The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting

Maeda, Hiroshi

doi:10.1016/s0065-2571(00)00013-3

Cited by 2,194 publications

(1,485 citation statements)

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“…The inferior target-independent in vivo effects of the control ADC at high doses are presumably due to enhanced permeability and retention (EPR) in solid tumors. This phenomenon of passive drug targeting of tumors has been widely described for macromolecules and lipids (45).…”

Section: Discussionmentioning

confidence: 97%

Anetumab Ravtansine: A Novel Mesothelin-Targeting Antibody–Drug Conjugate Cures Tumors with Heterogeneous Target Expression Favored by Bystander Effect

Golfier

Kopitz

Kahnert

et al. 2014

Molecular Cancer Therapeutics

199

166

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Mesothelin is a tumor differentiation antigen frequently overexpressed in tumors such as mesothelioma, ovarian, pancreatic, and lung adenocarcinomas while showing limited expression in nonmalignant tissues. Mesothelin is therefore an attractive target for cancer therapy using antibody-drug conjugates (ADC). This study describes the detailed characterization of anetumab ravtansine, here referred to as BAY 94-9343, a novel ADC consisting of a human anti-mesothelin antibody conjugated to the maytansinoid tubulin inhibitor DM4 via a disulfide-containing linker. Binding properties of the anti-mesothelin antibody were analyzed using surface plasmon resonance, immunohistochemistry, flow cytometry, and fluorescence microscopy. Effects of BAY 94-9343 on cell proliferation were first studied in vitro and subsequently in vivo using subcutaneous, orthotopic, and patient-derived xenograft tumor models. The antibody binds to human mesothelin with high affinity and selectivity, thereby inducing efficient antigen internalization. In vitro, BAY 94-9343 demonstrated potent and selective cytotoxicity of mesothelin-expressing cells with an IC 50 of 0.72 nmol/L, without affecting mesothelin-negative or nonproliferating cells. In vivo, BAY 94-9343 localized specifically to mesothelin-positive tumors and inhibited tumor growth in both subcutaneous and orthotopic xenograft models. In addition, BAY 94-9343 was able to induce a bystander effect on neighboring mesothelin-negative tumor cells. Antitumor efficacy of BAY 94-9343 correlated with the amount of mesothelin expressed and was generally superior to that of standard-of-care regimen resulting in complete tumor eradication in most of the models. BAY 94-9343 is a selective and highly potent ADC, and our data support its development for the treatment of patients with mesothelin-expressing tumors. Mol Cancer Ther; 13(6); 1537-48. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 97%

Anetumab Ravtansine: A Novel Mesothelin-Targeting Antibody–Drug Conjugate Cures Tumors with Heterogeneous Target Expression Favored by Bystander Effect

Golfier

Kopitz

Kahnert

et al. 2014

Molecular Cancer Therapeutics

199

166

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“…Vesicles larger than 200 nm accumulate in the spleen since their size does not allow them to pass through the walls of the venous sinuses in splenic red pulp tissue [2,17,18]. This has been clearly demonstrated with the PEG-coated [ 18 F]FDGlabeled liposomes; the vesicles smaller than 100 nm remained in the blood pool and were accumulated in the tumor tissue due to the enhanced permeability and retention effect [19,20]; conversely, liposomes larger then 200 nm accumulated in spleen and the liver [17]. It was also demonstrated that positively-charged liposomes are more likely to aggregate and become serum-bound compared with neutrally or negatively charged liposomes; and in vivo tests revealed that liver and spleen uptake was maximal in positively charged liposomes, while the neutral liposomes had minimal uptake [17].…”

mentioning

confidence: 99%

Long-circulating liposomes radiolabeled with [18F]fluorodipalmitin ([18F]FDP)

