Philip S Low

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

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Publications (270)1409.39 Total impact

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    ABSTRACT: Oxygen tension has emerged as a potent regulator of multiple erythrocyte properties, including glucose metabolism, cell volume, ATP release, and cytoskeletal organization. Because hemoglobin (Hb)(1) binds to the cytoplasmic domain of band 3 (cdb3) in an oxygen dependent manner, with deoxyHb exhibiting significantly greater affinity for cdb3 than oxyHb, the deoxyHb-cdb3 interaction has been hypothesized to constitute the molecular switch for all O2-controlled erythrocyte processes. In this study, we describe a rapid and accurate method for quantitating the interaction of deoxyHb binding to cdb3. For this purpose, enhanced green fluorescent protein (eGFP) is fused to the COOH-terminus of cdb3, and the binding of Hb to the NH2-terminus of cdb3-eGFP is quantitated by Hb-mediated quenching of cdb3-eGFP fluorescence. As expected, the intensity of cdb3-eGFP fluorescence decreases only slightly following addition of oxyHb. However, upon deoxygenation of the same Hb-cdb3 solution, the fluorescence decreases dramatically (i.e. confirming that deoxyHb exhibits much greater affinity for cdb3 than oxyHb). Using this fluorescence quenching method, we not only confirm previously established characteristics of the Hb-cdb3 interaction, but also establish an assay that can be exploited to screen for inhibitors of the sickle Hb-cdb3 interaction that accelerates sickle Hb polymerization. Copyright © 2015 Elsevier Inc. All rights reserved.
    Blood Cells Molecules and Diseases 10/2015; 55(3):266-271. DOI:10.1016/j.bcmd.2015.07.004 · 2.65 Impact Factor
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    ABSTRACT: Background: With increasing use of chest computed tomography scans, indeterminate pulmonary nodules are frequently detected as an incidental finding and present a diagnostic challenge. Tissue biopsy followed by histological review and immunohistochemistry is the gold standard to obtain a diagnosis and the most common malignant finding is a primary lung adenocarcinoma. Our objective was to determine whether an intraoperative optical biopsy (molecular imaging) may provide an alternative approach for determining if a pulmonary nodule is a primary lung adenocarcinoma. Methods: Before surgery, 30 patients with an indeterminate pulmonary nodule were intravenously administered a folate receptor-targeted fluorescent contrast agent specific for primary lung adenocarcinomas. During surgery, the nodule was removed and the presence of fluorescence (optical biopsy) was assessed in the operating room to determine if the nodule was a primary pulmonary adenocarcinoma. Standard-of-care frozen section and immunohistochemical staining on permanent sections were then performed as the gold standard to validate the results of the optical biopsy. Results: Optical biopsies identified 19 of 19 (100%) primary pulmonary adenocarcinomas. There were no false positive or false negative diagnoses. An optical biopsy required 2.4 minutes compared to 26.5 minutes for frozen section (P < 0.001) and it proved more accurate than frozen section in diagnosing lung adenocarcinomas. Conclusions: An optical biopsy has excellent positive predictive value for intraoperative diagnosis of primary lung adenocarcinomas. With refinement, this technology may prove to be an important supplement to standard pathology for examining close surgical margins, identifying lymph node involvement, and determining whether suspicious nodules are malignant.
    Annals of surgery 09/2015; 262(4):602-9. DOI:10.1097/SLA.0000000000001452 · 8.33 Impact Factor
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    ABSTRACT: The ability to select patients who will respond to therapy is especially acute for autoimmune/inflammatory diseases, where the costs of therapies can be high and the progressive damage associated with ineffective treatments can be irreversible. In this paper we describe a clinical test that will rapidly predict the response of patients with an autoimmune/inflammatory disease to many commonly employed therapies. This test involves quantitative assessment of uptake of a folate receptor-targeted radioimaging agent (99mTc-EC20) by a subset of inflammatory macrophages that accumulate at sites of inflammation. Murine models of four representative inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease, pulmonary fibrosis, and atherosclerosis) show markedly decreased uptake of 99mTc-EC20 in inflamed lesions upon initiation of successful therapies, but no decrease in uptake upon administration of ineffective therapies, in both cases long before changes in clinical symptoms can be detected. This predictive capability should reduce costs and minimize morbidities associated with failed autoimmune/inflammatory disease therapies.
