Philip S Low

Purdue University, ウェストラファイエット, Indiana, United States

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Publications (293)1522.47 Total impact

  • Guo Li, Philip S. Low
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    ABSTRACT: Over-expression of the somatostatin-2 (SST2) receptor on plasma membranes of neuroendocrine cancer cells renders it attractive for use in targeting both imaging and therapeutic agents to neuroendocrine tumors. Peptide analogs of somatostatin have dominated this approach to date, however, many peptide analogs are either unstable in vivo or exhibit unwanted non-specific uptake in the liver and kidneys. The purpose of this paper is to describe the preparation and evaluation of a non-peptide SST2 agonist for use in targeting drugs to neuroendocrine cancers.
    Bioorganic & Medicinal Chemistry Letters. 02/2015;
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    ABSTRACT: Most cancer drugs are designed to interfere with one or more events in cell proliferation or survival. As healthy cells may also need to proliferate and avoid apoptosis, anticancer agents can be toxic to such cells. To minimize these toxicities, strategies have been developed wherein the therapeutic agent is targeted to tumour cells through conjugation to a tumour-cell-specific small-molecule ligand, thereby reducing delivery to normal cells and the associated collateral toxicity. This Review describes the major principles in the design of ligand-targeted drugs and provides an overview of ligand-drug conjugates and ligand-imaging-agent conjugates that are currently in development.
    Nature reviews. Drug discovery. 02/2015;
  • Charity Wayua, Philip S Low
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    ABSTRACT: Tumor-specific targeting ligands have recently been exploited to deliver both imaging and therapeutic agents selectively to cancer tissues in vivo. Because the cholecystokinin 2 receptor (CCK2R) is over-expressed in a variety of human cancers (e.g. lung, medullary thyroid, pancreatic, colon, and GIST), but displays limited expression in normal tissues, natural ligands of CCK2R have been recently explored for use in imaging CCK2R positive cancers. Unfortunately, results from these studies reveal that peptidic CCK2R ligands are not only unstable in vivo, but those ligands that mediate good uptake by tumor tissue also promote high retention of the radioimaging agent in the kidneys, probably due to capture of the conjugates by peptide scavenger receptors. In an effort to reduce normal organ retention of CCK2R-targeted drugs, we have designed and synthesized a nonpeptidic ligand of CCK2R and examined its specificity for CCK2 receptors both in vitro and in vivo. Copyright © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    Journal of Nuclear Medicine 12/2014; · 5.56 Impact Factor
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    ABSTRACT: Humans and mice with sickle cell disease (SCD) have rigid red blood cells (RBCs). Omega-3 fatty acids, such as docosahexanoic acid (DHA), may influence RBC deformability via incorporation into the RBC membrane. In this study, sickle cell (SS) mice were fed natural ingredient rodent diets supplemented with 3% DHA (DHA diet) or a control diet matched in total fat (CTRL diet). After 8weeks of feeding, we examined the RBCs for: 1) stiffness, as measured by atomic force microscopy; 2) deformability, as measured by ektacytometry; and 3) percent irreversibly sickled RBCs on peripheral blood smears. Using atomic force microscopy, it is found that stiffness is increased and deformability decreased in RBCs from SS mice fed CTRL diet compared to wild-type mice. In contrast, RBCs from SS mice fed DHA diet had markedly decreased stiffness and increased deformability compared to RBCs from SS mice fed CTRL diet. Furthermore, examination of peripheral blood smears revealed less irreversibly sickled RBCs in SS mice fed DHA diet as compared to CTRL diet. In summary, our findings indicate that DHA supplementation improves RBC flexibility and reduces irreversibly sickled cells by 40% in SS mice. These results point to potential therapeutic benefits of dietary omega-3 fatty acids in SCD. Copyright © 2014 Elsevier Inc. All rights reserved.
    Blood Cells Molecules and Diseases 11/2014; 54(2). · 2.33 Impact Factor
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    ABSTRACT: In atherosclerotic plaques, the risk of rupture is increased at sites of macrophage accumulation. Activated macrophages express folate receptor-β (FR-β), which can be targeted by folate coupled to radioactive ligands to visualize vulnerability. The aim of this study was to explore the presence of activated macrophages in human atherosclerotic plaques by (99m)Tc-folate imaging and to evaluate whether this technique can discriminate between an M1-like and M2-like macrophage phenotype.
