scholarly journals Nanodrug Delivery Systems Modulate Tumor Vessels to Increase the Enhanced Permeability and Retention Effect

2021 ◽  
Vol 11 (2) ◽  
pp. 124
Author(s):  
Dong Huang ◽  
Lingna Sun ◽  
Leaf Huang ◽  
Yanzuo Chen
Keyword(s):  
Blood Vessels ◽  
Tumor Vessels ◽  
Epr Effect ◽  
Nanodrug Delivery ◽  
Enhanced Permeability And Retention ◽  
Macromolecular Drugs ◽  
Long Time ◽  
Vessel Network ◽  
Tumor Blood Vessels ◽  
The Relationship

The use of nanomedicine for antitumor therapy has been extensively investigated for a long time. Enhanced permeability and retention (EPR) effect-mediated drug delivery is currently regarded as an effective way to bring drugs to tumors, especially macromolecular drugs and drug-loaded pharmaceutical nanocarriers. However, a disordered vessel network, and occluded or embolized tumor blood vessels seriously limit the EPR effect. To augment the EPR effect and improve curative effects, in this review, we focused on the perspective of tumor blood vessels, and analyzed the relationship among abnormal angiogenesis, abnormal vascular structure, irregular blood flow, extensive permeability of tumor vessels, and the EPR effect. In this commentary, nanoparticles including liposomes, micelles, and polymers extravasate through the tumor vasculature, which are based on modulating tumor vessels, to increase the EPR effect, thereby increasing their therapeutic effect.

scholarly journals Three-dimensional relationships between tumor cells and microcirculation with double cyanine immunolabeling, laser scanning confocal microscopy, and computer-assisted reconstruction: an alternative to cast corrosion preparations.

1994 ◽  
Vol 42 (5) ◽  
pp. 681-686 ◽  
Author(s):  
V Rummelt ◽  
L M Gardner ◽  
R Folberg ◽  
S Beck ◽  
B Knosp ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Scanning Electron Microscopy ◽  
Blood Vessels ◽  
Tumor Cells ◽  
Laser Scanning ◽  
Three Dimensional ◽  
Melanoma Cells ◽  
Tumor Blood Vessels ◽  
The Relationship ◽  
Scanning Electron

The morphology of the microcirculation of uveal melanomas is a reliable market of tumor progression. Scanning electron microscopy of cast corrosion preparations can generate three-dimensional views of these vascular patterns, but this technique sacrifices the tumor parenchyma. Formalin-fixed wet tissue sections 100-150 microns thick from uveal melanomas were stained with the lectin Ulex europaeus agglutinin I (UEAI) and proliferating cell nuclear antigen (PCNA) to demonstrate simultaneously the tumor blood vessels and proliferating tumor cells. Indocarbocyanine (Cy3) was used as a fluorophore for UEAI and indodicarbocyanine (Cy5) was used for PCNA. Double labeled sections were examined with a laser scanning confocal microscope. Images of both stains were digitized at the same 5-microns intervals and each of the two images per interval was combined digitally to form one image. These combined images were visualized through voxel processing to study the relationship between melanoma cells expressing PCNA and various microcirculatory patterns. This technique produces images comparable to scanning electron microscopy of cast corrosion preparations while permitting simultaneous localization of melanoma cells expressing PCNA. The microcirculatory tree can be viewed from any perspective and the relationship between tumor cells and the tumor blood vessels can be studied concurrently in three dimensions. This technique is an alternative to cast corrosion preparations.

scholarly journals Enhanced nanodrug delivery in tumors after near-infrared photoimmunotherapy

Nanophotonics ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1673-1688 ◽  
Author(s):  
Fuyuki F. Inagaki ◽  
Aki Furusawa ◽  
Peter L. Choyke ◽  
Hisataka Kobayashi
Keyword(s):  
Near Infrared ◽  
Small Molecular Weight ◽  
Small Magnitude ◽  
Epr Effect ◽  
Nanodrug Delivery ◽  
Enhanced Permeability And Retention ◽  
Naturally Occurring ◽  
Limited Success ◽  
Effective Manner ◽  
Promising Avenue

