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Methods for enhancing permeability to blood-brain barrier and uses thereof

A kind of use, brain technology, applied in the field of enhancing the permeability of the blood-brain barrier and its use, can solve the problems of lack of drug delivery, low drug amount, and inability to trigger therapeutic responses of therapeutic compounds

Pending Publication Date: 2017-09-26
ACAD SINIC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although, although there is an ever-increasing number of potential therapeutic compounds for the treatment of these diseases, the lack of adequate methods to deliver these drugs to the central nervous system, especially the brain, limits their usefulness
Currently available drug delivery technologies still rely on systemic, intraspinal, or intracranial routes of drug administration; however, each of these approaches has limitations
For example, many compounds cannot enter the CNS from the circulatory system, limiting the applicability of systemic routes of administration
Even when a systemically administered drug enters the CNS, the amount of the drug is usually too low to elicit the desired therapeutic response

Method used

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  • Methods for enhancing permeability to blood-brain barrier and uses thereof
  • Methods for enhancing permeability to blood-brain barrier and uses thereof
  • Methods for enhancing permeability to blood-brain barrier and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] Example 1: VEGF can enhance blood-brain barrier barrier permeability in mouse model

[0086] Materials and methods

[0087] (i) Blood-brain barrier permeability was measured by the amount of Evans Blue (EB) exudation

[0088] The permeability of the blood-brain barrier was quantitatively assessed by Evans blue (Fluka). Evans blue (2% or 4% v / v in saline, 4ml / kg) was administered intravenously. For analysis of extravasation, perfuse 50 ml of 0.9% saline (containing 10 i.u. / ml of heparin) into the animal to remove intravascular dye until the body fluid sampled from the animal's arteries, kidneys, and liver is colorless until liquid. Then, the animal was sacrificed and its brain weight was weighed, and the brain tissue was homogenized in N,N-dimethylformamide (N,N-dimethylformamide) (Sigma-Aldrich Company) (1ml / 150mg tissue weight), It was incubated at 55° C. for 18 hours and centrifuged (14000 rpm / 20 minutes). The dye supernatant was analyzed spectrophotometrically...

Embodiment 2

[0109] Example 2: VEGF pretreatment can enhance the effect of hMSC-based cell therapy after stroke

[0110] Stroke A stroke (also known as a cerebrovascular accident (CVA) is a disturbance in the flow of blood to the brain, causing a rapid loss of brain function. There are two types of stroke: a hemorrhagic stroke or an ischemic stroke. Hemorrhagic stroke is caused by an acute intracranial hematoma caused by rupture of an intracranial artery. Ischemic stroke (also called cerebral infarction) is a blockage of blood flow to the brain (eg, thrombus or distal embolism) Caused by the death of brain cells in the region. Currently, the two standard treatments for ischemic stroke are thrombolytic injection and endovascular surgery. flow and quickly reduce hypoxic damage to brain tissue.

[0111] Mesenchymal stem cells (MSCs) are a heterogeneous population of pluripotent stromal stem cells that can differentiate into osteoblasts, chondrocytes and adipocytes. Previous studies have sho...

Embodiment 3

[0118] Example 3: VEGF pretreatment can delay the growth of brain tumors in mice treated with anticancer drugs and improve the survival rate of GBM mice

[0119] Glioblastoma multiform (GBM) (also known as grade 4 glioma) is the most common and aggressive type of malignant tumor in brain tissue. The current standard treatment for these tumors is a combination of surgical resection, radiation therapy and chemotherapy. GBM is highly aggressive and infiltrates healthy tissue, and by the time most patients are diagnosed with GBM, the tumor is often too large and disseminated for surgical removal. Therefore, even with modern treatments, the median survival rate of GBM patients is 12-15 months from the start of treatment, which is one of the lowest 5-year survival rates of all human cancers. Because of the low success rate of surgical resection, medical therapy is the most promising area of ​​improvement. Appropriate anticancer drugs are currently available, but the blood-brain ba...

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Abstract

Disclosed herein is a method of facilitating the delivery of an agent across blood-brain barrier (BBB) of a subject. The method includes administering to the subject in sequence or concomitantly, an effective amount of a growth factor selected from the group consisting of, vascular endothelial growth factor (VEGF), insulin-like growth factor I (IGF-1), IGF-II, a portion thereof and a combination thereof; and an agent that is any of a therapeutic agent or an imaging agent. The administered amount of the growth factor is capable of transiently increasing BBB permeability of the subject and thereby allowing the agent to be delivered across BBB. Also disclosed herein is a method of treating a subject suffering from a brain tumor, a brain stroke, a neuropsychiatric disorder and / or a neurodegenerative disease.

Description

[0001] related application [0002] Pursuant to 35 U.S.C. §119(e), this application claims priority to U.S. Provisional Application No. 62 / 039,899, filed August 20, 2014, the contents of which are incorporated herein by reference in their entirety. Background technique [0003] The blood-brain barrier (BBB) ​​is a network formed by capillary endothelial cells tightly bound to each other, which can restrict the freedom of small molecules, proteins and cells between the systemic circulation and the central nervous system (CNS). exchange. The blood-brain barrier protects the brain from damage caused by pathogens, toxins or other causes (insults, should be results typos), but this is a serious challenge for the treatment of many neurological diseases. For example, common and serious brain disorders such as tumors, infections, infarcts / hemorrhages, physical trauma, and degenerative diseases (e.g., Parkinson's disease) where adequate drug delivery and accurate diagnostic imaging ar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/18A61K45/06A61K49/00A61P35/00
CPCA61K38/1866A61K45/06A61K49/0002A61K2300/00C07K14/52A61K47/6835A61P25/00A61P25/18A61P25/28A61P35/00A61P9/10A61K51/08A61K2039/505C07K16/00C07K16/22C07K16/28C07K2319/00
Inventor P·C·H·谢D·伦迪
Owner ACAD SINIC
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