Philip S Low

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

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Publications (339)1827.74 Total impact

  • [Show abstract] [Hide abstract]
    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; DOI:10.1021/acs.molpharmaceut.5b00218
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    ABSTRACT: Over 80,000 people undergo resection of a pulmonary tumor each year, and the only method to determine if the tumor is malignant is histological analysis. We propose that a targeted molecular contrast agent could bind lung adenocarcinomas and then identify these tumors by real-time optical imaging at the time of surgery.
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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
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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
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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;
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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
  • 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
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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.
    dressNature Reviews Drug Discovery 02/2015; DOI:10.1038/nrd4519
  • 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; DOI:10.2967/jnumed.114.144998
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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). DOI:10.1016/j.bcmd.2014.11.004
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    ABSTRACT: Surgical biopsy of potential tumor recurrence is a common challenge facing oncologists, surgeons, and cancer patients. Imaging modalities have limited ability to accurately detect recurrent cancer in fields affected by previous surgery, chemotherapy, or radiation. However, definitive tissue diagnosis is often needed to initiate treatment and to direct therapy. We sought to determine if a targeted fluorescent intraoperative molecular imaging technique could be applied in a clinical setting to assist a surgical biopsy in a "hostile" field. We describe the use of a folate-fluorescein conjugate to direct the biopsy of a suspected recurrent lung adenocarcinoma invading the mediastinum that had been previously treated with chemoradiation. We found that intraoperative imaging allowed the identification of small viable tumor deposits that were otherwise indistinguishable from scar and necrosis. Our operative observations were confirmed by histology, fluorescence microscopy, and immunohistochemistry. Our results demonstrate one possible application and clinical value of intraoperative molecular imaging.
    Molecular Imaging 11/2014; 13:1-6. DOI:10.2310/7290.2014.00051
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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; DOI:10.2967/jnumed.114.143180
  • Nimalka A. Bandara, Philip S. Low
    Cancer Research 10/2014; 74(19 Supplement):2593-2593. DOI:10.1158/1538-7445.AM2014-2593
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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; 11(10). DOI:10.1021/mp500348e
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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). DOI:10.1364/BOE.5.002662
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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 08/2014; 124(8). DOI:10.1002/lary.24606
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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; 96(4). DOI:10.1189/jlb.2AB0713-372R
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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. DOI:10.1097/CJI.0000000000000029
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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; 11(5). DOI:10.1021/mp5000967
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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; DOI:10.1039/c3ob41230j

Publication Stats

17k Citations
1,827.74 Total Impact Points

Institutions

  • 1977–2015
    • Purdue University
      • • Department of Chemistry
      • • School of Electrical and Computer Engineering
      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
  • 2011
    • Università degli Studi di Torino
      • Dipartimento di Scienze Cliniche e Biologiche
      Torino, Piedmont, Italy
  • 2008
    • The Ohio State University
      • Division of Pharmaceutics and Pharmaceutical Chemistry
      Columbus, OH, United States
  • 2000
    • Endocyte
      West Lafayette, Indiana, United States
  • 1989
    • The University of Western Ontario
      London, Ontario, Canada
  • 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