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Dendrimer compositions and use in treatment of neurological and cns disorders

A dendritic and polymer technology, which can be used in drug combinations, neurological diseases, medical preparations of non-active ingredients, etc., and can solve problems such as drug and gene delivery difficulties

Inactive Publication Date: 2017-05-10
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In summary, drug and gene delivery to the brain is difficult because of the diffuse nature of the BBB, brain microenvironment, and neuroinflammation

Method used

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  • Dendrimer compositions and use in treatment of neurological and cns disorders
  • Dendrimer compositions and use in treatment of neurological and cns disorders
  • Dendrimer compositions and use in treatment of neurological and cns disorders

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0128] Example 1: Systemic administration of dendrimer-drug conjugates to mice with RTT

[0129] Materials and methods

[0130] Detailed materials and methods used in the experiments below (including protocols for making dendrimer-Cy5 and dendrimer-drug conjugates) have been reviewed by Kanana S et al. Science. Translational Medicine, 4:130ra46( 2012) and described in U.S. Patent No. 8,889.101.

[0131] RTT mice are the Adrian Bird model commercially available from Jackson Laboratory.

[0132] Dendrimer injection and animal sacrifice. Dendrimers were injected intravenously into RTT mice. For intravenous injection, after making a small incision in the femoral region, 600 μg D-Cy5 dissolved in 100 μL sterile PBS was injected into the femoral vein via a 30 g needle. Animals injected with free Cy5 and PBS served as positive or negative controls for this study. At appropriate time points after dendrimer injection (24 hours, 72 hours, and 21 days, and up to six weeks later), ...

example 2

[0151] Example 2: Treatment of Brain Injury in a Canine Model

[0152] Materials and methods

[0153] Dendrimer Brain Uptake and Targeted Therapy for Brain Injury in a Canine Animal Model of Hypothermic Cyclic Arrest by Manoj et al., American Chemical Society Nano, 2014, 8(3), p. 2134 - 2147 pages of description.

[0154] Six-stage primary hydroxyl-functionalized PAMAM dendrimers with an ethylenediamine (EDA) core were used in these studies.

[0155] Prepare conjugates

[0156] Conjugates were prepared as described above.

[0157] Canine HCA Model and Experimental Design

[0158] All experiments were performed with the canine model of HCA developed by the Baumgartner laboratory. (Redmond et al., Ann. Thorac. Surg. 1995, 59, 579-584; Redmond et al., Thoracic and Cardiovascular Surgery (Thorac. Cardiovasc. Surg), 1994, 107, 776-786). This large animal model exploits certain inherent physiological similarities between humans and canines to develop readily translatable th...

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Abstract

A dendrimer formation, such as a PAMAM dendrimer or a multiarm PEG polymeric formulation has been developed for systemic administration to the brain or central nervous system. In the preferred embodiment, the dendrimers are in the form of dendrimer nanoparticles comprising poly(amidoamine) (PAMAM) hydroxyl-terminated dendrimers covalently linked to at least one therapeutic, prophylactic or diagnostic agent for treatment of one or more symptoms of neurodegenerative, neurodevelopmental or neurological disorders such as Rett syndrome or autism spectrum disorders, D6 generation dendrimers provide significantly enhanced uptake into areas of brain Injury, providing a means for diagnosis as well, as drug delivery.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Patent Application Nos. 62 / 036,675, filed August 13, 2014, and 62 / 036,839, filed August 13, 2014, which are incorporated herein by reference middle. Background technique [0003] Drug delivery to the brain and central nervous system (CNS) is difficult, especially when targeted delivery to specific cells in the CNS is required. Drugs and delivery vehicles must overcome the blood-brain barrier (BBB), move through brain tissue, and localize in target cells. Patients with neurological diseases (including Parkinson's disease, Alzheimer's disease, brain tumors and most neurogenetic conditions) suffer from severe debilitating symptoms and lack treatments that provide curative treatment Option. Various strategies to manipulate or bypass the blood-brain barrier (BBB) ​​have been developed [Jain (Jain), Nanomedicine (Lind) (Nanomedicine (Lond)), 2012.7 (8): 1225-33; Special ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/59A61K45/06A61K49/00A61P25/00A61P25/28
CPCA61K45/06A61K49/0032A61K49/0054A61K31/19A61K31/198A61K47/595A61P25/00A61P25/20A61P25/28A61P29/00A61P37/06A61K9/0019
Inventor K·兰格拉曼奴贾姆S·卡纳安E·南斯M·E·布鲁M·V·约翰斯顿W·鲍姆加特纳张帆M·A·威尔逊B·斯拉舍
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE