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Philip S. Low - One of the best experts on this subject based on the ideXlab platform.

  • identification of a Folate Receptor targeted near infrared molecular contrast agent to localize pulmonary adenocarcinomas
    Molecular Therapy, 2017
    Co-Authors: Jarrod D Predina, Andrew D Newton, Courtney Connolly, Ashley Dunbar, Michael Baldassari, Charuhas Deshpande, Edward Cantu, Jason Stadanlick, Sumith A Kularatne, Philip S. Low
    Abstract:

    Non-small cell lung cancer (NSCLC) is the number one cancer killer in the United States. Despite attempted curative surgical resection, nearly 40% of patients succumb to recurrent disease. High recurrence rates may be partially explained by data suggesting that 20% of NSCLC patients harbor synchronous disease that is missed during resection. In this report, we describe the use of a novel Folate Receptor-targeted near-infrared contrast agent (OTL38) to improve the intraoperative localization of NSCLC during pulmonary resection. Using optical phantoms, fluorescent imaging with OTL38 was associated with less autofluorescence and greater depth of detection compared to traditional optical contrast agents. Next, in in vitro and in vivo NSCLC models, OTL38 reliably localized NSCLC models in a Folate Receptor-dependent manner. Before testing intraoperative molecular imaging with OTL38 in humans, Folate Receptor-alpha expression was confirmed to be present in 86% of pulmonary adenocarcinomas upon histopathologic review of 100 human pulmonary resection specimens. Lastly, in a human feasibility study, intraoperative molecular imaging with OTL38 accurately identified 100% of pulmonary adenocarcinomas and allowed for identification of additional subcentimeter neoplastic processes in 30% of subjects. This technology may enhance the surgeon's ability to identify NSCLC during oncologic resection and potentially improve long-term outcomes.

  • assessment of Folate Receptor β expression in human neoplastic tissues
    PMC, 2015
    Co-Authors: Jiayin Shen, Sunil Singhal, Karson S Putt, Daniel W Visscher, Linda M Murphy, Cynthia Cohen, George E Sandusky, Yang Feng, Dimiter S Dimitrov, Philip S. Low
    Abstract:

    // Jiayin Shen 1 , Karson S. Putt 2 , Daniel W. Visscher 3 , Linda Murphy 4 , Cynthia Cohen 5 , Sunil Singhal 6 , George Sandusky 7 , Yang Feng 8 , Dimiter S. Dimitrov 8 and Philip S. Low 1,2 1 Department of Chemistry, Purdue University, West Lafayette, IN, USA 2 Center for Drug Discovery, Purdue University, West Lafayette, IN, USA 3 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA 4 Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA 5 Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, GA, USA 6 Division of Thoracic Surgery, Department of Surgery, Hospital of the University of Pennsylvania School of Medicine, Philadelphia, PA, USA 7 Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA 8 Protein Interactions Section, Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD, USA Correspondence to: Philip S. Low, email: // Keywords : Folate Receptor, Folate Receptor beta, activated macrophage, tumor associated macrophage Received : February 10, 2015 Accepted : March 03, 2015 Published : March 30, 2015 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.

  • effect of Receptor occupancy on Folate Receptor internalization
    Molecular Pharmaceutics, 2014
    Co-Authors: Achini N Bandara, Michael J Hansen, Philip S. Low
    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, multiFolate derivatized nanoparticles, and monoclonal antibodies to FR. We report here that FR occupancy has no impact on the rate of FR internalization. W...

  • the effect of chemotherapy on expression of Folate Receptor alpha in ovarian cancer
    Cellular Oncology, 2012
    Co-Authors: Lucia M A Crane, Philip S. Low, Henriette J G Arts, Marleen Van Oosten, Ate G J Van Der Zee, Gooitzen M Van Dam, Joost Bart
    Abstract:

    Background Folate Receptor alpha (FR-α) has been identified as a potential target in ovarian cancer for diagnostic and therapeutic purposes, based on its overexpression in serous epithelial ovarian carcinoma. The effect of chemotherapy on FR-α expression may be important in the applicability of FR-α directed agents in the case of residual tumor tissue. The objective of this study was to assess FR-α expression in ovarian carcinoma and to evaluate whether FR-α expression is altered by chemotherapy.