AbstractTo date, the delivery of nanosized therapeutic agents to cancers largely relies on the enhanced permeability and retention (EPR) effects that are caused by the leaky nature of cancer vasculature. Whereas leaky vessels are often found in mouse xenografts, nanosized agents have demonstrated limited success in humans due to the relatively small magnitude of the EPR effect in naturally occurring cancers. To achieve the superior delivery of nanosized agents, alternate methods of increasing permeability and retention are needed. Near-infrared photoimmunotherapy (NIR-PIT) is a recently reported therapy that relies on an antibody-photon absorber conjugate that binds to tumors and then is activated by light. NIR-PIT causes an increase in nanodrug delivery by up to 24-fold compared to untreated tumors in which only the EPR effect is present. This effect, termed super-EPR (SUPR), can enhance the delivery of a wide variety of nanosized agents, including nanoparticles, antibodies, and protein-binding small-molecular-weight agents into tumors. Therefore, taking advantage of the SUPR effect after NIR-PIT may be a promising avenue to use a wide variety of nanodrugs in a highly effective manner.

scholarly journals Selective Priming of Tumor Blood Vessels by Radiation Therapy Enhances Nanodrug Delivery

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Sijumon Kunjachan ◽  
Shady Kotb ◽  
Robert Pola ◽  
Michal Pechar ◽  
Rajiv Kumar ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Blood Vessels ◽  
Fold Increase ◽  
Effective Drug ◽  
Human Pancreatic Cancer ◽  
Standard Drug ◽  
Fluorescence Studies ◽  
Nanodrug Delivery ◽  
Functional Changes ◽  
Tumor Blood Vessels

Abstract Effective drug delivery is restricted by pathophysiological barriers in solid tumors. In human pancreatic adenocarcinoma, poorly-permeable blood vessels limit the intratumoral permeation and penetration of chemo or nanotherapeutic drugs. New and clinically viable strategies are urgently sought to breach the neoplastic barriers that prevent effective drug delivery. Here, we present an original idea to boost drug delivery by selectively knocking down the tumor vascular barrier in a human pancreatic cancer model. Clinical radiation activates the tumor endothelial-targeted gold nanoparticles to induce a physical vascular damage due to the high photoelectric interactions. Active modulation of these tumor neovessels lead to distinct changes in tumor vascular permeability. Noninvasive MRI and fluorescence studies, using a short-circulating nanocarrier with MR-sensitive gadolinium and a long-circulating nanocarrier with fluorescence-sensitive nearinfrared dye, demonstrate more than two-fold increase in nanodrug delivery, post tumor vascular modulation. Functional changes in altered tumor blood vessels and its downstream parameters, particularly, changes in Ktrans (permeability), Kep (flux rate), and Ve (extracellular interstitial volume), reflect changes that relate to augmented drug delivery. The proposed dual-targeted therapy effectively invades the tumor vascular barrier and improve nanodrug delivery in a human pancreatic tumor model and it may also be applied to other nonresectable, intransigent tumors that barely respond to standard drug therapies.

scholarly journals Author Correction: Selective Priming of Tumor Blood Vessels by Radiation Therapy Enhances Nanodrug Delivery

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sijumon Kunjachan ◽  
Shady Kotb ◽  
Robert Pola ◽  
Michal Pechar ◽  
Rajiv Kumar ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Blood Vessels ◽  
Nanodrug Delivery ◽  
Tumor Blood Vessels

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

scholarly journals Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels.

1991 ◽  
Vol 174 (5) ◽  
pp. 1275-1278 ◽  
Author(s):  
H F Dvorak ◽  
T M Sioussat ◽  
L F Brown ◽  
B Berse ◽  
J A Nagy ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Blood Vessels ◽  
Vascular Permeability ◽  
Tumor Cells ◽  
Vascular Endothelial Cell ◽  
Vascular Endothelial ◽  
Vascular Permeability Factor ◽  
Tumor Vessels ◽  
Tumor Blood Vessels