    Journal of Nuclear Medicine 10/2014; · 5.56 Impact Factor
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    ABSTRACT: Activated macrophages overexpress a receptor for the vitamin folic acid termed the folate receptor β (FR-β). Because conjugation of folate to low molecular weight drugs, genes, liposomes, nanoparticles, and imaging agents has minor effects on FR binding, the vitamin can be exploited to target both therapeutic and imaging agents to activated macrophages without promoting their uptake by other healthy cells. In this paper we characterize the binding, internalization and recycling kinetics of FR-β on activated macrophages in inflamed tissues of rats with adjuvant-induced arthritis. Our results demonstrate that saturation of macrophage FR is achieved at injection doses of ~150-300 nmol/kg, with more rapidly perfused tissues saturating at lower doses than inflamed appendages. After binding, FR-β internalizes and recycles back to the cell surface every ~10-20 minutes, providing empty receptors for additional folate conjugate uptake. Because the half-life of low molecular weight folate conjugates in the vasculature is usually <1 hour, these data suggest that targeting of folate conjugates to activated macrophages in vivo can be maximized by frequent dosing at conjugate concentrations that barely saturate FR (~150 nmol/kg), thereby minimizing nonspecific binding to receptor-negative tissues and maximizing the probability that unoccupied cell surface receptors will be exposed to folate-drug conjugate.
    Molecular Pharmaceutics 08/2014; · 4.79 Impact Factor
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    ABSTRACT: Many cancer cells over-express folate receptors, and this provides an opportunity for both folate-targeted fluorescence imaging and the development of targeted anti-cancer drugs. We present an optical imaging modality that allows for the monitoring and evaluation of drug delivery and release through disulfide bond reduction inside a tumor in vivo for the first time. A near-infrared folate-targeting fluorophore pair was synthesized and used to image a xenograft tumor grown from KB cells in a live mouse. The in vivo results are shown to be in agreement with previous in vitro studies, confirming the validity and feasibility of our method as an effective tool for preclinical studies in drug development.
    Biomedical Optics Express 08/2014; 5(8). · 3.50 Impact Factor
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    ABSTRACT: Activated macrophages are commonly involved in the pathogenesis of inflammatory and autoimmune diseases and have been frequently reported to overexpress FR-β. Although FR-targeted therapies aimed at eliminating activated macrophages have shown promise for treating inflammatory diseases, little work has been performed to evaluate whether other hematopoietic cells might also express FR-β. Analysis of peripheral blood cells with a mAb to human FR-β reveals that only monocytes express FR-β. Molecular characterization of these circulating monocytes further demonstrates that solely the classic/proinflammatory subset (CD14(high)CD16(-)) expresses the FR and that only CD14(high)CD16(-) FR-β(+) monocytes also display the ability to bind folate-linked molecules. Confirmation that this subset of monocytes indeed constitutes the proinflammatory subpopulation was obtained by demonstrating coexpression of FR-β with other proinflammatory markers, including CCR2 and HLA-DR. Synovial monocytes from the joints of patients with RA were also shown to express FR-β. As inhibition of the chemotaxis of proinflammatory monocytes into sites of inflammation has been explored frequently as a means of controlling autoimmune diseases, demonstration that FR-β is uniquely expressed on this proinflammatory subpopulation offers a new strategy to suppress migration of inflammatory monocytes into sites of inflammation.