  • functional Folate Receptor alpha is elevated in the blood of ovarian cancer patients
    PLOS ONE, 2009
    Co-Authors: Eati Basal, Barton A. Kamen, Philip S. Low, Lynn C Hartmann, Guiti Z Eghbalifatourechi, Kimberly R Kalli, Karin Goodman, Ellen L Goode, Keith L Knutson
    Abstract:

    Background Despite low incidence, ovarian cancer is the fifth leading cause of cancer deaths and it has the highest mortality rate of all gynecologic malignancies among US women. The mortality rate would be reduced with an early detection marker. The Folate Receptor alpha (FRα) is one logical choice for a biomarker because of its prevalent overexpression in ovarian cancer and its exclusive expression in only a few normal tissues. In prior work, it was observed that patients with ovarian cancer had elevated serum levels of a protein that bound to a FRα-specific monoclonal antibody relative to healthy individuals. However, it was not shown that the protein detected was intact functional FRα. In the current study, the goal was to determine whether ovarian cancer patients (n = 30) had elevated serum levels of a fully functional intact FRα compared to matched healthy controls (n = 30).

Caicun Zhou - One of the best experts on this subject based on the ideXlab platform.

Tae Gwan Park - One of the best experts on this subject based on the ideXlab platform.

  • Folate Receptor mediated intracellular delivery of recombinant caspase 3 for inducing apoptosis
    Journal of Controlled Release, 2005
    Co-Authors: Kyung Chul Cho, Ji Hoon Jeong, Hyun Chung, Cheol O Joe, Sung Wan Kim, Tae Gwan Park
    Abstract:

    Abstract Recombinant reversed caspase-3 (rev-caspase-3) is a pro-apoptotic gene capable of intracellular autocatalytic processing, which leads to programmed cell death. Folate Receptor-specific intracellular delivery of the rev-caspase-3 gene into KB cells over-expressing Folate Receptors was explored by employing the Folate–poly(ethylene glycol)–polyethylenimine (FOL–PEG–PEI) conjugate as a nonviral polymeric carrier. Using luciferase as a reporter gene, the conditions for formulation of DNA/polymer polyplexes were pre-optimized to attain the highest Folate Receptor-mediated gene transfection efficiency. FOL–PEG–PEI conjugate complexed with rev-caspase-3 plasmid in an optimized condition gave rise to a great increase in expression and activation of exogenous rev-caspase-3 in KB cells when pretreated with doxorubicin. The synthesized conjugate exhibited higher transfection efficiency than other commercially available transfection agents due to a unique mechanism of Folate-Receptor mediated endocytic gene transfer. The transfected cells showed a significant extent of apoptosis by rev-caspase-3. This study suggests the potential of using Folate-Receptor-mediated delivery of rev-caspase-3 gene for inducing tumor cell death in a target-specific manner.

  • Folate Receptor targeted delivery of doxorubicin nano aggregates stabilized by doxorubicin peg Folate conjugate
    Journal of Controlled Release, 2004
    Co-Authors: Tae Gwan Park
    Abstract:

    Abstract For Folate-Receptor-targeted anti-cancer therapy, doxorubicin aggregates in a nano-scale size were produced employing doxorubicin–polyethylene glycol–Folate (DOX–PEG–FOL) conjugate. Doxorubicin and Folate were respectively conjugated to α- and ω-terminal end group of a PEG chain. The conjugates assisted to form doxorubicin nano-aggregates with an average size of 200 nm in diameter when combined with an excess amount of deprotonated doxorubicin in an aqueous phase. Hydrophobically deprotonated doxorubicin molecules were aggregated within the core, while the DOX–PEG–FOL conjugates stabilized the aggregates with exposing Folate moieties on the surface. The doxorubicin nano-aggregates showed a greater extent of intracellular uptake against Folate-Receptor-positive cancer cells than Folate-Receptor-negative cells, indicating that the cellular uptake occurred via a Folate-Receptor-mediated endocytosis mechanism. They also exhibited more potent cytotoxic effect on KB cells than free doxorubicin. In a human tumor xenograft nude mouse model, Folate-targeted doxorubicin nano-aggregates significantly reduced the tumor volume compared to non-targeted doxorubicin aggregates or free doxorubicin. These results suggested that Folate-targeted doxorubicin nano-aggregates could be a potentially useful delivery system for Folate-Receptor-positive cancer cells.

