Online citations, reference lists, and bibliographies.
← Back to Search

Enhanced Permeability And Retention Of Macromolecular Drugs In Solid Tumors: A Royal Gate For Targeted Anticancer Nanomedicines

K. Greish
Published 2007 · Medicine

Cite This
Download PDF
Analyze on Scholarcy
Over the past two decades cancer has ascended the causes of human death to be number one or two in many nations world wide. A major limitation inherent to most conventional anticancer chemotherapeutic agents is their lack of tumor selectivity. One way to achieve selective drug targeting to solid tumors is to exploit abnormalities of tumor vasculature, namely, hypervascularisation; aberrant vascular architecture; extensive production of vascular permeability factors stimulating extravasation within tumor tissues; and lack of lymphatic drainage. Maeda and his colleagues have extensively studied tumor vascular abnormalities in terms of active and selective delivery of anticancer drugs to tumor tissues, notably defining the enhanced permeability and retention effect (EPR effect) of macromolecular drugs in solid tumors. Due to their large molecular size, nanosized macromolecular anticancer drugs administered intravenously (i.v.) escape renal clearance. Often they can not penetrate the tight endothelial junctions of normal blood vessels, but they can extravasate in tumour vasculature and become trapped in the tumor vicinity. With time the tumor concentration will build up reaching several folds higher than that of the plasma due to lack of efficient lymphatic drainage in solid tumor; an ideal application for EPR-based selective anticancer drug delivery. Establishing this principle hastened development of various polymer conjugates and polymeric micelles as well as multifunctional nanoparticles for targeted cancer chemotherapy. Indeed this selective high local concentration of nanosized anticancer drugs in tumor tissues has proven superior in therapeutic effect with minimal side effects in both preclinical and clinical settings. In this review the mechanisms and factors involved in the EPR effect, as well as the uniqueness of nanoscale drugs for tumor targeting through EPR effect, will be discussed in detail.
This paper references
Kinin‐generating Cascade in Advanced Cancer Patients and in vitro Study
Yasuhiro Matsumura (1991)
Bifidobacterium longum as a delivery system for cancer gene therapy: Selective localization and growth in hypoxic tumors
K. Yazawa (2000)
Tumoritropic and lymphotropic principles of macromolecular drugs.
H. Maeda (1989)
Combination of interferonbeta and the angiotensin-converting enzyme inhibitor, perindopril, attenuates murine hepatocellular carcinoma development
R Noguchi (2003)
Tumor-targeted delivery of polyethylene glycol-conjugated D-amino acid oxidase for antitumor therapy via enzymatic generation of hydrogen peroxide.
J. Fang (2002)
Angiogenesis in cancer, vascular, rheumatoid and other disease
J. Folkman (1995)
A lipophilic derivative of neocarzinostatin. A polymer conjugation of an antitumor protein antibiotic.
Hiroshi Maeda (1979)
Antitumor Effects due to Irreversible Stoppage of Tumor Tissue Blood Flow: Evaluation of a Novel Combretastatin A‐4 Derivative, AC7700
K. Hori (1999)
Activation of Matrix Metalloproteinases by Peroxynitrite-induced Protein S-Glutathiolation via Disulfide S-Oxide Formation*
T. Okamoto (2001)
Openings between defective endothelial cells explain tumor vessel leakiness.
H. Hashizume (2000)
Biphasic effect of hydrogen peroxide on skeletal muscle arteriolar tone via activation of endothelial and smooth muscle signaling pathways.
C. Csekő (2004)
Vascular permeability enhancement in solid tumor: various factors, mechanisms involved and its implications.
H. Maeda (2003)
Enhanced Vascular Permeability in Solid Tumor Involving Peroxynitrite and Matrix Metalloproteinases
J. Wu (2001)
A new approach to cancer chemotherapy: selective enhancement of tumor blood flow with angiotensin II.
M. Suzuki (1981)
Polyethylene glycol-coated (pegylated) liposomal doxorubicin. Rationale for use in solid tumours.