    Journal of Leukocyte Biology 07/2014; · 4.30 Impact Factor
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    ABSTRACT: Folate immune (EC90 vaccine with GPI-0100 adjuvant followed by EC17) is a novel folate-targeted hapten immunotherapy designed to exploit the overexpression of folate receptors on renal cell carcinoma (RCC) cells. In this open-label, phase I/II clinical study, we report the safety, pharmacokinetics, and antitumor activity of folate immune with concurrent interleukin-2 (IL-2) and interferon-α (IFN-α) in patients with recurrent or metastatic RCC. Twenty-four patients were enrolled. Following 2 phase I cohorts of 6 patients each, we extended the study to 12 additional patients: 18 received weekly vaccination of 1.2 mg of EC90 with 3.0 mg of GPI-0100 adjuvant for 4 weeks. Beginning on cycle 1, day 8, 0.3 mg/kg of EC17 was administered once daily, 5 days per week (Monday-Friday) for 4 consecutive weeks. Beginning on cycle 1, day 15, IL-2 and IFN-α were administered at doses of 12 and 3.0 MIU, respectively, after the EC17 dose, 3 times per week (Monday, Wednesday, and Friday) for 3 weeks. In cycle 2, IL-2 and IFN-α, doses of 7.0 and 3.0 MIU, respectively, were administered 3 days per week (Monday, Wednesday, and Friday) for 4 consecutive weeks. No dose-limiting toxicities were observed. Most adverse events reported were grade 1 or 2, with only twelve grade ≥3 toxicities reported. Sixteen patients had progressive disease, 7 patients were observed to have stable disease, and 1 patient achieved a partial response lasting 71 days. Overall, folate immune plus low-dose IFN-α and IL-2 was safe and well tolerated with some observed clinical activity.
    Journal of immunotherapy (Hagerstown, Md.: 1997) 05/2014; 37(4):237-44. · 3.20 Impact Factor
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    ABSTRACT: Multivalent conjugation of folic acid has been employed to target cells overexpressing folate receptors. Such polymer conjugates have been previously demonstrated to have high avidity to folate binding protein. However, the lack of a monovalent folic acid-polymer material has prevented a full binding analysis of these conjugates, as multivalent binding mechanisms and polymer-mass mechanisms are convoluted in samples with broad distributions of folic acid-to-dendrimer ratios. In this work, the synthesis of a monovalent folic acid-dendrimer conjugate allowed the elucidation of the mechanism for increased binding between the folic acid-polymer conjugate and a folate binding protein surface. The increased avidity is due to a folate-keyed interaction between the dendrimer and protein surfaces that fits into the general framework of slow-onset, tight-binding mechanisms of ligand/protein interactions.
    Molecular Pharmaceutics 04/2014; · 4.57 Impact Factor
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    ABSTRACT: The chemical synthesis of staphyloferrin A, a siderophore used by Staphylococcus bacteria for ferric iron retrieval, has been achieved with 79% yield via solid phase peptide synthesis (SPPS). Biological activity of synthetic staphyloferrin A has been confirmed by demonstrating its capture and uptake by live S. aureus.
    Organic & Biomolecular Chemistry 02/2014; · 3.49 Impact Factor
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    ABSTRACT: Objective-To determine expression of folate receptors (FRs) and folate uptake in multicentric lymphomas in dogs. Sample-10 dogs with histopathologically confirmed multicentric lymphoma and 20 archival lymph node biopsy specimens from dogs with multicentric lymphoma. Procedures-Multicentric lymphomas in 10 dogs were prospectively evaluated for FR expression by use of immunohistochemical analysis and for in vivo folate uptake by use of nuclear scintigraphy. Dogs with FR-expressing tumors were eligible for FR-targeted chemotherapy. Twenty archival lymphoma biopsy specimens were also evaluated with immunohistochemical analysis. Results-FRs were not detected with immunohistochemical analysis in lymph node samples obtained from the 10 dogs or in archival biopsy specimens. However, nuclear scintigraphy revealed uptake of radioactive tracer in 6 of 10 dogs. Five of these 6 dogs were treated with an FR-targeted chemotherapeutic agent; results of treatment were complete remission in 1 dog, stable disease in 2 dogs, and progressive disease in 2 dogs. Treatment-related toxicoses generally were mild. Conclusions and Clinical Relevance-This study provided strong evidence for folate uptake in a substantial portion of multicentric lymphomas of dogs and indicated the antitumor activity of FR-targeted chemotherapeutics for these cancers. Use of FR-targeted chemotherapeutics may be promising for the treatment of FR-expressing multicentric lymphomas in dogs. Further studies are needed to determine reasons for lack of immunoreactivity to currently identified anti-FR antibodies and to develop improved methods for detecting FRs in lymphomas of dogs.
