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.

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 History of IgA Nephropathy Mouse Models

2021 ◽  
Vol 10 (14) ◽  
pp. 3142
Author(s):  
Batoul Wehbi ◽  
Virginie Pascal ◽  
Lina Zawil ◽  
Michel Cogné ◽  
Jean-Claude Aldigier
Keyword(s):  
Iga Nephropathy ◽  
Small Animal ◽  
Experimental Models ◽  
Murine Models ◽  
Therapeutic Approaches ◽  
Complement Components ◽  
Simple Description ◽  
Primary Glomerulonephritis ◽  
History Of ◽  
Small Animal Models

IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. It was first described in 1968 by Jean Berger and Nicole Hinglais as the presence of intercapillary deposits of IgA. Despite this simple description, patients with IgAN may present very broad clinical features ranging from the isolated presence of IgA in the mesangium without clinical or biological manifestations to rapidly progressive kidney failure. These features are associated with a variety of histological lesions, from the discrete thickening of the mesangial matrix to diffuse cell proliferation. Immunofluorescence on IgAN kidney specimens shows the isolated presence of IgA or its inconsistent association with IgG and complement components. This clinical heterogeneity of IgAN clearly echoes its complex and multifactorial pathophysiology in humans, inviting further analyses of its various aspects through the use of experimental models. Small-animal models of IgAN provide the most pertinent strategies for studying the multifactorial aspects of IgAN pathogenesis and progression. Although only primates have the IgA1 subclass, several murine models have been developed in which various aspects of immune responses are deregulated and which are useful in the understanding of IgAN physiopathology as well as in the assessment of IgAN therapeutic approaches. In this manuscript, we review all murine IgAN models developed since 1968 and discuss their remarkable contribution to understanding the disease.

The Evolution of Tumor-Targeted Drug Delivery: From the EPR Effect to Nanoswimmers

2013 ◽  
pp. n/a-n/a
Author(s):  
Nour Zoabi ◽  
Adi Golani-Armon ◽  
Assaf Zinger ◽  
Maayan Reshef ◽  
Zvi Yaari ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Targeted Drug Delivery ◽  
Epr Effect ◽  
Targeted Drug

Description of a method for inducing fetal growth restriction in the spiny mouse

2017 ◽  
Vol 8 (5) ◽  
pp. 550-555 ◽  
Author(s):  
H. Dickinson ◽  
S. Ellery ◽  
M. Davies-Tuck ◽  
M. Tolcos ◽  
I. Nitsos ◽  
...  
Keyword(s):  
Blood Flow ◽  
Fetal Growth ◽  
Gestational Age ◽  
Fetal Growth Restriction ◽  
Fetal Loss ◽  
Small Animal ◽  
Major Complication ◽  
Growth Restriction ◽  
Spiny Mouse ◽  
Uterine Blood Flow

Intrauterine or fetal growth restriction (IUGR) is a major complication of pregnancy and leads to significant perinatal morbidities and mortality. Typically, induction of IUGR in animals involves the complete occlusion or ablation of vessels to the uterus or placenta, acutely impairing blood flow and fetal growth, usually with high fetal loss. We aimed to produce a model of reduced fetal growth in the spiny mouse with minimal fetal loss. At 27 days gestational age (term is 38–39 days), a piece of silastic tubing was placed around the left uterine artery to prevent the further increase of uterine blood flow with advancing gestation to induce IUGR (occluded). Controls were generated from sham surgeries without placement of the tubing. Dams were humanely euthanized at 37 days gestational age and all fetuses and placentas were weighed and collected. Of the 17 dams that underwent surgery, 15 carried their pregnancies to 37 days gestational age and 95% of fetuses survived to this time. The difference in fetal body weight between occluded and control was ~21% for fetuses in the left uterus side: there were no differences for fetuses in the right uterus side. Offspring from the occluded group had significantly lower brain, liver, lung, kidney and carcass weights compared with shams. Preventing the gestation-related increase of uterine blood flow induced significant growth restriction in the fetal spiny mouse, with minimal fetal loss. This technique could be readily adapted for other small animal.

