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.

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 The 35th Anniversary of the Discovery of EPR Effect: A New Wave of Nanomedicines for Tumor-Targeted Drug Delivery—Personal Remarks and Future Prospects

2021 ◽  
Vol 11 (3) ◽  
pp. 229
Author(s):  
Hiroshi Maeda
Keyword(s):  
Drug Delivery ◽  
Blood Flow ◽  
Small Animal ◽  
Experimental Models ◽  
New Wave ◽  
Epr Effect ◽  
Vascular Abnormalities ◽  
Boron Neutron Capture ◽  
Drug Doses ◽  
Tumor Emboli

This Special Issue on the enhanced permeability and retention (EPR) effect commemorates the 35th anniversary of its discovery, the original 1986 Matsumura and Maeda finding being published in Cancer Research as a new concept in cancer chemotherapy. My review here describes the history and heterogeneity of the EPR effect, which involves defective tumor blood vessels and blood flow. We reported that restoring obstructed tumor blood flow overcomes impaired drug delivery, leading to improved EPR effects. I also discuss gaps between small animal cancers used in experimental models and large clinical cancers in humans, which usually involve heterogeneous EPR effects, vascular abnormalities in multiple necrotic foci, and tumor emboli. Here, I emphasize arterial infusion of oily formulations of nanodrugs into tumor-feeding arteries, which is the most tumor-selective drug delivery method, with tumor/blood ratios of 100-fold. This method is literally the most personalized medicine because arterial infusions differ for each patient, and drug doses infused depend on tumor size and anatomy in each patient. Future developments in EPR effect-based treatment will range from chemotherapy to photodynamic therapy, boron neutron capture therapy, and therapies for free radical diseases. This review focuses on our own work, which stimulated numerous scientists to perform research in nanotechnology and drug delivery systems, thereby spawning a new cancer treatment era.

Polymeric micelles of zinc protoporphyrin for tumor targeted delivery based on EPR effect and singlet oxygen generation

2007 ◽  
Vol 15 (7-8) ◽  
pp. 496-506 ◽  
Author(s):  
Arun K. Iyer ◽  
Khaled Greish ◽  
Takahiro Seki ◽  
Shoko Okazaki ◽  
Jun Fang ◽  
...  
Keyword(s):  
Singlet Oxygen ◽  
Targeted Delivery ◽  
Polymeric Micelles ◽  
Zinc Protoporphyrin ◽  
Epr Effect ◽  
Oxygen Generation ◽  
Singlet Oxygen Generation

Innervation of endoneurial microvessels in human sural nerve

1992 ◽  
Vol 50 (1) ◽  
pp. 920-921
Author(s):  
John L. Beggs ◽  
Peter C. Johnson ◽  
Astrid G. Olafsen ◽  
C. Jane Watkins
Keyword(s):  
Blood Flow ◽  
Blood Vessels ◽  
Blood Supply ◽  
Peripheral Nerves ◽  
Sural Nerve ◽  
Nerve Fibers ◽  
Arterial Supply ◽  
Autonomic Nerve ◽  
Vasa Nervorum ◽  
Endoneurial Blood Flow

The blood supply (vasa nervorum) to peripheral nerves is composed of an interconnected dual circulation. The endoneurium of nerve fascicles is maintained by the intrinsic circulation which is composed of microvessels primarily of capillary caliber. Transperineurial arterioles link the intrinsic circulation with the extrinsic arterial supply located in the epineurium. Blood flow in the vasa nervorum is neurogenically influenced (1,2). Although a recent hypothesis proposes that endoneurial blood flow is controlled by the action of autonomic nerve fibers associated with epineurial arterioles (2), our recent studies (3) show that in addition to epineurial arterioles other segments of the vasa nervorum are also innervated. In this study, we examine blood vessels of the endoneurium for possible innervation.

COMPARISON OF ANTIHYPERTENSIVE EFFECT OF MOXONIDINE VERSUS CLONIDINE IN RENAL FAILURE PATIENTS.

