← Back to Search
Discovery And Development Of Folic-acid-based Receptor Targeting For Imaging And Therapy Of Cancer And Inflammatory Diseases.
P. Low, Walter A. Henne, Derek D. Doorneweerd
Published 2008 · Chemistry, Medicine
Download PDFAnalyze on Scholarcy
In order to avoid the toxicities associated with prescription drug use today, we have explored novel methods for delivering drugs selectively to pathologic cells, thereby avoiding the collateral damage that accompanies their uptake by healthy cells. In this Account, we describe our quest for the ideal targeted therapeutic agent. This effort began with a search for ligands that would bind selectively to pathologic cells, displaying no affinity for healthy cells. After identification of an optimal targeting ligand, effort was focused on construction of linkers that would carry the attached drug to pathologic cells with receptors for the selected ligand. In the case of cancer, we exploited the well-characterized up-regulation of folate receptors on malignant cells to target folate-linked pharmaceuticals to cancer tissues in vivo. Drugs that have been linked to folic acid for tumor-selective drug delivery to date include (i) protein toxins, (ii) chemotherapeutic agents, (iii) gene therapy vectors, (iv) oligonucleotides (including small interfering RNA (siRNA)), (v) radioimaging agents, (vi) magnetic resonance imaging (MRI) contrast agents, (vii) liposomes with entrapped drugs, (viii) radiotherapeutic agents, (ix) immunotherapeutic agents, and (x) enzyme constructs for prodrug therapy. Current clinical trials of four folate-linked drugs demonstrate that folate receptor-targeting holds great promise for increasing the potency while reducing toxicity of many cancer therapies. In the course of developing folate-conjugated drugs for cancer, we discovered that folate receptors are also overexpressed on activated (but not resting or quiescent) macrophages. Recognizing that activated macrophages either cause or contribute to such diseases as rheumatoid arthritis, Crohn's disease, atherosclerosis, lupus, inflammatory osteoarthritis, diabetes, ischemia reperfusion injury, glomerulonephritis, sarcoidosis, psoriasis, Sjogren's disease, and vasculitis, we initiated studies aimed at developing folate-conjugated imaging and therapeutic agents for the diagnosis and treatment of such diseases. In very brief time, significant progress has been made towards identification of clinical candidates for targeted treatment of several inflammatory and autoimmune diseases. This Account summarizes the discovery and development of a variety of folate-targeted drugs for the diagnosis and therapy of cancers and inflammatory/autoimmune diseases.
This paper references
Receptor-Mediated Endocytosis in Plant Cells.
M. Horn (1989)
Folate receptor specific anti-tumor activity of folate–mitomycin conjugates
J. Reddy (2005)
Cytotoxicity of momordin-folate conjugates in cultured human cells.
C. P. Leamon (1992)
Uptake and trafficking of fluorescent conjugates of folic acid in intact kidney determined using intravital two-photon microscopy.
R. Sandoval (2004)
Introduction — Morphology of the Liver Lobule
Z. Kmiec (2001)
Synthesis and activity of a folate peptide camptothecin prodrug.
Walter A. Henne (2006)
Selective expression of folate receptor beta and its possible role in methotrexate transport in synovial macrophages from patients with rheumatoid arthritis.
N. Nakashima-Matsushita (1999)
Evaluation of disulfide reduction during receptor-mediated endocytosis by using FRET imaging
J. Yang (2006)
Optical imaging of metastatic tumors using a folate-targeted fluorescent probe.
M. Kennedy (2003)
Inhibition of glycinamide ribonucleotide formyltransferase results in selective inhibition of macrophage cytokine secretion in vitro and in vivo efficacy in rat adjuvant arthritis.
S. Chintalacharuvu (2005)
Selective delivery of CB300638, a cyclopenta[g]quinazoline-based thymidylate synthase inhibitor into human tumor cell lines overexpressing the alpha-isoform of the folate receptor.
D. Theti (2003)
Celecoxib, a selective cyclooxygenase-2 inhibitor for the treatment of rheumatoid arthritis and osteoarthritis.
M. Goldenberg (1999)
Characterization of parameters influencing receptor-mediated endocytosis in cultured soybean cells.
M. Horn (1992)
Delivery of antisense oligodeoxyribonucleotides against the human epidermal growth factor receptor into cultured KB cells with liposomes conjugated to folate via polyethylene glycol.
S. Wang (1995)
Macrophages in rheumatoid arthritis
R. Kinne (2000)
Riboflavin-Enhanced Transport of Serum Albumin Across the Distal Pulmonary Epithelium
O. Wangensteen (2004)
LY309887, antifolate via the folate receptor suppresses murine type II collagen-induced arthritis.
R. Nagayoshi (2003)
Cloning of a tumor-associated antigen: MOv18 and MOv19 antibodies recognize a folate-binding protein.