Vascular permeability factor (VPF) is a highly conserved 34-42-kD protein secreted by many tumor cells. Among the most potent vascular permeability-enhancing factors known, VPF is also a selective vascular endothelial cell mitogen, and therefore has been called vascular endothelial cell growth factor (VEGF). Our goal was to define the cellular sites of VPF (VEGF) synthesis and accumulation in tumors in vivo. Immunohistochemical studies were performed on solid and ascites guinea pig line 1 and line 10 bile duct carcinomas using antibodies directed against peptides synthesized to represent the NH2-terminal and internal sequences of VPF. These antibodies stained tumor cells and, uniformly and most intensely, the endothelium of immediately adjacent blood vessels, both preexisting and those newly induced by tumor angiogenesis. A similar pattern of VPF staining was observed in autochthonous human lymphoma. In situ hybridization demonstrated VPF mRNA in nearly all line 10 tumor cells but not in tumor blood vessels, indicating that immunohistochemical labeling of tumor vessels with antibodies to VPF peptides reflects uptake of VPF, not endogenous synthesis. VPF protein staining was evident in adjacent preexisting venules and small veins as early as 5 h after tumor transplant and plateaued at maximally intense levels in newly induced tumor vessels by approximately 5 d. VPF-stained vessels were also hyperpermeable to macromolecules as judged by their capacity to accumulate circulating colloidal carbon. In contrast, vessels more than approximately 0.5 mm distant from tumors were not hyperpermeable and did not exhibit immunohistochemical staining for VPF. Vessel staining disappeared within 24-48 h of tumor rejection. These studies indicate that VPF is synthesized by tumor cells in vivo and accumulates in nearby blood vessels, its target of action. Because leaky tumor vessels initiate a cascade of events, which include plasma extravasation and which lead ultimately to angiogenesis and tumor stroma formation, VPF may have a pivotal role in promoting tumor growth. Also, VPF immunostaining provides a new marker for tumor blood vessels that may be exploitable for tumor imaging or therapy.

scholarly journals EPR effect based nanocarriers targeting for treatment of cancer

2017 ◽  
Vol 8 (4) ◽  
Author(s):  
Kavita Rai Gajbhiye ◽  
J M Gajbhiye
Keyword(s):  
Solid Tumors ◽  
Molecular Mechanisms ◽  
Drug Effects ◽  
Vascular Density ◽  
Epr Effect ◽  
Normal Tissues ◽  
Enhanced Permeability And Retention ◽  
Macromolecular Drugs ◽  
Intratumoral Delivery

<p>The enhanced permeability and retention (EPR) effect is a unique phenomenon of solid tumors related to their anatomical and pathophysiological differences from normal tissues. In solid tumors, angiogenesis leads to high vascular density. Large gaps exist between endothelial cells in tumor blood vessels, which lead to selective extravasations and retention of macromolecular drugs. This EPR effect served as a basis for development of macromolecular anticancer therapy. There are various factors, which lead to a significantly increased EPR effect and enhanced antitumor drug effects as well. This review discusses the unique anatomy of tumor vessels, molecular mechanisms of factors related to the EPR effect and the role of the EPR effect in the intratumoral delivery of protein and peptide drugs, macromolecular drugs and drug-loaded long-circulating nanocarriers.</p>

scholarly journals Augmentation of EPR Effect and Efficacy of Anticancer Nanomedicine by Carbon Monoxide Generating Agents

Pharmaceutics ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 343 ◽  
Author(s):  
Jun Fang ◽  
Rayhanul Islam ◽  
Waliul Islam ◽  
Hongzhuan Yin ◽  
Vladimir Subr ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Solid Tumors ◽  
Normal Tissue ◽  
Heme Oxygenase 1 ◽  
Anticancer Effect ◽  
Epr Effect ◽  
Enhanced Permeability And Retention ◽  
Tumor Blood Vessels ◽  
Tumor Accumulation

One obstacle to the successful delivery of nanodrugs into solid tumors is the heterogeneity of an enhanced permeability and retention (EPR) effect as a result of occluded or embolized tumor blood vessels. Therefore, the augmentation of the EPR effect is critical for satisfactory anticancer nanomedicine. In this study, we focused on one vascular mediator involved in the EPR effect, carbon monoxide (CO), and utilized two CO generating agents, one is an extrinsic CO donor (SMA/CORM2 micelle) and another is an inducer of endogenous CO generation via heme oxygenase-1 (HO-1) induction that is carried out using pegylated hemin. Both agents generated CO selectively in solid tumors, which resulted in an enhanced EPR effect and a two- to three-folds increased tumor accumulation of nanodrugs. An increase in drug accumulation in the normal tissue did not occur with the treatment of CO generators. In vivo imaging also clearly indicated a more intensified fluorescence of macromolecular nanoprobe in solid tumors when combined with these CO generators. Consequently, the combination of CO generators with anticancer nanodrugs resulted in an increased anticancer effect in the different transplanted solid tumor models. These findings strongly warrant the potential application of these CO generators as EPR enhancers in order to enhance tumor detection and therapy using nanodrugs.