    American Journal of Veterinary Research 02/2014; 75(2):187-94. · 1.21 Impact Factor
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    ABSTRACT: Medicines for the treatment of most human pathologies are encumbered by unwanted side effects that arise from the deposition of an effective drug into the wrong tissues. The logical remedy for these undesirable properties involves selective targeting of the therapeutic agent to pathologic cells, thereby avoiding collateral toxicity to healthy cells. Since significant advantages can also accrue by incorporating a therapeutic or imaging agent into a nanoparticle, many laboratories are now combining both benefits into a single formulation. This review will focus on the major guiding principles in the design of ligand-targeted nanoparticles, including optimization of their chemical and physical properties, selection of the ideal targeting ligand, engineering of the appropriate surface passivation and linker strategies to achieve selective delivery of the entrapped cargo to the desired diseased cell.
    Nanomedicine 02/2014; 9(2):313-330. · 5.26 Impact Factor
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    ABSTRACT: Objective: Folate receptor (FR) expression, while known to be elevated in many types of cancer and inflammatory cells, has not been well characterized in head and neck squamous cell carcinoma (HNSCC). We hypothesized that tumor infiltrating inflammatory cells expressing FR-β could allow fluorescent visualization of HNSCC tumors using folate conjugated dyes even when FR expression in cancer cells is low. Study Design: Retrospective review of clinical pathologic specimens and in vivo animal study. Methods: A tissue microarray (TMA) with tumor and tumor free tissue from 22 patients with HNSCC was stained with antibodies to FR-α and FR-β. We characterized FR-β(+) cells by examining CD45, CD68, CD206 and TGF-β expression. To investigate fluorescent imaging, mice with orthotopic tumor xenografts were imaged in vivo after intravenous injections of folate conjugated fluorescein isothiocyanate (folate-FITC) and were histologically evaluated ex vivo. Results: All tumor samples demonstrated significant FR-β staining and negligible FR-α staining. FR-β(+) cells found in tumors coexpressed CD68 and had increased expression of CD206 and TGF-β characteristic of tumor-associated macrophages. In the xenograft models, tumors showed strong in vivo fluorescence after folate-FITC injection in contrast to surrounding normal tissues. Histologic examination of the xenograft tissue similarly showed folate-FITC uptake in areas of inflammatory cellular infiltrate. Conclusion: While HNSCC tumor cells do not express FR, HNSCC tumors contain a significant population of FR-β expressing macrophages. Folate conjugated fluorescent dye is able to specifically target and label tumor xenografts to permit macroscopic fluorescence imaging due to FR-β expression on the infiltrating inflammatory cells.
    The Laryngoscope 01/2014; · 2.03 Impact Factor
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    ABSTRACT: The folate receptor (FR) is a GPI anchored cell surface glycoprotein that functions to facilitate folic acid uptake and mediate signal transduction. With the introduction of multiple folate-targeted drugs into the clinic, the question has arisen regarding how frequently a patient can be dosed with a FR-targeted drug or antibody, and whether dosing frequency exerts any impact on the availability of FR for subsequent rounds of FR-mediated drug uptake. Although the rate of FR recycling has been examined in murine tumor models, little or no information exists on the impact of FR occupancy on its rate of endocytosis. The present study quantitates the number of cell surface FR-α and FR-β following exposure to saturating concentrations of a variety of folate-linked molecules and anti-FR antibodies, including the unmodified vitamin, folate-linked drug mimetics, multi-folate derivatized nanoparticles, and monoclonal antibodies to FR. We report here that FR occupancy has no impact on the rate of FR internalization. We also demonstrate that multivalent conjugates that bind and cross-link FRs at the cell surface internalize at the same rate as monovalent folate conjugates that have no impact on FR clustering, even though the multivalent conjugates traffic through a different endocytic pathway.