    Molecular Pharmaceutics 09/2015; DOI:10.1021/acs.molpharmaceut.5b00134 · 4.38 Impact Factor
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    ABSTRACT: Bone fractures constitute a major cause of morbidity and mortality especially in the elderly. Complications associated with osteoporosis drugs and the age of the patient slow bone turnover and render such fractures difficult to heal. Increasing the speed of fracture repair by administration of a fracture-targeted bone anabolic agent could find considerable application. Aspartic acid oligopeptides are negatively charged molecules at physiological pH that adsorb to hydroxyapatite, the mineral portion of bone. This general adsorption is the strongest where bone turnover is highest or where hydroxyapatite is freshly exposed. Importantly, both of these conditions are prominent at fracture sites. GSK3β inhibitors are potent anabolic agents that can promote tissue repair when concentrated in a damaged tissue. Unfortunately, they can also cause significant toxicity when administered systemically and are furthermore difficult to deliver due to their strong hydrophobicity. In this paper, we solve both problems by conjugating the hydrophobic GSK3β inhibitor to a hydrophilic aspartic acid octapeptide using a hydrolyzable bond, thereby generating a bone fracture-targeted water-soluble form of the drug. The resulting amphiphile is shown to assemble into micelles, extending its circulation time while maintaining its fracture-targeting abilities. For measurement of pharmacokinetics, an 125I was introduced at the location of the bromine in the GSK3β inhibitor to minimize any structural differences. Biodistribution studies demonstrate a greater than 4-fold increase in fracture accumulation over healthy bone.
    Biomacromolecules 09/2015; DOI:10.1021/acs.biomac.5b00777 · 5.75 Impact Factor
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    ABSTRACT: Aims: Tumor-specific targeted imaging is rapidly evolving in cancer diagnosis. The folate receptor alpha (FR-α) has already been identified as a suitable target for cancer therapy and imaging. FR-α is present on ~40% of human cancers. FR-β is known to be expressed on several hematologic malignancies and on activated macrophages, but little is known about FR-β expression in solid tumors. Additional or simultaneous expression of FR-β could help extend the indications for folate-based drugs and imaging agents. In this study, the expression pattern of FR-β is evaluated in ovarian, breast and colorectal cancer. Methods: FR-β expression was analyzed by semi-quantitative scoring of immunohistochemical staining on tissue microarrays (TMAs) of 339 ovarian cancer patients, 418 breast cancer patients, on 20 slides of colorectal cancer samples and on 25 samples of diverticulitis. Results: FR-β expression was seen in 21% of ovarian cancer samples, 9% of breast cancer samples, and 55% of colorectal cancer samples. Expression was weak or moderate. Of the diverticulitis samples, 80% were positive for FR-β expression in macrophages. FR-β status neither correlated to known disease-related variables, nor showed association with overall survival and progression free survival in ovarian and breast cancer. In breast cancer, negative axillary status was significantly correlated to FR-β expression (p=0.022). Conclusions: FR-β expression was low or absent in the majority of ovarian, breast and colorectal tumor samples. From the present study we conclude that the low FR-β expression in ovarian and breast tumor tissue indicates limited practical use of this receptor in diagnostic imaging and therapeutic purposes. Due to weak expression, FR-β is not regarded as a suitable target in colorectal cancer.