L. Coney (1991)
Antifolates targeted specifically to the folate receptor.
A. Jackman (2004)
Synthesis and preclinical evaluation of a folic acid derivative labeled with 18F for PET imaging of folate receptor-positive tumors.
Andrea Bettio (2006)
Design and synthesis of [111In]DTPA-folate for use as a tumor-targeted radiopharmaceutical.
S. Wang (1997)
Folate receptor-targeted drugs for cancer and inflammatory diseases.
P. Low (2004)
Characterization of the pH of Folate Receptor-Containing Endosomes and the Rate of Hydrolysis of Internalized Acid-Labile Folate-Drug Conjugates
J. Yang (2007)
Synthesis of [(99m)Tc]DTPA-folate and its evaluation as a folate-receptor-targeted radiopharmaceutical.
C. Mathias (2000)
Enhanced folate receptor mediated gene therapy using a novel pH-sensitive lipid formulation.
J. Reddy (2000)
Folate targeting of haptens to cancer cell surfaces mediates immunotherapy of syngeneic murine tumors
Y. Lu (2002)
Synthesis and biological evaluation of EC72: a new folate-targeted chemotherapeutic.
C. P. Leamon (2005)
Measurement of endosome pH following folate receptor-mediated endocytosis.
R. Lee (1996)
Synthesis and evaluation of 99mTc(CO)(3)-DTPA-folate as a folate-receptor-targeted radiopharmaceutical.
David P Trump (2002)
Preparation of 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate as potential folate-receptor-targeted PET radiopharmaceuticals.
C. Mathias (2003)
Folate receptor-mediated targeting of therapeutic and imaging agents to activated macrophages in rheumatoid arthritis.
Chrystal M. Paulos (2004)
Diplasmenylcholine−Folate Liposomes: An Efficient Vehicle for Intracellular Drug Delivery†
Y. Rui (1998)
A Review of the Use of Infliximab to Manage Cutaneous Dermatoses
A. Gupta (2004)
Folate-mediated tumor cell targeting of liposome-entrapped doxorubicin in vitro.
R. Lee (1995)
Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues.
S. Weitman (1992)
Folate-targeted immunotherapy effectively treats established adjuvant and collagen-induced arthritis
Chrystal M. Paulos (2006)
Role of interleukin 1 and interleukin 1 receptor antagonist in the mediation of rheumatoid arthritis
M. Schiff (2000)
Design and regioselective synthesis of a new generation of targeted chemotherapeutics. Part 1: EC145, a folic acid conjugate of desacetylvinblastine monohydrazide.
I. Vlahov (2006)
Receptor-mediated folate accumulation is regulated by the cellular folate content.
B. Kamen (1986)
Indium-111-DTPA-folate as a potential folate-receptor-targeted radiopharmaceutical.
C. Mathias (1998)
Folate-binding protein is a marker for ovarian cancer.
I. Campbell (1991)
The folate receptor: What does it promise in tissue-targeted therapeutics?
M. D. Salazar (2007)
Ligand Binding and Kinetics of Folate Receptor Recycling in Vivo: Impact on Receptor-Mediated Drug Delivery
Chrystal M. Paulos (2004)
Optimization of folate-conjugated liposomal vectors for folate receptor-mediated gene therapy.
J. Reddy (1999)
The Effects of pH and Intraliposomal Buffer Strength on the Rate of Liposome Content Release and Intracellular Drug Delivery
R. Lee (1998)
Delivery of macromolecules into living cells: a method that exploits folate receptor endocytosis.
C. P. Leamon (1991)
Folate-conjugated liposomes preferentially target macrophages associated with ovarian carcinoma.
M. Turk (2004)
Folate-targeted imaging of activated macrophages in rats with adjuvant-induced arthritis.
M. Turk (2002)
Synthesis and Biological Evaluation of EC20: A New Folate-Derived, 99mTc-Based Radiopharmaceutical
C. P. Leamon (2002)
Targeting folate receptor with folate linked to extremities of poly(ethylene glycol)-grafted liposomes: in vitro studies.
A. Gabizon (1999)
BGC 945, a novel tumor-selective thymidylate synthase inhibitor targeted to alpha-folate receptor-overexpressing tumors.
David D. Gibbs (2005)
Studies of the role of a particulate folate-binding protein in the uptake of 5-methyltetrahydrofolate by cultured human KB cells.
A. Antony (1985)
Cytotoxicity of folate-Pseudomonas exotoxin conjugates toward tumor cells. Contribution of translocation domain.
C. P. Leamon (1993)
Characterization of a novel pH-sensitive peptide that enhances drug release from folate-targeted liposomes at endosomal pHs.
M. Turk (2002)
Synthesis and biological evaluation of EC140: a novel folate-targeted vinca alkaloid conjugate.