  • Folate-Receptor-targeted delivery of doxorubicin nano-aggregates stabilized by doxorubicin-PEG-Folate conjugate.
    Journal of controlled release : official journal of the Controlled Release Society, 2004
    Co-Authors: Hyuk Sang Yoo, Tae Gwan Park
    Abstract:

    For Folate-Receptor-targeted anti-cancer therapy, doxorubicin aggregates in a nano-scale size were produced employing doxorubicin-polyethylene glycol-Folate (DOX-PEG-FOL) conjugate. Doxorubicin and Folate were respectively conjugated to alpha- and omega-terminal end group of a PEG chain. The conjugates assisted to form doxorubicin nano-aggregates with an average size of 200 nm in diameter when combined with an excess amount of deprotonated doxorubicin in an aqueous phase. Hydrophobically deprotonated doxorubicin molecules were aggregated within the core, while the DOX-PEG-FOL conjugates stabilized the aggregates with exposing Folate moieties on the surface. The doxorubicin nano-aggregates showed a greater extent of intracellular uptake against Folate-Receptor-positive cancer cells than Folate-Receptor-negative cells, indicating that the cellular uptake occurred via a Folate-Receptor-mediated endocytosis mechanism. They also exhibited more potent cytotoxic effect on KB cells than free doxorubicin. In a human tumor xenograft nude mouse model, Folate-targeted doxorubicin nano-aggregates significantly reduced the tumor volume compared to non-targeted doxorubicin aggregates or free doxorubicin. These results suggested that Folate-targeted doxorubicin nano-aggregates could be a potentially useful delivery system for Folate-Receptor-positive cancer cells.

  • Folate Receptor targeted biodegradable polymeric doxorubicin micelles
    Journal of Controlled Release, 2004
    Co-Authors: Hyuk Sang Yoo, Tae Gwan Park
    Abstract:

    Biodegradable polymeric micelles, self-assembled from a di-block copolymer of poly(D,L-lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG), were prepared to achieve Folate Receptor targeted delivery of doxorubicin (DOX). In the di-block copolymer structure of PLGA-b-PEG, DOX was chemically conjugated to a terminal end of PLGA to produce DOX-PLGA-mPEG, and Folate was separately conjugated to a terminal end of PEG to produce PLGA-PEG-FOL. The two di-block copolymers with different functional moieties at their chains ends were physically mixed with free base DOX in an aqueous solution to form mixed micelles. It was expected that Folate moieties were exposed on the micellar surface, while DOX was physically and chemically entrapped in the core of micelles. Flow cytometry and confocal image analysis revealed that Folate conjugated mixed micelles exhibited far greater extent of cellular uptake than Folate unconjugated micelles against KB cells over-expressing Folate Receptors on the surface. They also showed higher cytotoxicity than DOX, suggesting that Folate Receptor medicated endocytosis of the micelles played an important role in transporting an increased amount of DOX within cells. In vivo animal experiments, using a nude mice xenograft model, demonstrated that when systemically administered, tumor volume was significantly regressed. Biodistribution studies also indicated that an increased amount of DOX was accumulated in the tumor tissue.

Robert J. Lee - One of the best experts on this subject based on the ideXlab platform.

  • Folate Receptor targeted lipid albumin nanoparticles f lan for therapeutic delivery of an akt1 antisense oligonucleotide
    Journal of Drug Targeting, 2018
    Co-Authors: Yang Liu, Lihua Chen, Qibing Liu, Xinwei Cheng, Young B Lee, Changho Ahn, Deog Joong Kim, Robert J. Lee
    Abstract:

    Background: RX-0201 is an antisense oligonucleotide (ASO) against Akt1 currently in clinical trial for metastatic renal cancer.Purpose: To improve the delivery of RX-0201 using Folate Receptor-targ...

  • a Folate Receptor targeted liposomal formulation for paclitaxel
    International Journal of Pharmaceutics, 2006
    Co-Authors: Qing Liu, Robert J. Lee
    Abstract:

    A novel liposomal formulation of paclitaxel targeting the Folate Receptor (FR) was synthesized and characterized. This formulation was designed to overcome vehicle toxicity associated with the traditional Cremophor EL-based formulation and to provide the added advantages of prolonged systemic circulation time and selective targeting of the FR, which is frequently overexpressed on epithelial cancer cells. The formulation had the composition of dipalmitoyl phosphatidylcholine/dimyristoyl phosphatidylglycerol/monomethoxy-polyethylene glycol (PEG)2000-distearoyl phosphatidylethanolamine/Folate-PEG3350-distearoyl phosphatidylethanolamine (DPPC/DMPG/mPEG-DSPE/Folate-PEG-DSPE) at molar ratios of (85.5:9.5:4.5:0.5) and a drug-to-lipid molar ratio of 1:33. The liposomes were prepared by polycarbonate membrane extrusion. The mean particle size of the liposomes was 97.1 nm and remained stable for at least 72 h at 4 degrees C. FR-targeted liposomes of the same lipid composition entrapping calcein were shown to be efficiently taken up by KB oral carcinoma cells, which are highly FR+. FR-targeted liposomes containing paclitaxel showed 3.8-fold greater cytotoxicity compared to non-targeted control liposomes in KB cells. Plasma clearance profiles of paclitaxel in the liposomal formulations were then compared to paclitaxel in Cremophor EL formulation. The liposomal formulations showed much longer terminal half-lives (12.33 and 14.23 h for FR-targeted and non-targeted liposomes, respectively) than paclitaxel in Cremophor EL (1.78 h). In conclusion, the paclitaxel formulation described in this study has substantial stability and favorable pharmacokinetic properties. The FR-targeted paclitaxel formulation is potentially useful for treatment of FR+ tumors and warrants further investigation.