    PLoS ONE 08/2015; 10(8):e0135012. DOI:10.1371/journal.pone.0135012 · 3.23 Impact Factor
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    ABSTRACT: Although current therapies for many inflammatory/autoimmune diseases are effective, a significant number of patients still exhibit only partial or negligible responses to therapeutic intervention. Since prolonged use of an inadequate therapy can result in both progressive tissue damage and unnecessary expense, methods to identify nonresponding patients are necessary. Four murine models of inflammatory disease (rheumatoid arthritis, ulcerative colitis, pulmonary fibrosis, and atherosclerosis) were induced, treated with anti-inflammatory agents, and evaluated for inflammatory response. The mice were also injected intraperitoneally with OTL0038, a folate receptor-targeted near-infrared dye that accumulates in activated macrophages at sites of inflammation. Uptake of OTL0038 in inflamed lesions was then correlated with clinical measurements of disease severity. OTL0038 accumulated at sites of inflammation in all four animal models. More importantly, changes in lesion-associated OTL0038 preceded changes in clinical symptoms in mice treated with all anti-inflammatory drugs examined. OTL0038 has the ability to predict responses to multiple therapies in four murine models of inflammation.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 08/2015; DOI:10.1007/s11307-015-0876-y · 2.77 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):4495-4495. DOI:10.1158/1538-7445.AM2015-4495 · 9.33 Impact Factor
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    ABSTRACT: During lung surgery, identification of surgical margins is challenging. We hypothesized that molecular imaging with a fluorescent probe to pulmonary adenocarcinomas could enhance residual tumor during resection. Mice with flank tumors received a contrast agent targeting folate receptor alpha. Optimal dose and time of injection was established. Margin detection was compared using traditional methods versus molecular imaging. A pilot study was then performed in three humans with lung adenocarcinoma. The peak tumor-to-background ratio (TBR) of murine tumors was 3.9. Fluorescence peaked at 2 h and was not improved beyond 0.1 mg/kg. Traditional inspection identified 30 % of mice with positive margins. Molecular imaging identified an additional 50 % of residual tumor deposits (p < 0.05). The fluorescent probe visually enhanced all human tumors with a mean TBR of 3.5. Molecular imaging is an important adjunct to traditional inspection to identify surgical margins after tumor resection.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 07/2015; DOI:10.1007/s11307-015-0878-9 · 2.77 Impact Factor
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    ABSTRACT: We report a simple detection system for simultaneous measurement of cellular and molecular markers of cancer. Magnetic beads conjugated with antibodies against a specific antigen are used to capture both free molecules and whole cells over-expressing the antigen. The target-bound beads then flow through a microfluidic chamber where they are drawn to a glass surface by an external magnetic field. The cells and molecules captured on the surface are quantitatively analyzed using fluorescent microscopy. The system was characterized by detecting free folate receptor (FR), and an FR+ cancer cell line (KB) in culture media. The system detected as low as 10 pM of FR, and captured 87% of the spiked KB cells at a volumetric throughput of 3 mL/min. We further demonstrated the detection of 100 KB cells and 200 pM FR spiked into healthy human blood to simulate detection of rare cells and protein biomarkers present in a cancer patient's blood sample. The FR concentration was measured to be 244 pM (including the intrinsic FR present in the blood), and the total number of KB cells in the sample was estimated to be 98. The potential of this approach in clinical diagnostics was also demonstrated by detecting both FR+ cells and FR in an ascites sample obtained from an ovarian cancer patient. Due to the system's capability to detect multiple targets at the same time, its high throughput and overall simplicity, we expect it to be highly useful in a wide range of research settings.
    Analytical Chemistry 07/2015; DOI:10.1021/acs.analchem.5b02215 · 5.64 Impact Factor
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    ABSTRACT: Folate receptor (FR)-β has been identified as a promising target for anti-macrophage and anti-inflammatory therapies. In the present study we investigated EC0565, a folic acid derivative of everolimus, as a FR-specific inhibitor of the mammalian target of rapamycin (mTOR). Due to its amphiphilic nature, EC0565 was first evaluated for water solubility, critical micelle formation, stability in culture, and FR-binding specificity. Using FR-expressing macrophages, the effect of EC0565 on mTOR signaling and cellular proliferation was studied. EC0565's pharmacokinetics, metabolism, and bioavailability were studied in normal rats. EC0565's in-vivo activity was assessed in rats with adjuvant arthritis, a "macrophage-rich" model with close resemblance to rheumatoid arthritis.EC0565 forms micellar aggregates in physiological buffers and demonstrates good water solubility as well as strong multivalent FR-binding capacity. EC0565 inhibited mTOR signaling in rat macrophages at nanomolar concentrations and induced G0/G1 cell cycle arrest in serum-starved RAW264.7 cells. Subcutaneously administered EC0565 in rats displayed good bioavailability and a relatively long half-life (~12 h). When given at 250 nmol/kg, EC0565 selectively inhibited proliferating cell nuclear antigen expression in thioglycollate-stimulated rat peritoneal cells. With limited dosing regimens, EC0565's anti-arthritic activity was found superior to that of etanercept, everolimus, and a non-targeted everolimus analog. EC0565's in-vivo activity was also comparable to that of a folate-targeted aminopterin. Folate-targeted mTOR inhibition may be an effective way of suppressing activated macrophages in sites of inflammation, especially in nutrient deprived conditions such as in the arthritic joints. Further investigation and improvement upon EC0565's physical and biochemical properties are warranted.