Mařı́k

Tartis

Zhang

et al. 2007

Nuclear Medicine and Biology

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Synthesis of a radiolabeled diglyceride 3-[ 18 F]fluorodipalmitoyl-1,2-glycerol ( 18 F-fluorodipalmitin, [ 18 F]FDP) and its potential as a reagent for radiolabeling long-circulating liposomes were investigated. The incorporation of 18 F into the lipid molecule was accomplished by nucleophilic substitution of p-toluenesolfonyl moiety with a decay corrected yield of 43 ± 10% (n = 12). Radiolabeled long-circulating PEG-coated liposomes were prepared using a mixture of DPPC, cholesterol, DSPE-PEG2000 (61:30:9) and [ 18 F]FDP with a decay corrected yield of 70 ± 8% (n = 4). PET imaging and biodistribution studies were performed with free [ 18 Liposomes are vesicles composed of one or more concentric phospholipid bi-layers and such vesicles have been widely investigated as possible drug carriers [1,2]. Prolonged blood circulation of the liposomes is achieved with the addition of a polyethylene glycol (PEG) coating, which efficiently minimizes their removal by macrophages of the reticuloendothelial system [3][4][5][6]. Liposomes with various target-specific ligands attached to their surface are being investigated for targeted drug delivery [1,2,7]. Liposomes labeled with radioisotopes such as 99m Tc, 186 Re, 67 Ga, 111 In, and 18 F were previously employed to study the biodistribution of different types of liposomes in various animal models using scintigraphy, SPECT and PET. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Materials and Methods GeneralThe solvents and chemicals were purchased from Aldrich (Milwaukee, WI). The 1 H and 13 C NMR spectra were recorded using a Bruker Avance 500 spectrometer and the chemical shifts are reported relative to TMS. Analytical reversed-phase HPLC was performed using a Phenomenex Jupiter 5μ C4 300A column ( . The size distribution of liposomes was determined using a particle size analyzer Nanotrac NPA150 purchased from Microtrac Inc. (North Largo, FL). The lipid concentration was determined using a Phospholipids B kit purchased from Wako Chemicals, Inc. (Richmond, VA). Synthesis of 3-tosyl-1,2-dipalmitoyl glycerol (2)The precursor 2 was prepared according to the previously published procedure [32] from 1,2-dipalmitoyl-sn-glycerol (1) and 4-toluenesulfonyl chloride. The crude product was subsequently purified by recrystalization from hexane. 1 mL). The content of the vial was dissolved in anhydrous acetonitrile (0.35 mL) and transferred into a suspension of 2 (5.5 mg) in anhydrous acetonitrile (0.5 mL). The reaction mixture was heated to 100 ºC for 20 minutes and allowed to cool to room temperature for 5 min...

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“…We attribute the observed photoacoustic imaging patterns to the leaky nature of the tumor vessels, which contain wide interendothelial junctions, an incomplete or absent basement membrane, and large numbers of transendothelial channels. 19,20 The photoacoustic images acquired with both the 3.5-and the 20-MHz transducers disclose the distorted vasculature associated with the tumorigenesis, but the two images present different characteristics. In the close-up image acquired with the 3.5-MHz transducer, the vessels exhibit solid, blurred contours, whereas in the close-up image acquired with the 20-MHz transducer the vessel contours are better delineated.…”

Section: Resultsmentioning

confidence: 99%

“…The increased density of tumor-bearing tissues is most likely due to a passive mechanism referred to as the enhanced permeability and retention effect. 2 In this paper, however, we focus solely on the optical contrast that is due to high hemoglobin absorption.…”

Section: Introductionmentioning

confidence: 99%

Imaging of tumor angiogenesis in rat brains in vivo by photoacoustic tomography

Ku¹,

Wang²,

Xie³

et al. 2005

Appl. Opt.

213

137

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Green laser pulses at a wavelength of 532 nm from a Q-switched Nd:YAG laser were employed as irradiation sources for photoacoustic tomography (PAT). The vascular structure of the brain was imaged clearly, with optimal contrast, because blood has strong absorption near this wavelength. The photoacoustic images of rat brain tumors in this study clearly reveal the angiogenesis that is associated with tumors. Brain tumors can be identified based on the distorted vascular architecture of brain tumorigenesis and related vascular changes, such as hemorrhage. This research demonstrates that PAT can potentially provide a powerful tool for small-animal biological research.

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The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting

Cited by 2,194 publications

References 43 publications

Anetumab Ravtansine: A Novel Mesothelin-Targeting Antibody–Drug Conjugate Cures Tumors with Heterogeneous Target Expression Favored by Bystander Effect

Anetumab Ravtansine: A Novel Mesothelin-Targeting Antibody–Drug Conjugate Cures Tumors with Heterogeneous Target Expression Favored by Bystander Effect

Long-circulating liposomes radiolabeled with [18F]fluorodipalmitin ([18F]FDP)

Imaging of tumor angiogenesis in rat brains in vivo by photoacoustic tomography

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