than with albumin.PET imaging of radiolabeled particles, validated by confocal imaging and histology, detected the transition from premalignant to malignant lesions and effectively quantified the associated changes in vascular permeability.

    View details for PubMedID 21106723

  • Fast and Easy Drying Method for the Preparation of Activated [F-18]Fluoride Using Polymer Cartridge BULLETIN OF THE KOREAN CHEMICAL SOCIETY Seo, J., Lee, B., Lee, S., Oh, S., Chi, D. 2011; 32 (1): 71?76
  • Copper-Doxorubicin as a Nanoparticle Cargo Retains Efficacy with Minimal Toxicity MOLECULAR PHARMACEUTICS Kheirolomoom, A., Mahakian, L. M., Lai, C., Lindfors, H. A., Seo, J., Paoli, E. E., Watson, K. D., Haynam, E. M., Ingham, E. S., Xing, L., Cheng, R., Borowsky, A. D., Cardiff, R. D., Ferrara, K. W. 2010; 7 (6): 1948?58


    Repeated administration of chemotherapeutics is typically required for the effective treatment of highly aggressive tumors and often results in systemic toxicity. We have created a copper-doxorubicin complex within the core of liposomes and applied the resulting particle in multidose therapy. Copper and doxorubicin concentrations in the blood pool were similar at 24 h (?40% of the injected dose), indicating stable circulation of the complex. Highly quenched doxorubicin fluorescence remained in the blood pool over tens of hours, with fluorescence increasing only with the combination of liposome disruption and copper trans-chelation. At 48 h after injection, doxorubicin fluorescence within the heart and skin was one-fifth and one-half, respectively, of fluorescence observed with ammonium sulfate-loaded doxorubicin liposomes. After 28 days of twice per week doxorubicin administration of 6 mg/kg, systemic toxicity (cardiac hypertrophy and weight and hair loss) was not detected with the copper-doxorubicin liposomes but was substantial with ammonium sulfate-loaded doxorubicin liposomes. We then incorporated two strategies designed to enhance efficacy, mTOR inhibition (rapamycin) to slow proliferation and therapeutic ultrasound to enhance accumulation and local diffusion. Tumor accumulation was ?10% ID/g and was enhanced approximately 2-fold with the addition of therapeutic ultrasound. After the 28-day course of therapy, syngeneic tumors regressed to a premalignant phenotype of ?(1 mm)(3) or could not be detected.

    View details for PubMedID 20925429

  • Imaging nanoparticle stability and activation in vivo Ferrara, K. W., Seo, J. W., Zhang, H., IEEE IEEE. 2009: 4580-+


    While liposomes and nanoparticles have been the subject of intense research for more than 40 years, few particles have been translated into clinical practice. Advantages of these particles include the potential to overcome the cardiac, renal or neural toxicity of systemic chemotherapy, the opportunities for multivalent targeting, the gradual yet significant accumulation within tumors due to leaky blood vessels and the myriad of new approaches to locally alter the properties of the particle in the region of interest. Given the complexity of the design and co-optimization of the surface architecture, shell formulation and drug loading, methods to image the pharmacokinetics of nanoparticles in living systems are an essential part of an efficient research methodology. Here, we describe our efforts to label the shell and drug core of lipid-shelled particles with a goal of facilitating translation of activatable particles.

    View details for PubMedID 19963843

  • Syntheses of tetrahydroisoquinoline derivatives that inhibit NO production in activated BV-2 microglial cells EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY Seo, J., Srisook, E., Son, H., Hwang, O., Cha, Y., Chi, D. 2008; 43 (6): 1160?70


    Seventeen tetrahydroisoquinoline derivatives were designed, synthesized and evaluated for inhibition of NO production in lipopolysaccharide-stimulated BV-2 microglial cells. Compounds 5a, 9c and 11a potently attenuated NO production by >60%, and 5a and 11a inhibited BH4 production by >48% at 100 microM. In particular, N-ethylcarbonyl-7-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline (11a) reduced NO production by 64% and tetrahydrobiopterin (BH4) production by 49%. Introducing longer alkyl component at C1 or N2 position led to attenuation of the inhibitory effect. It is possible that 11a inhibits NO production by blocking BH4-dependent dimerization of newly synthesized iNOS monomers.