    Molecular Medicine 07/2015; DOI:10.2119/molmed.2015.00040 · 4.51 Impact Factor
  • Michael J Hansen · N Achini Bandara · Philip S Low
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    ABSTRACT: Adipose tissue macrophages (ATMs) have been implicated in a number of obesity-related diseases. Because the activated macrophages associated with many types of autoimmune and inflammatory diseases express a folate receptor (FR) that can be exploited for FR-targeted drug delivery, we examined the visceral adipose tissue of obese mice and humans to determine whether ATMs also express FR that are accessible by folate conjugates. C57BL/6 or FATSO mice fed on either a low- or high-fat diet were used in murine studies. Human adipose tissue were obtained from healthy volunteers during adipose reduction surgery. Visceral adipose tissue was collected from both obese mice and humans, collagenase digested, and stained with folate-Oregon Green and antibodies for macrophage markers including F4/80, mannose receptor (CD206), CD11b, and CD11c. Cells were then examined for expression of the above markers by flow cytometry. Furthermore, the ability of folate conjugates to target the FR-expressing ATMs in obese mice was evaluated in vivo. A subset of the ATMs harvested from obese mice were found to express FR. Subpopulations of ATMs also simultaneously express both pro- and anti-inflammatory markers, and FR is expressed on both subsets. We then demonstrate that FR-expressing ATMs can be targeted with folate-linked fluorescent dyes in vivo. FR are expressed on multiple subsets of ATMs and these subsets can be targeted with folate-linked drugs, allowing for the possible development of FR-targeted therapies for obesity-related inflammatory diseases.
    Agents and Actions 07/2015; 64(9). DOI:10.1007/s00011-015-0849-2 · 2.35 Impact Factor
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    Charity Wayua · Jyoti Roy · Karson S Putt · Philip S Low
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    ABSTRACT: As the delivery of selectively targeted cytotoxic agents via antibodies or small molecule ligands to malignancies has begun to show promise in the clinic, the need to identify and validate additional cellular targets for specific therapeutic delivery is critical. While a multitude of cancers have been targeted using the folate receptor, PSMA, bombesin receptor, somatostatin receptor, LHRH and αvβ3, there is a notable lack of specific small molecule ligand/receptor pairs to cellular targets found within cancers of the GI tract. Due to the selective GI tract expression of the cholecystokinin 2 receptor, we undertook to create conjugates that would deliver microtubule disrupting drugs to malignancies through the specific targeting of the cholecystokinin 2 receptor via a high affinity small molecule ligand. The cytotoxic activity of these conjugates were shown to be receptor mediated in vitro and in vivo with xenograft mouse models exhibiting delayed growth or regression of tumors that expressed the cholecystokinin 2 receptor. Overall, this work demonstrates that ligands to the cholecystokinin 2 receptor can be used to create selectively targeted therapeutic conjugates.