Intrathecal Magnetic Drug Targeting: A New Approach to Treating Diseases of the Central Nervous System

2013 ◽  
Author(s):  
Eric Lueshen ◽  
Indu Venugopal ◽  
Andreas Linninger
Keyword(s):  
Magnetic Field ◽  
Drug Delivery ◽  
Central Nervous System ◽  
Nervous System ◽  
Spinal Canal ◽  
Drug Targeting ◽  
Superparamagnetic Nanoparticles ◽  
Magnetic Drug Targeting ◽  
The Central Nervous System ◽  
Drug Doses

Intrathecal (IT) drug delivery is a standard technique which involves direct injection of drugs into the cerebrospinal fluid (CSF)-filled space within the spinal canal to treat many diseases of the central nervous system. Currently, in order to reach the therapeutic drug concentration at certain locations within the spinal canal, high drug doses are used. With no method to deliver the large drug doses locally, current IT drug delivery treatments are hindered with wide drug distributions throughout the central nervous system (CNS) which cause harmful side effects. In order to overcome the current limitations of IT drug delivery, we have developed the novel method of intrathecal magnetic drug targeting (IT-MDT). Gold-coated magnetite nanoparticles are infused into a physiologically and anatomically relevant in vitro human spine model and then targeted to a specific site using external magnetic fields, resulting in a substantial increase in therapeutic nanoparticle localization at the site of interest. Experiments aiming to determine the effect of key parameters such as magnet strength, duration of magnetic field exposure, location of magnetic field, and ferrous implants on the collection efficiency of our superparamagnetic nanoparticles in the targeting region were performed. Our experiments indicate that intrathecal magnetic drug targeting and implant-assisted IT-MDT are promising techniques for concentrating and localizing drug-functionalized nanoparticles at required target sites within the spinal canal for potential treatment of diseases affecting the central nervous system.

Effects of dopamine in the renal vascular bed of fetal, newborn, and adult sheep

1987 ◽  
Vol 252 (3) ◽  
pp. R490-R497 ◽  
Author(s):  
K. T. Nakamura ◽  
R. A. Felder ◽  
P. A. Jose ◽  
J. E. Robillard
Keyword(s):  
Blood Flow ◽  
Flow Velocity ◽  
Renal Blood Flow ◽  
Blood Flow Velocity ◽  
Experimental Models ◽  
Dose Ratio ◽  
Fetal Sheep ◽  
Adult Sheep ◽  
Beta Adrenoceptor ◽  
Arterial Blood

The renal hemodynamic response to renal arterial dopamine infusions was compared in unanesthetized fetal (129-137 days gestation, full term 145 days), newborn, and adult sheep. Mean arterial blood pressure and heart rate remained unchanged during intrarenal dopamine infusions. Dopamine produced dose-related decreases in mean renal blood flow velocity in all three groups. When compared with adult sheep fetal sheep were slightly more sensitive to the vasoconstrictive effects of dopamine ED50 (mean effective dose ratio: fetus/ED50 adult = 0.368 +/- 0.047, P less than 0.05). Increases in mean renal blood flow velocity were not seen at any dose given (1-16 micrograms/kg body wt in fetuses, 2-32 micrograms/kg body wt in newborns and adults) until dopamine was infused during alpha- and beta-adrenoceptor blockade. The largest mean increase in renal flow velocity was 13 +/- 3, 16 +/- 3, and 17 +/- 4% in fetal, newborn, and adult sheep, respectively. cis-Flupentixol inhibited the vasodilation. This study demonstrates the presence of renal vasodilation following renal arterial dopamine infusions in fetal, newborn, and adult sheep when renal alpha- and beta-adrenoceptors are blocked. Vasodilator responses are similar in all three groups, and increases in renal blood flow velocity are small compared with that of other experimental models.