    View details for DOI 10.1016/j.ejmech.2007.09.009

    View details for Web of Science ID 000257261500003

    View details for PubMedID 17980460

  • Dynamic imaging of arginine-rich heart-targeted vehicles in a mouse model BIOMATERIALS Zhang, H., Kusunose, J., Kheirolomoom, A., Seo, J. W., Qi, J., Watson, K. D., Lindfors, H. A., Ruoslahti, E., Sutcliffe, J. L., Ferrara, K. W. 2008; 29 (12): 1976?88


    Efficacious delivery of drugs and genes to the heart is an important goal. Here, a radiolabeled peptide-targeted liposome was engineered to bind to the heart, and the biodistribution and pharmacokinetics were determined by dynamic positron emission tomography in the FVB mouse. Efficient targeting occurred only with an exposed ligand and a dense concentration of peptide (6000 peptides/particles). Liposomes targeted with CRPPR or other arginine-rich peptides with an exposed guanidine moiety bound within 100 s after intravenous injection and remained stably bound. With CRPPR-targeted particles, the radioisotope density in the heart averaged 44 +/- 9% injected dose/gram of tissue, more than 30-fold higher than in skeletal muscle. The rapid and efficient targeting of these particles can be exploited in drug and gene delivery systems and with dynamic positron emission tomography provides a model system to optimize targeting of engineered particles.

    View details for PubMedID 18255141

  • Convenient one-pot synthesis of 2,2-bis-(4-hydroxyphenyl)-cyclopentanone JOURNAL OF ORGANIC CHEMISTRY Seo, J., Kim, H., Lee, B., Katzenellenbogen, J. A., Chi, D. 2008; 73 (2): 715?18


    2,2-Bis-(4-hydroxyphenyl)-cyclopentanone (3a) was unexpectedly obtained in 76% yield from a reductive coupling reaction of 4,4'-dihydroxybenzophenone (1a) and cyclobutanone with TiCl4 and Zn. Further optimization showed that catechol as an external ligand and a hydroxy group on benzophenone facilitated the generation of a quinonemethide (intermediate II) that is involved in the pinacol-type rearrangement of intermediate I to give the rearranged product.

    View details for DOI 10.1021/jo701850u

    View details for Web of Science ID 000252325200049

    View details for PubMedID 18088140

  • An efficient F-18 labeling method for PET study: Huisgen 1,3-dipolar cycloaddition of bioactive substances and F-18-labeled compounds TETRAHEDRON LETTERS Sirion, U., Kim, H., Lee, J., Seo, J., Lee, B., Lee, S., Oh, S., Chi, D. 2007; 48 (23): 3953?57
  • Synthesis and biodistribution of fluorine-18-labeled fluorocyclofenils for imaging the estrogen receptor NUCLEAR MEDICINE AND BIOLOGY Seo, J., Chi, D., Dence, C. S., Welch, M. J., Katzenellenbogen, J. A. 2007; 34 (4): 383?90


    C4-[18F]Fluorocyclofenil ([18F]FCF, 6) and C3-[18F]fluoroethylcyclofenil ([18F]FECF, 9), two high-affinity nonsteroidal estrogens, were prepared and investigated as potential agents for imaging estrogen receptors (ERs) in breast tumors. Both of these compounds could be prepared conveniently from alkyl methanesulfonate precursors (5,8) by fluoride displacement reactions, and they were obtained in high radiochemical purity and radiochemical yields, with effective specific activities sufficient for in vivo biodistribution studies. While the biodistribution of [18F]FCF (6) in immature female rats showed no selective target tissue uptake, the biodistribution of [18F]FECF (9) showed selective uptake by the uterus, but this uptake could not be blocked by excess estradiol. The poor in vivo biodistribution of these otherwise high-affinity ligands arouses curiosity, and together with recent results on the biodistribution of other nonsteroidal ligands suggests that factors other than receptor binding affinity are important for in vivo imaging of estrogen target tissues and ER-positive breast tumors.