    Molecular Pharmaceutics 01/2014; · 4.57 Impact Factor
  • Charity Wayua, Philip S Low
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    ABSTRACT: Optical surgical resection of human tissue is reported to significantly increase the rate of patient survival in a variety of cancers. Tumors targeted near infrared dyes have the potential to improve contrast between normal and malignant tissue thus aiding surgeons to delineate tumor and nontumor tissue. In this study, we exploit the selective overexpression of the cholecystokinin 2 receptor in human cancers to target a near infrared dye, LS-288, to a xenograft and metastasis model of cancer in live mice. The targeted dye conjugate, CRL-LS288 binds cells expressing the cholecystokinin receptor with low nanomolar affinity and high specificity. Imaging and biodistribution studies revealed that CRL-LS288 localizes primarily to HEK 293 CCK2R and HEK 293 CCK2i4svR tumor xenografts and metastases. Tumor targeting was blocked upon administration of excess CRL and no fluorescence was observed in CCK2 receptor negative tissues confirming the specificity of CRL-LS288. These results demonstrate the potential of CRL-LS288 as a tumor targeted optical imaging agent to identify malignant disease during fluorescent image guided surgery.
    Molecular Pharmaceutics 12/2013; · 4.57 Impact Factor
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    ABSTRACT: Human pituitary adenomas express folate receptors (FR); therefore, we hypothesized that parathyroid (PT) tumors also might express FR, whereas normal human thyroids might not. The purpose of our study was to characterize the functionality of FRs on human PT tumors, with the goal of developing an imaging tool that would concentrate in PT more than in the thyroid. Human PTs and thyroids were evaluated for FR expression by immunohistochemistry. Expression of genes for FRα and FRβ was measured with the Illumina Human HT-12 Expression Bead Chips and verified by quantitative reverse-transcription polymerase chain reaction. Folate incorporation by PT cells versus normal thyroid cells was determined by incubation with (99m)Technetium ((99m)Tc)(CO)3-folate and (99m)Tc-Etarfolatide, and uptake was determined by gamma counting. Specific targeting of FRs was demonstrated by blocking with cold folate. A549 cells and Jurkat cells served as FR-negative controls, and KB cells and HeLa cells were FR-positive controls. On immunohistochemistry and Western blotting, human PT cells expressed FRs, whereas human thyroid cells did not. The FRα gene was expressed in all PTs analyzed, and the FRβ gene was expressed by most. Uptake of (99m)Tc(CO)3-folate was increased in PT cells versus thyroid cells. There was dose-dependent uptake of (99m)Tc-etarfolatide, and uptake was inhibited by preincubation with cold folate, confirming FR-mediated binding. This is the first report of the expression and functionality of FRs on human PT cells. These findings suggest that (99m)Tc-folate holds potential for localization of PT tumors preoperatively and their treatment.
    Surgery 10/2013; · 3.37 Impact Factor
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    ABSTRACT: Targeted therapies are emerging as a preferred strategy for the treatment of cancer and other diseases. To evaluate the impact of a high affinity targeting ligand on the rate and extent of tumor penetration of different sized nanomedicines, we have used intravital multiphoton microscopy to quantitate the kinetics of tumor accumulation of a homologous series of folate-PEG-rhodamine conjugates prepared with polyethylene glycols (PEG) of different molecular weights. We demonstrate that increasing the size of the folate-PEG-rhodamine conjugates results in both longer circulation times and slower tumor penetration rates. Although a "binding site barrier" is observed with the folate-linked polymers in folate receptor expressing tumors, ligand targeting eventually leads to increased tumor accumulation, with endocytosis of the targeted nanocarriers contributing to their enhanced tumor retention. Because the effects of nanocarrier size, shape, chemistry, and targeting ligand are interconnected and complex, we suggest that these parameters must be carefully optimized for each nanocarrier to assure optimal drug delivery in vivo.