A. Gabizon (1997)
Improvement of Pharmacological Properties of Protein-Drugs by Tailoring with Synthetic Polymers
H. Maeda (1988)
Experimental studies on the spread of cancer in the lymphatic system. II. Absence of a lymphatic supply in carcinoma
I. Zeidman (1955)
Quantum dots spectrally distinguish multiple species within the tumor milieu in vivo
M. Stroh (2005)
Water soluble polymers in tumor targeted delivery.
J. Kopeček (2001)
Cancer selective macromolecular therapeutics: Tailoring of an antitumor protein drug
H Maeda (1986)
Reactive oxygen species signaling through regulation of protein tyrosine phosphorylation in endothelial cells.
V. Natarajan (1998)
Tumor‐selective Blood Flow Decrease Induced by an Angiotensin Converting Enzyme Inhibitor, Temocapril Hydrochloride
K. Hori (2000)
Biocompatibility of N-(2-hydroxypropyl) methacrylamide copolymers containing adriamycin. Immunogenicity, and effect on haematopoietic stem cells in bone marrow in vivo and mouse splenocytes and human peripheral blood lymphocytes in vitro.
B. Říhová (1989)
Targeting chemotherapy for hepatoma: arterial administration of anticancer drugs dissolved in Lipiodol.
T. Konno (1992)
Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation.
A. Leu (2000)
Combination of interferon-beta and the angiotensin-converting enzyme inhibitor, perindopril, attenuates murine hepatocellular carcinoma development and angiogenesis.
R. Noguchi (2003)
Antiproliferative efficacy of angiotensin II receptor blockers in prostate cancer.
H. Uemura (2005)
Macromolecular therapeutics: advantages and prospects with special emphasis on solid tumour targeting.
K. Greish (2003)
Purification and identification of [hydroxyprolyl3]bradykinin in ascitic fluid from a patient with gastric cancer.
H. Maeda (1988)
Changes in the microvascular architecture of colorectal liver metastases following the administration of SMANCS/lipiodol.
D. Kuruppu (2002)
Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid.
D. Senger (1983)
High-loading nanosized micelles of copoly(styrene-maleic acid)-zinc protoporphyrin for targeted delivery of a potent heme oxygenase inhibitor.
A. Iyer (2007)
The mechanism of acute hypoxic pulmonary vasoconstriction: the tale of two channels
E. Weir (1995)
Hydrogen peroxide activation of cytosolic phospholipase A2 in vascular smooth muscle cells.
G. N. Rao (1995)
The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting.
H. Maeda (2001)
Photodynamic therapy.
T. Dougherty (1993)
Involvement of the Kinin‐generating Cascade in Enhanced Vascular Permeability in Tumor Tissue
Yasuhiro Matsumura (1988)
Fluctuations in Tumor Blood Flow under Normotension and the Effect of Angiotensin II‐induced Hypertension
K. Hori (1991)
Polymer conjugates for tumor targeting and interacytoplasmic delivery. The EPR effect as a common gateaway
R Duncan (1999)
Early Phase Tumor Accumulation of Macromolecules: A Great Difference in Clearance Rate between Tumor and Normal Tissues
Youichiro Noguchi (1998)
Copoly(styrene-maleic acid)-pirarubicin micelles: high tumor-targeting efficiency with little toxicity.
K. Greish (2005)
Vascular effects of photodynamic therapy.
V. Fingar (1996)
Modulation of Tumor-selective Vascular Blood Flow and Extravasation by the Stable Prostaglandin I2 Analogue Beraprost Sodium
S. Tanaka (2003)
Binding to and internalization by cultured cells of neocarzinostatin and enhancement of its actions by conjugation with lipophilic styrene-maleic acid copolymer.
T. Oda (1987)
Why we're losing the war on cancer (and how to win it).
C. Leaf (2004)
Transplacental carcinogenesis by stilbestrol.
J. Folkman (1971)
Bradykinin and nitric oxide in infectious disease and cancer.