scholarly journals Targeted Drug Delivery by Radiation-Induced Tumor Vascular Modulation

2018 ◽  
Author(s):  
Sijumon Kunjachan ◽  
Shady Kotb ◽  
Rajiv Kumar ◽  
Robert Pola ◽  
Michal Pechar ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Blood Vessels ◽  
Targeted Drug Delivery ◽  
Therapeutic Benefit ◽  
Human Pancreatic Cancer ◽  
Nanodrug Delivery ◽  
Functional Changes ◽  
Radiation Induced ◽  
Targeted Drug ◽  
Tumor Blood Vessels

Effective drug delivery is severely restricted by the presence of complex pathophysiological barriers in solid tumors. In human pancreatic adenocarcinoma, mature and hypopermeable tumor blood vessels limit the permeation and penetration of chemo or nanotherapeutics to cancer cells and substantially reduce the treatment efficacy. New, clinically-viable strategies are therefore sought to breach the neoplastic barriers that prevent optimal tumor-specific drug delivery. Here, we present an original idea to boost targeted drug delivery by selectively knocking down the tumor vascular barrier in a poorly permeable human pancreatic cancer model. For the first time, we demonstrate that clinical irradiation (10 Gy, 6 MV) can induce tumor vascular modulation when combined with tumor endothelial-targeting gold nanoparticles. Active disruption of tumor blood vessels by nanoparticle-combined radiotherapy led to increased vessel permeability and improved tumor uptake of two prototypical model nanodrugs: i) a short-circulating nanocarrier with MR-sensitive gadolinium (Gad-NC; 8 kDa; t1/2=1.5 h) and ii) a long-circulating nanocarrier with fluorescence-sensitive NIR dye (FL-NC; 30 kDa; t1/2=25 h). Functional changes in the altered tumor vessel dynamics, measured by relative changes in permeability (Ktrans), flux rate (Kep) and extracellular interstitial volume (Ve) were consistent with the concomitant increase in nanodrug delivery. This combination of radiation-induced antivascular and nanodrug-mediated anti-tumor treatment offers high therapeutic benefit for tumors with pathophysiology that restricts efficient drug delivery.

scholarly journals EPR-Effect Enhancers Strongly Potentiate Tumor-Targeted Delivery of Nanomedicines to Advanced Cancers: Further Extension to Enhancement of the Therapeutic Effect

2021 ◽  
Vol 11 (6) ◽  
pp. 487
Author(s):  
Waliul Islam ◽  
Shintaro Kimura ◽  
Rayhanul Islam ◽  
Ayaka Harada ◽  
Katsuhiko Ono ◽  
...  
Keyword(s):  
Blood Flow ◽  
Blood Vessels ◽  
Targeted Delivery ◽  
Zinc Protoporphyrin ◽  
Selective Treatment ◽  
Acid Complex ◽  
Epr Effect ◽  
Boron Neutron Capture ◽  
Macromolecular Drugs ◽  
Tumor Delivery

For more than three decades, enhanced permeability and retention (EPR)-effect-based nanomedicines have received considerable attention for tumor-selective treatment of solid tumors. However, treatment of advanced cancers remains a huge challenge in clinical situations because of occluded or embolized tumor blood vessels, which lead to so-called heterogeneity of the EPR effect. We previously developed a method to restore impaired blood flow in blood vessels by using nitric oxide donors and other agents called EPR-effect enhancers. Here, we show that two novel EPR-effect enhancers—isosorbide dinitrate (ISDN, Nitrol®) and sildenafil citrate—strongly potentiated delivery of three macromolecular drugs to tumors: a complex of poly(styrene-co-maleic acid) (SMA) and cisplatin, named Smaplatin® (chemotherapy); poly(N-(2-hydroxypropyl)methacrylamide) polymer-conjugated zinc protoporphyrin (photodynamic therapy and imaging); and SMA glucosamine-conjugated boric acid complex (boron neutron capture therapy). We tested these nanodrugs in mice with advanced C26 tumors. When these nanomedicines were administered together with ISDN or sildenafil, tumor delivery and thus positive therapeutic results increased two- to four-fold in tumors with diameters of 15 mm or more. These results confirmed the rationale for using EPR-effect enhancers to restore tumor blood flow. In conclusion, all EPR-effect enhancers tested showed great potential for application in cancer therapy.

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