    View details for DOI 10.1016/j.nucmedbio.2007.01.010

    View details for Web of Science ID 000246775600005

    View details for PubMedID 17499727

    View details for PubMedCentralID PMC1948026

  • Fluorine-substituted cyclofenil derivatives as estrogen receptor ligands: Synthesis and structure-affinity relationship study of potential positron emission tomography agents for Imaging estrogen receptors in breast cancer JOURNAL OF MEDICINAL CHEMISTRY Seo, J. W., Comninos, J. S., Chi, D. Y., Kim, D. W., Carlson, K. E., Katzenellenbogen, J. A. 2006; 49 (8): 2496?2511


    In a search for estrogen receptor (ER) ligands to be radiolabeled with fluorine-18 for imaging of ER-positive breast tumors with positron emission tomography (PET), we investigated cyclofenil analogues substituted at the C3 or C4 position of the cyclohexyl group. McMurry coupling of 4,4'-dihydroxybenzophenone with various ketones produced key cyclofenil intermediates, from which C3 and C4 substituents containing alkyl and various oxygen or fluorine-substituted alkyl groups were elaborated. Binding assays to both ERalpha and ERbeta revealed that the C3 site is more tolerant of steric bulk and polar groups than the C4 site, consistent with a computational model of the ERalpha ligand binding pocket. Fluorine substitution is tolerated very well at some sites, giving some compounds having affinities comparable to or higher than that of estradiol. These fluoro and fluoroalkyl cyclofenils merit further consideration as fluorine-18 labeled ER ligands for PET imaging of ERs in breast tumors.

    View details for DOI 10.1021/jm0512037

    View details for Web of Science ID 000236979100015

    View details for PubMedID 16610793

    View details for PubMedCentralID PMC2522267

  • Syntheses of NAMDA derivatives inhibiting NO production in BV-2 cells stimulated with lipopolysaccharide BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Seo, J. W., Srisook, E., Son, H. J., Hwang, O., Cha, Y. N., Chi, D. Y. 2005; 15 (14): 3369?73


    Sixteen derivatives of N-acetyl-3-O-methyldopamine (NAMDA), an inhibitor of BH4 synthesis, were designed and synthesized. The ability of these derivatives to inhibit NO and BH4 production by lipopolysaccharide-stimulated BV-2 microglial cells was determined. While NAMDA at 100 microM inhibited NO and BH4 production by only about 20%, its catecholamide 8, indole 23 derivative, 13, and N-acetyl tetrahydroisoquinoline 25 inhibited the NO production by >50% at the same concentration. In particular, 13 and 25 inhibited both NO and BH4 production to similar degrees, which suggested that these compounds might inhibit NO production by blocking BH4-dependent dimerization of the newly synthesized iNOS monomer.

    View details for DOI 10.1016/j.bmcl.2005.05.033

    View details for Web of Science ID 000230337100010

    View details for PubMedID 15953725

  • Hydroxylation of alkyl halides with water in ionic liquid: Significantly enhanced nucleophilicity of water JOURNAL OF ORGANIC CHEMISTRY Kim, D. W., Hong, D. J., Seo, J. W., Kim, H. S., Kim, H. K., Song, C. E., Chi, D. Y. 2004; 69 (9): 3186?89


    A facile method for the nucleophilic hydroxylation of alkyl halides and mesylates with water has been developed in which the use of ionic liquid as an alternative reaction medium not only enhanced the nucleophilicity of water but also reduced the formation of elimination products predominantly formed under the conventional basic reaction conditions. For example, hydroxylation of model compound 2-(3-bromopropyl)naphthalene (1) to 2-(3-hydroxypropyl)naphthalene (2) with water in 1-n-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF(4)]) and 1,4-dioxane proceeded selectively in high yield (94%). The reactivity of other nucleophilic oxygen sources such as alcohol, phenol, and acetic acid in an ionic liquid was also investigated.

    View details for DOI 10.1021/jo035563i

    View details for Web of Science ID 000221268200036

    View details for PubMedID 15104461

  • Syntheses and radical scavenging activities of resveratrol derivatives BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Lee, H. J., Seo, J. W., Lee, B. H., Chung, K. H., Chi, D. Y. 2004; 14 (2): 463?66


    Nine new resveratrol derivatives, having bromo, iodo, and fluoroethyl groups, were designed and synthesized. All compounds having free phenol groups showed good free radical scavenging activity. Among them, 2-bromoresveratrol 19 has a similar free radical scavenging activity to (+)-catechin.

    View details for DOI 10.1016/j.bmcl.2003.10.038

    View details for Web of Science ID 000188119500036

    View details for PubMedID 14698182

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