scholarly journals Accessing neuroinflammation sites: Monocyte/neutrophil-mediated drug delivery for cerebral ischemia

2019 ◽  
Vol 5 (7) ◽  
pp. eaau8301 ◽  
Author(s):  
Jia Hou ◽  
Xu Yang ◽  
Shiyi Li ◽  
Zhekang Cheng ◽  
Yuhua Wang ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Blood Flow ◽  
Cerebral Ischemia ◽  
Inflammatory Response ◽  
Target Cells ◽  
Ischemic Brain ◽  
Therapeutic Molecules ◽  
Cerebral Parenchyma ◽  
Cell Carriers ◽  
The Brain

Cerebral ischemia (CI) results from inadequate blood flow to the brain. The difficulty of delivering therapeutic molecules to lesions resulting from CI hinders the effective treatment of this disease. The inflammatory response following CI offers a unique opportunity for drug delivery to the ischemic brain and targeted cells because of the recruitment of leukocytes to the stroke core and penumbra. In the present study, neutrophils and monocytes were explored as cell carriers after selectively carrying cRGD liposomes, which effectively transmigrated the blood-brain barrier, infiltrated the cerebral parenchyma, and delivered therapeutic molecules to the injured sites and target cells. Our results showed the successful comigration of liposomes with neutrophils/monocytes and that both monocytes and neutrophils were important for successful delivery. Enhanced protection against ischemic injury was achieved in the CI/reperfusion model. The strategy presented here shows potential in the treatment of CI and other diseases related to inflammation.

Splanchnic hemodynamics in portal-hypertensive rats: measurement with gamma-labeled microspheres

1982 ◽  
Vol 242 (2) ◽  
pp. G156-G160 ◽  
Author(s):  
R. J. Groszmann ◽  
J. Vorobioff ◽  
E. Riley
Keyword(s):  
Blood Flow ◽  
Portal Vein ◽  
Experimental Models ◽  
Hypertensive Rats ◽  
Venous Flow ◽  
Reliable Technique ◽  
Splanchnic Hemodynamics ◽  
Significant Difference ◽  
Normal Rat ◽  
The Difference

A method to quantitate hepatic arterial flow (HA), portal venous flow (PBF), and blood flow through portal-systemic shunts (ShBF) in portal-hypertensive rats is described. This method relies on the injection of two differently radiolabeled microspheres (15 micrometers) into the left ventricle and spleen. To evaluate the usefulness of this technique, studies were performed on normal, cirrhotic, and portal vein-ligated rats anesthetized with ketamine. With this method, PBF is calculated indirectly from the sums of the blood flow of the splanchnic organs that drain into the portal vein. In the portal-hypertensive animals with portal-systemic shunting, this technique allows for the determination of PBF perfusing the liver [hepatic fraction of portal flow (HFP)] and PBF escaping through portal-systemic shunts (ShBF). The portal vein-ligated rats have higher HA flow (0.68 +/- 0.08 ml . min-1 . g-1) and lower HFP (0.08 +/- 0.01 ml . min-1 . g-1) than either the cirrhotic (HA: 0.27 +/- 0.03 ml . min-1 . g-1, P less than 0.01; HFP: 1.20 +/- 0.20 ml . min-1 . g-1, P less than 0.01) or the normal rat (HA: 0.29 +/- 0.06 ml . min-1 . g-1, P less than 0.01; HFP: 1.39 +/- 0.16 ml . min-1 . g-1, P less than 0.01). No significant difference was found between the cirrhotic and normal rats. The ShBF was higher in the portal vein-ligated rats (21.4 +/- 2.8 ml/min) than in the cirrhotic (4.6 +/- 2.5 ml/min, P less than 0.001) or normal rats (0.03 +/- 0.005 ml/min, P less than 0.01). The difference between the cirrhotic and normal animals was also significant (P less than 0.05). This is a simple, rapid, and reliable technique that allows for the quantitation of splanchnic hemodynamics in experimental models with portal hypertension.

Sign in / Sign up

Export Citation Format

Share Document