    Molecular Pharmaceutics 06/2015; 12(7). DOI:10.1021/acs.molpharmaceut.5b00218 · 4.38 Impact Factor
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    Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):929.2-929. DOI:10.1136/annrheumdis-2015-eular.5451 · 10.38 Impact Factor
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    ABSTRACT: More than 80,000 people undergo resection of a pulmonary tumor each year, and the only method to determine if the tumor is malignant is histologic analysis. We propose that a targeted molecular contrast agent could bind lung adenocarcinomas, which could be identified using real-time optical imaging at the time of surgery. Fifty patients with a biopsy-proven lung adenocarcinoma were enrolled. Before surgery, patients were systemically administered 0.1 mg/kg of a fluorescent folate receptor alpha (FRα)-targeted molecular contrast agent by intravenous infusion. During surgery, tumors were imaged in situ and ex vivo, after the lung parenchyma was dissected to directly expose the tumor to the imaging system. Tumors ranged from 0.3 to 7.5 cm (mean: 2.6 cm), and 46 of 50 (92%) lung adenocarcinomas were fluorescent. No false uptake occurred, and in 2 cases, intraoperative imaging revealed tumor metastases (3 mm and 6 mm) that were not recognized preoperatively. Four adenocarcinomas were not fluorescent, and immunohistochemistry showed that these adenocarcinomas did not express FRα. Tumor fluorescence was independent of nodule size, uptake of 2-deoxy-2-((18)F)fluoro-D-glucose, histology, and tumor differentiation. Molecular imaging could identify only 7 of the 50 adenocarcinomas in situ in the patient without bisection. The most important predictor of the success of molecular imaging in locating the tumor in situ was the distance of the nodule from the pleural surface. Intraoperative molecular imaging with a targeted contrast agent can identify lung adenocarcinomas, and this technology is currently useful in patients with subpleural tumors, irrespective of size. With further refinements, this tool may prove useful in locating adenocarcinomas that are deeper in the lung parenchyma, in lymph nodes, and at pleural and resection margins. Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
    The Journal of thoracic and cardiovascular surgery 05/2015; 150(1). DOI:10.1016/j.jtcvs.2015.05.014 · 4.17 Impact Factor
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    Scott Poh · Venkatesh Chelvam · Philip S Low
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    ABSTRACT: The vast majority of nanomedicine research is focused on the use of nanoparticles for the diagnosis and treatment of cancer. However, the dense extracellular matrix of solid tumors restricts nanoparticle penetration, raising the question of whether the best applications of nanomedicines lie in oncology. In this study, the uptake of folate-conjugated liposomes was compared between folate receptor-expressing tumors and folate receptor+ inflammatory lesions within the same mouse. We demonstrate here that both folate-targeted and nontargeted liposomes accumulate more readily at sites of inflammation than in solid tumors. These data suggest that nanosized imaging and therapeutic agents may be better suited for the treatment and diagnosis of inflammatory/autoimmune diseases than cancer.
    Nanomedicine 05/2015; 10(9):1439-49. DOI:10.2217/nnm.14.237 · 5.41 Impact Factor
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    ABSTRACT: T cells expressing a chimeric antigen receptor (CAR) can produce dramatic results in lymphocytic leukemia patients; however, therapeutic strategies for myeloid leukemia remain limited. Folate receptor beta (FRβ) is a myeloid-lineage antigen expressed on 70% of acute myeloid leukemia (AML) patient samples. Here, we describe development and evaluation of the first CARs specific for human FRβ (m909) in vitro and in vivo. m909 CAR T cells exhibited selective activation and lytic function against engineered C30-FRβ as well as endogenous FRβ(+) AML cell lines in vitro. In mouse models of human AML, m909 CAR T cells mediated the regression of engrafted FRβ(+) THP1 AML in vivo. In addition, we demonstrated that treatment of AML with all-trans retinoic acid (ATRA) enhanced FRβ expression, resulting in improved immune recognition by m909 CAR T cells. As many cell-surface markers are shared between AML blasts and healthy hematopoietic stem and progenitor cells (HSCs), we evaluated FRβ expression and recognition of HSCs by CAR T cells. m909 CAR T cells were not toxic against healthy human CD34+ HSCs in vitro. Our results indicate that FRβ is a promising target for CAR T cell therapy of AML, which may be augmented by combination with ATRA. Copyright © 2015 American Society of Hematology.