H. Maeda (1996)
Enhanced Vascular Permeability in Solid Tumor Is Mediated by Nitric Oxide and Inhibited by Both New Nitric Oxide Scavenger and Nitric Oxide Synthase Inhibitor
H. Maeda (1994)
Selective targeting of anti‐cancer drug and simultaneous image enhancement in solid tumors by arterially administered lipid contrast medium
T. Konno (1984)
[Tumor selective drug delivery with lipid contrast medium (smancs/lipiodol): sustained antitumor effect, enhanced diagnostic value and quantification of dosage regimen].
H. Maeda (1984)
Modulation of enhanced vascular permeability in tumors by a bradykinin antagonist, a cyclooxygenase inhibitor, and a nitric oxide scavenger.
J. Wu (1998)
Hydrogen peroxide-induced endothelium-dependent
Z. Yang (1999)
Comparison of IgG diffusion and extracellular matrix composition in rhabdomyosarcomas grown in mice versus in vitro as spheroids reveals the role of host stromal cells
C. Davies (2002)
The Influence of Cytotoxicity of Macromolecules and of VEGF Gene Modulated Vascular Permeability on the Enhanced Permeability and Retention Effect in Resistant Solid Tumors
T. Minko (2004)
Fluctuation in tumor blood flow under normotension and the effect of angiotensin-II induced hypertension
K Hori (1991)
Tumor angiogenesis in cancer, Therapeutic implications
J. Folkman (1971)
On the constancy of the systolic output under varying conditions
J. Markwalder (1914)
SMANCS and polymer-conjugated macromolecular drugs: advantages in cancer chemotherapy.
H. Maeda (2001)
A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs.
Y. Matsumura (1986)
Kallikrein-kinin in infection and cancer.
H. Maeda (1999)
Tumor Vascular Permeabilization by Vascular-Targeting Photosensitization: Effects, Mechanism, and Therapeutic Implications
B. Chen (2006)
Mechanism of tumor-targeted delivery of macromolecular drugs, including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug SMANCS.
H. Maeda (2001)
SMA-doxorubicin, a new polymeric micellar drug for effective targeting to solid tumours.
K. Greish (2004)
Protein Binding of Macromolecular Anticancer Agent SMANCS: Characterization of Poly(styrene-co-maleic acid) Derivatives as an Albumin Binding Ligand
A. Kobayashi (1988)
The origin of lipoproteins in lymph
Courtice FC. (1963)
Determinants of tumor blood flow: a review.
R. Jain (1988)
Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size.
F. Yuan (1995)
Augmentation of tumour delivery of macromolecular drugs with reduced bone marrow delivery by elevating blood pressure.
C. J. Li (1993)
Pegylated Liposomal Doxorubicin: Metamorphosis of an Old Drug into a New Form of Chemotherapy
A. Gabizon (2001)
Recent advances in SMANCS/Lipiodol therapy-enhanced targeting and delivery efficacy using vascular modulators
A. Nagamitsu (2003)
Medial regression and its functional significance in tumor‐supplying host arteries. A morphometric study of hepatic arteries in human livers with hepatocellular carcinoma
M. Suzuki (1987)
A lipophilic derivative of neocarzinostatin
H Maeda (1979)
Microvascular architecture of experimental colon tumors in the rat.
S. Skinner (1990)
Tumor-targeted delivery of PEG-conjugated D-amino acid oxidase for antitumor therapy via enzymatic generation of hydrogen peroxide
J Fang (2002)
Polymer conjugates for tumor targeting and interacytoplasmic delivery
R. Duncan (1999)
Hydrogen peroxide-induced endothelium-dependent relaxation of rat aorta: Involvement of intracellular Ca2þ and other cellular metabolites
Yang Z-W (1999)
Polymer conjugates for tumour targeting and intracytoplasmic delivery. The EPR effect as a common gateway?
Duncan (1999)

This paper is referenced by
The role of carrier size in the pharmacodynamics of antisense and siRNA oligonucleotides
L. Huang (2010)
Characterization of drug delivery particles produced by supercritical carbon dioxide technologies
Onanong Nuchuchua (2017)
Novel pH-responsive nanovectors for controlled release of ionisable drugs.