C. P. Leamon (2006)
Receptor-mediated targeting of 67Ga-deferoxamine-folate to folate-receptor-positive human KB tumor xenografts.
C. Mathias (1999)
Delivery of liposomes into cultured KB cells via folate receptor-mediated endocytosis.
R. Lee (1994)
Endocytosis of folate-protein conjugates: ultrastructural localization in KB cells.
J. Turek (1993)
Synthesis and evaluation of taxol-folic acid conjugates as targeted antineoplastics.
J. Lee (2002)
Membrane folate-binding proteins are responsible for folate-protein conjugate endocytosis into cultured cells.
C. P. Leamon (1993)
This paper is referenced by
Synthesis and evaluation of methionine and folate co-decorated chitosan self-assembly polymeric micelles as a potential hydrophobic drug-delivery system
Yuqi Chen (2013)
Bifunctional agents for imaging and therapy.
R. Pandey (2010)
Hormonal Control of Folate Receptor Genes
M. Gonit (2011)
Selective Delivery of an Anticancer Drug with Aptamer-Functionalized Liposomes to Breast Cancer Cells in Vitro and in Vivo.
Hang Xing (2013)
Folate-targeted docetaxel-lipid-based-nanosuspensions for active-targeted cancer therapy
Lili Wang (2012)
Strategies for photoluminescence enhancement of AgInS2 quantum dots and their application as bioimaging probes
Jia-Yaw Chang (2012)
Spontaneous ultra fast synthesis of gold nanoparticles using Punica granatum for cancer targeted drug delivery.
M. Ganeshkumar (2013)
A folate receptor beta-specific human monoclonal antibody recognizes activated macrophage of rheumatoid patients and mediates antibody-dependent cell-mediated cytotoxicity
Y. Feng (2011)
Effects of surface modifications on the physicochemical properties of iron oxide nanoparticles and their performance as anticancer drug carriers
Lingling Guo (2018)
Potential of targeted drug delivery systems in treatment of rheumatoid arthritis
A. Syed (2019)
Dendrimers as macromolecular tools to tackle from colon to brain tumor types: a concise overview
S. Mignani (2013)
Folate mediated in vitro targeting of depolymerised trimethylated chitosan having arginine functionality.
V. B. Morris (2010)
Liposomes and Polymers in Folate-Targeted Cancer Therapeutics
A. Gabizon (2011)
Degradation of BMS-753493, a novel epothilone folate conjugate anticancer agent
Madhushree Gokhale (2013)
Engineered viral nanoparticles for flow cytometry and fluorescence microscopy applications.
K. Robertson (2012)
Engineering and Study of Biocompatible Nanoceramics
K. Bogusz (2018)
Targeted delivery of photoactive diazido PtIV complexes conjugated with fluorescent carbon dots
X. Yang (2015)
Potential Application of Oleylamine-encapsulated AgInS2-ZnS Quantum Dots for Cancer Cell Labeling
M. Fahmi (2016)
A Targeting Membrane Injury Strategy via Calcification for the Inhibition of Leukemia Cells
L. Zhu (2019)
Photocaged prodrug under NIR light-triggering with dual-channel fluorescence: in vivo real-time tracking for precise drug delivery
Zhiqian Guo (2018)
Multifunctional Surface Modification: Facile and Flexible Reactivity toward a Precisely Controlled Biointerface.
Ruei-Hung Yuan (2017)
FK506 protects against articular cartilage collagenous extra-cellular matrix degradation.
M. Siebelt (2014)
DOTA Conjugate with an Albumin-Binding Entity Enables the First Folic Acid–Targeted 177Lu-Radionuclide Tumor Therapy in Mice
C. Müller (2013)
Platinum folate nanoparticles toxicity: cancer vs. normal cells.
T. Mironava (2013)
Bioconjugated Pluronic Triblock-Copolymer Micelle-Encapsulated Quantum Dots for Targeted Imaging of Cancer: In Vitro and In Vivo Studies
L. Liu (2012)
Enhanced loading of doxorubicin into polymeric micelles by a combination of ionic bonding and hydrophobic effect, and the pH-sensitive and ligand-mediated delivery of loaded drug
Z. Xu (2013)
Targeting specific membranes with an azide derivative of the pore-forming peptide ceratotoxin A.
S. F. Mayer (2019)
Photocontrolled Release of Doxorubicin Conjugated through a Thioacetal Photocage in Folate-Targeted Nanodelivery Systems.
Pamela T Wong (2017)
Folate receptor-targeted novel boron compound for boron neutron capture therapy on F98 glioma-bearing rats
T. Kanemitsu (2019)
Fluoride as an inducible DNA cross-linking agent for new antitumor prodrug.
J. Wu (2013)
Polymer Nanoparticles: Newer Strategies towards Targeted Cancer
Ajay Vidyasagar (2013)
Targeted MRI Contrast Agents
P. Caravan (2013)See more