    Blood 04/2015; 125(22). DOI:10.1182/blood-2014-11-612721 · 10.45 Impact Factor
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    ABSTRACT: Over-expression of folate receptor alpha on cancer cells has been frequently exploited for delivery of folate-targeted imaging and therapeutic agents to tumors. Because limited information exists on expression of the beta isoform of the folate receptor in human cancers (FR-β), we have evaluated the immunohistochemical staining pattern of FR-β in 992 tumor sections from 20 different human cancer types using a new anti-human FR-β monoclonal antibody. FR-β expression was shown to be more pronounced in cells within the stroma, primarily macrophages and macrophage-like cells than cancer cells in every cancer type studied. Moreover, FR-β expression in both cancer and stromal cells was found to be statistically more prominent in females than males. A significant positive correlation was also observed between FR-β expression on stromal cells and both the stage of the cancer and the presence of lymph node metastases. Based on these data we conclude FR-β may constitute a good target for specific delivery of therapeutic agents to activated macrophages and that accumulation of FR-β positive macrophages in the stroma could serve as a useful indicator of a tumor's metastatic potential.
    Oncotarget 03/2015; 6(16). DOI:10.18632/oncotarget.3739 · 6.36 Impact Factor
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    ABSTRACT: Prostate-specific membrane antigen (PSMA) is overexpressed in most prostate cancer cells while being present at low or undetectable levels in normal cells. This difference provides an opportunity to selectively deliver cytotoxic drugs to prostate cancer cells while sparing normal cells that lack PSMA, thus improving potencies and reducing toxicities. PSMA has high affinity for 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid (DUPA) (Ki = 8 nM). After binding to a DUPA-drug conjugate, PSMA internalizes, unloads the conjugate, and returns to the surface. In the present studies, an indenoisoquinoline topoisomerase I inhibitor was conjugated to DUPA via a peptide linker and a drug-release segment that facilitates intracellular cleavage to liberate the drug cargo. The DUPA-indenoisoquinoline conjugate exhibited an IC50 in the low nanomolar range in 22RV1 cell cultures and induced a complete cessation of tumor growth with no toxicity, as determined by loss of body weight and death of treated mice.
    Journal of Medicinal Chemistry 03/2015; 58(7). DOI:10.1021/jm5018384 · 5.45 Impact Factor
  • 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 Letter is to describe the preparation and evaluation of a non-peptide SST2 agonist for use in targeting drugs to neuroendocrine cancers. A non-peptide ligand for the SST2 receptor was identified from the literature as a candidate for development of targeted pharmaceuticals for neuroendocrine tumors, based on its SST2 binding affinity and selectivity for SST2 over other somatostatin receptors. It also offered a multiplicity of possible conjugation sites. Rhodamine conjugates in two positions were used for optical imaging and two compounds were internalized in an SST2 receptor transduced cell line (C6-SST2) via SST2 receptor-mediated endocytosis. Radionuclide conjugates were prepared for in vivo imaging and biodistribution studies in mice. The in vitro binding affinity of (99m)Tc conjugates ranged from a Kd of 37-494. Of these, one (99m)Tc conjugate was selected and dosed by IV injection into mice bearing C6-SST2 tumor xenografts. The highest uptake was into tumor, intestine and skin four hours after IV injection. Competition studies with octreotide, a synthetic peptide and SST2 agonist, confirmed that uptake was SST2 receptor mediated. While relatively high uptake in intestine, liver, kidneys and skin discouraged further development of the conjugate for delivery of chemotherapeutic agents, the conjugate may still be worthy of further development for neuroendocrine tumor imaging. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Bioorganic & medicinal chemistry letters 02/2015; 25(8). DOI:10.1016/j.bmcl.2015.02.033 · 2.42 Impact Factor
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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; 14(3). DOI:10.1038/nrd4519 · 41.91 Impact Factor

Publication Stats

12k Citations
1,409.39 Total Impact Points


  • 1977–2015
    • Purdue University
      • Department of Chemistry
      ウェストラファイエット, Indiana, United States
  • 2014
    • Emory University
      • Department of Chemistry
      Atlanta, Georgia, United States
  • 2008
    • The Ohio State University
      • Division of Pharmaceutics and Pharmaceutical Chemistry
      Columbus, OH, United States
  • 1984
    • University of Illinois, Urbana-Champaign
      • Department of Plant Biology
      Urbana, Illinois, United States
  • 1978
    • University of Massachusetts Amherst
      • Department of Chemistry
      Amherst Center, Massachusetts, United States
  • 1976
    • National University (California)
      San Diego, California, United States