    ACS Nano 09/2013; · 12.03 Impact Factor
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    ABSTRACT: Eukaryotic parasites of the Plasmodium genus cause malaria by invading and developing within host erythrocytes. Here, we demonstrate that PfShelph2, a gene product of Plasmodium falciparum that belongs to the Shewanella-like phosphatase (Shelph) subfamily, selectively hydrolyzes phosphotyrosine, as shown for other previously studied Shelph family members. In the extracellular 'merozoite' stage, PfShelph2 localizes to vesicles that appear to be distinct from those of rhoptry, dense granule or microneme organelles. During invasion, PfShelph2 is released from these vesicles and exported to the host erythrocyte. In vitro, PfShelph2 shows tyrosine phosphatase activity against the host erythrocyte protein Band 3, which is the most abundant tyrosine-phosphorylated species of the erythrocyte. During P. falciparum invasion, Band 3 undergoes dynamic and rapid clearance from the invasion junction within 1-2 seconds of parasite attachment to the erythrocyte. Release of Pfshelph2 occurs after clearance of Band 3 from the parasite-host cell interface, and when the parasite is nearly or completely enclosed in the nascent vacuole. We propose a model in which the phosphatase modifies Band 3 in time to restore its interaction with cytoskeleton and thus re-establishes the erythrocyte cytoskeletal network at the end of the invasion process.
    Eukaryotic Cell 07/2013; · 3.18 Impact Factor
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    ABSTRACT: Activated macrophages play a significant role in initiation and progression of inflammatory diseases, and may serve as the basis for the development of targeted diagnostic methods for imaging sites of inflammation. Folate receptor beta (FR-β) is differentially expressed on activated macrophages associated with inflammatory disease states yet is absent in either quiescent or resting macrophages. Because folate binds with high affinity to FR-β, development of folate directed imaging agents has proceeded rapidly in the past decade. However, reports of PET based imaging agents for use in inflammatory conditions remains limited. To investigate whether FR-β expressing macrophages could be exploited for PET based inflammatory imaging, two separate folate-targeted PET imaging agents were developed, 4-[18F]fluoro-phenyl-folate and [68Ga]-DOTA-folate, and their ability to target activated macrophages were examined in a rodent inflammatory paw model. We further compared inflamed tissue uptake with 2-[18F]fluoro-2-deoxy-D-glucose ([18F]-FDG). microPET analysis demonstrated that both folate-targeted PET tracers had higher uptake in the inflamed paw compared to the control paw. When these radiotracers were compared to [18F]-FDG, both folate PET tracers had a higher signal-to-noise ratio (SNR) than [18F]-FDG, suggesting that folate tracers may be superior to [18F]-FDG in detecting diseases with an inflammatory component. Moreover, both folate-PET imaging agents also bind to FR-α which is over-expressed on multiple human cancers. Therefore, these folate derived PET tracers may also find use for localizing and staging FR+ cancers, monitoring response to therapy, and for selecting patients for tandem folate-targeted therapies.
    Molecular Pharmaceutics 07/2013; · 4.57 Impact Factor

Publication Stats

14k Citations
1,522.47 Total Impact Points

Institutions

  • 1984–2015
    • Purdue University
      • • Department of Chemistry
      • • Department of Biological Sciences
      ウェストラファイエット, Indiana, United States
  • 2013
    • University of Texas Health Science Center at Houston
      Houston, Texas, United States
  • 2012
    • St. Jude Children's Research Hospital
      Memphis, Tennessee, United States
  • 1992–2011
    • Università degli Studi di Torino
      • Dipartimento di Scienze Cliniche e Biologiche
      Torino, Piedmont, Italy
  • 2009
    • University of Wisconsin, Madison
      • Department of Biochemistry
      Madison, MS, United States
  • 1998–2008
    • The Ohio State University
      • Division of Pharmaceutics and Pharmaceutical Chemistry
      Columbus, OH, United States
  • 2005
    • University of Padova
      • Interdepartmental Research Centre for Innovative Biotechnologies CRIBI
      Padova, Veneto, Italy
    • Georgia State University
      • Department of Chemistry
      Atlanta, Georgia, United States
  • 2004
    • Indiana University-Purdue University Indianapolis
      Indianapolis, Indiana, United States
    • Aarhus University
      • Department of Zoophysiology
      Aars, Region North Jutland, Denmark
  • 2000–2004
    • Endocyte
      West Lafayette, Indiana, United States
  • 2003
    • Yale University
      • Department of Pediatrics
      New Haven, CT, United States