F. Mastrotto (2013)
Drug delivery strategies for therapeutic angiogenesis and antiangiogenesis
Nupura S. Bhise (2011)
Functionalized mesoporous silica nanoparticle-based visible light responsive controlled release delivery system.
N. Knežević (2011)
Thermo‐Responsive Polymers
D. Raucher (2011)
Biodegradable Polymers Induce CD54 on THP-1 Cells in Skin Sensitization Test
Yeon Suk Jung (2011)
In vitro and in vivo efficacy of doxorubicin loaded biodegradable semi-interpenetrating hydrogel implants of poly (acrylic acid)/gelatin for post surgical tumor treatment.
Maneesh Jaiswal (2013)
Intracellular drug distribution-based targeting: Exploiting lysosomes to enhance the selectivity of drugs towards cancer cells
Rosemary A. Ndolo (2012)
In vivo enhancement of anticancer therapy using bare or chemotherapeutic drug-bearing nanodiamond particles
Y. Li (2014)
Quantitative determination of 64Cu-liposome accumulation at inflammatory and infectious sites: Potential for future theranostic system.
Anne Skovsbo Clausen (2020)
Aptamer-Mediated siRNA Targeting
J. Zhou (2013)
Enhanced Permeability and Retention ( EPR ) Effect Based Tumor Targeting : The Concept , Application and Prospect
H. Yin (2014)
Oligonucleotide-based theranostic nanoparticles in cancer therapy.
R. Shahbazi (2016)
Intraoperative 186Re-Liposome Radionuclide Therapy in a Head and Neck Squamous Cell Carcinoma Xenograft Positive Surgical Margin Model
S. X. Wang (2008)
Acid‐sensitive hybrid polymeric micelles containing a reversibly activatable cell‐penetrating peptide for tumor‐specific cytoplasm targeting
Baoqiang Tang (2018)
Gold nanoparticles: a paradigm shift in biomedical applications.
M. S. Khan (2013)
Biological applications of fluorescence lifetime imaging beyond microscopy
W. Akers (2010)
Strategies for the production of long-acting therapeutics and efficient drug delivery for cancer treatment.
Alanod D AlQahtani (2019)
Bismuth-based nanoparticles as theranostic agents for x-ray Computed Tomography (CT) and radiation therapy
M. Algethami (2018)
Intraperitoneal Chemotherapy For The Treatment Of Malignant Peritoneal Mesothelioma
B. Zhao (2017)
Magnetic nanoparticles: recent developments in drug delivery system
F. Xiong (2018)
Nutrient scavenging in cancer
Brendan T. Finicle (2018)
Molecular binding of self-assembling peptide EAK16-II with anticancer agent EPT and its implication in cancer cell inhibition.
S. Lu (2012)
A new method for the determination of total and released docetaxel from docetaxel‐entrapped core‐crosslinked polymeric micelles (CriPec®) by LC–MS/MS and its clinical application in plasma and tissues in patients with various tumours
C. L. Braal (2018)
Nanomaterials: applications in cancer imaging and therapy.
J. A. Barreto (2011)
Desarrollo in vitro de nuevas terapias dirigidas con nanopartículas para el tratamiento del cáncer de tiroides.
Flora María Gordillo Martínez (2014)
In vitro and in vivo Anticancer Activity of Nanosize Zinc Oxide Composites of Doxorubicin
E. R. Arakelova (2014)
Strategies for targeted nonviral delivery of siRNAs in vivo.
Sang-Soo Kim (2009)
Nanoparticle-Based Delivery of RNAi Therapeutics: Progress and Challenges
Jiehua Zhou (2013)
Augmenting the protein C pathway with endothelial targeted biotherapeutics: Strategies to promote partnering of TM and EPCR
C. Greineder (2014)
BODIPYs in antitumoral and antimicrobial photodynamic therapy: An integrating review
Maximiliano L Agazzi (2019)
See more
Semantic Scholar Logo Some data provided by SemanticScholar