  • a Folate Receptor targeted lipid nanoparticle formulation for a lipophilic paclitaxel prodrug
    Pharmaceutical Research, 2004
    Co-Authors: Phillip J Stevens, Masaru Sekido, Robert J. Lee
    Abstract:

    Purpose. The anticancer drug paclitaxel has poor aqueous solubility and is difficult to formulate in a lipid-based formulation due to its limited lipid solubility. Paclitaxel-7-carbonyl-cholesterol (Tax-Chol), a prodrug of paclitaxel with increased lipophilicity, was therefore synthesized and evaluated for incorporation into a lipid nanoparticle (LN) formulation, which also contained Folate-polyethylene glycol-cholesterol (f-PEG-Chol) as a ligand that targets the tumor marker Folate Receptor (FR). This novel formulation was designed for prolonged systemic circulation and selective targeting of tumor cells with amplified FR expression.

  • synthesis and biological evaluation of Folate Receptor targeted boronated pamam dendrimers as potential agents for neutron capture therapy
    Bioconjugate Chemistry, 2003
    Co-Authors: Supriya Shukla, Robert J. Lee, Madhumita Chatterjee, Weilian Yang, Masaru Sekido, Lamine A Diop, Rainer Muller, Jennifer J Sudimack, Rolf F Barth, Werner Tjarks
    Abstract:

    Successful treatment of cancer by boron neutron capture therapy (BNCT) requires the selective delivery of 10B to constituent cells within a tumor. The expression of the Folate Receptor is amplified in a variety of human tumors and potentially might serve as a molecular target for BNCT. In the present study we have investigated the possibility of targeting the Folate Receptor on cancer cells using folic acid conjugates of boronated poly(ethylene glycol) (PEG) containing 3rd generation polyamidoamine dendrimers to obtain 10B concentrations necessary for BNCT by reducing the uptake of these conjugates by the reticuloendothelial system. First we covalently attached 12−15 decaborate clusters to 3rd generation polyamidoamine dendrimers. Varying quantities of PEG units with varying chain lengths were then linked to these boronated dendrimers to reduce hepatic uptake. Among all prepared combinations, boronated dendrimers with 1−1.5 PEG2000 units exhibited the lowest hepatic uptake in C57BL/6 mice (7.2−7.7% inject...

  • targeted drug delivery via the Folate Receptor
    Advanced Drug Delivery Reviews, 2000
    Co-Authors: Jennifer J Sudimack, Robert J. Lee
    Abstract:

    The Folate Receptor is a highly selective tumor marker overexpressed in greater than 90% of ovarian carcinomas. Two general strategies have been developed for the targeted delivery of drugs to Folate Receptor-positive tumor cells: by coupling to a monoclonal antibody against the Receptor and by coupling to a high affinity ligand, folic acid. First, antibodies against the Folate Receptor, including their fragments and derivatives, have been evaluated for tumor imaging and immunotherapy clinically and have shown significant targeting efficacy in ovarian cancer patients. Folic acid, a high affinity ligand of the Folate Receptor, retains its Receptor binding properties when derivatized via its γ-carboxyl. Folate conjugation, therefore, presents an alternative method of targeting the Folate Receptor. This second strategy has been successfully applied in vitro for the Receptor-specific delivery of protein toxins, anti-T-cell Receptor antibodies, interleukin-2, chemotherapy agents, γ-emitting radiopharmaceuticals, magnetic resonance imaging contrast agents, liposomal drug carriers, and gene transfer vectors. Low molecular weight radiopharmaceuticals based on Folate conjugates showed much more favorable pharmacokinetic properties than radiolabeled antibodies and greater tumor selectivity in Folate Receptor-positive animal tumor models. The small size, convenient availability, simple conjugation chemistry, and presumed lack of immunogenicity of folic acid make it an ideal ligand for targeted delivery to tumors.

Xiaoxia Chen - One of the best experts on this subject based on the ideXlab platform.