2018 ◽  
Vol 6 (9) ◽  
Author(s):  
DR.MATHEW GEORGE ◽  
DR.LINCY JOSEPH ◽  
MRS.DEEPTHI MATHEW ◽  
ALISHA MARIA SHAJI ◽  
BIJI JOSEPH ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Failure ◽  
Blood Flow ◽  
Blood Vessel ◽  
Blood Vessels ◽  
High Blood Pressure ◽  
Antihypertensive Effect ◽  
The Body ◽  
Ability To Work ◽  
Blood Flows

Blood pressure is the force of blood pushing against blood vessel walls as the heart pumps out blood, and high blood pressure, also called hypertension, is an increase in the amount of force that blood places on blood vessels as it moves through the body. Factors that can increase this force include higher blood volume due to extra fluid in the blood and blood vessels that are narrow, stiff, or clogged(1). High blood pressure can damage blood vessels in the kidneys, reducing their ability to work properly. When the force of blood flow is high, blood vessels stretch so blood flows more easily. Eventually, this stretching scars and weakens blood vessels throughout the body, including those in the kidneys.

Microfluidics of blood in blood vessels stenosis

2016 ◽  
Vol 11 (2) ◽  
pp. 210-217 ◽  
Author(s):  
A.T. Akhmetov ◽  
A.A. Valiev ◽  
A.A. Rakhimov ◽  
S.P. Sametov ◽  
R.R. Habibullina
Keyword(s):  
Blood Flow ◽  
Blood Vessels ◽  
Hydraulic Resistance ◽  
Microfluidic Device ◽  
Human Body ◽  
Vascular System ◽  
Hydrodynamic Conditions ◽  
Microstructure Change ◽  
Healthy Part

It is mentioned in the paper that hydrodynamic conditions of a flow in blood vessels with the stenosis are abnormal in relation to the total hemodynamic conditions of blood flow in a vascular system of a human body. A microfluidic device developed with a stepped narrowing for studying of the blood flow at abnormal conditions allowed to reveal blood structure in microchannels simulating the stenosis. Microstructure change is observed during the flow of both native and diluted blood through the narrowing. The study of hemorheological properties allowed us to determine an increasing contribution of the hydraulic resistance of the healthy part of the vessel during the stenosis formation.

scholarly journals Age-Dependent Dysregulation of Muscle Vasculature and Blood Flow Recovery after Hindlimb Ischemia in the mdx Model of Duchenne Muscular Dystrophy

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 481
Author(s):  
Paulina Podkalicka ◽  
Olga Mucha ◽  
Katarzyna Kaziród ◽  
Iwona Bronisz-Budzyńska ◽  
Sophie Ostrowska-Paton ◽  
...  
Keyword(s):  
Blood Flow ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Blood Vessels ◽  
Mdx Mice ◽  
Hindlimb Ischemia ◽  
Double Positive ◽  
Functional Studies ◽  
Age Dependent ◽  
Dystrophic Mice

Duchenne muscular dystrophy (DMD), caused by a lack of functional dystrophin, is characterized by progressive muscle degeneration. Interestingly, dystrophin is also expressed in endothelial cells (ECs), and insufficient angiogenesis has already been hypothesized to contribute to DMD pathology, however, its status in mdx mice, a model of DMD, is still not fully clear. Our study aimed to reveal angiogenesis-related alterations in skeletal muscles of mdx mice compared to wild-type (WT) counterparts. By investigating 6- and 12-week-old mice, we sought to verify if those changes are age-dependent. We utilized a broad spectrum of methods ranging from gene expression analysis, flow cytometry, and immunofluorescence imaging to determine the level of angiogenic markers and to assess muscle blood vessel abundance. Finally, we implemented the hindlimb ischemia (HLI) model, more biologically relevant in the context of functional studies evaluating angiogenesis/arteriogenesis processes. We demonstrated that both 6- and 12-week-old dystrophic mice exhibited dysregulation of several angiogenic factors, including decreased vascular endothelial growth factor A (VEGF) in different muscle types. Nonetheless, in younger, 6-week-old mdx animals, neither the abundance of CD31+α-SMA+ double-positive blood vessels nor basal blood flow and its restoration after HLI was affected. In 12-week-old mdx mice, although a higher number of CD31+α-SMA+ double-positive blood vessels and an increased percentage of skeletal muscle ECs were found, the abundance of pericytes was diminished, and blood flow was reduced. Moreover, impeded perfusion recovery after HLI associated with a blunted inflammatory and regenerative response was evident in 12-week-old dystrophic mice. Hence, our results reinforce the hypothesis of age-dependent angiogenic dysfunction in dystrophic mice. In conclusion, we suggest that older mdx mice constitute an appropriate model for preclinical studies evaluating the effectiveness of vascular-based therapies aimed at the restoration of functional angiogenesis to mitigate DMD severity.

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