Compositions and methods for inducing angiogenesis

A composition and biological technology, applied in the direction of drug combination, cardiovascular system diseases, medical preparations containing active ingredients, etc.

Inactive Publication Date: 2013-04-10
THE BRIGHAM & WOMEN S HOSPITAL INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A second challenge is the stability of angiogenic factors, which are large proteins that are often unstable under normal physiological conditions
Furthermore, glycosylation of these proteins presents significant challenges in clinical development

Method used

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  • Compositions and methods for inducing angiogenesis
  • Compositions and methods for inducing angiogenesis
  • Compositions and methods for inducing angiogenesis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0164] Example 1. Engineering 1K1, an aglycosylated HGF / SF variant.

[0165]In the presence of heparan sulfate or heparin, NK1 behaves as a partial receptor agonist (14). To develop 1K1, a rational protein engineering approach based on structural and functional studies of NK1 (15), the NK1-heparin complex (16) and the individual N and K1 domains (17) was employed. NK1 binds to heparin through two distinct sites: a high-affinity site located within the N domain and formed by the side chains of R73, K60, T61, R76, K62, and K58 and the backbone atoms of T61, K63, and G79 (18 ), and a low-affinity site within the K1 domain that includes the side chains of K132, R134, K170, and R181. Mutation 1K1 carries two reverse charge mutations at K132 and R134 (1K1:K132E:R134E), which disrupt heparin binding to the kringle domain (Figures 1A to 1H) and appear to be identical to wild-type on several cell types. than increased signal transduction activity (16). Without wishing to be bound ...

Embodiment 2

[0166] Example 2. 1K1 induces angiogenesis in vitro by binding to MET kinase.

[0167] The angiogenic phenotype is the culmination of discrete cellular steps characterized by endothelial chemoinvasion, proliferation and tubule formation (18). As shown in Figures 2A to 2D, both HGF / SF and 1K1 induced endothelial cell proliferation. Furthermore, 1K1-induced endothelial cell proliferation was inhibited in a concentration-dependent manner by the MET kinase inhibitor PHA 665752 (FIG. 2C), confirming that 1K1 induces angiogenesis through the Met receptor. Previous studies have revealed that MET binding by HGF / SF ligands leads to downstream signaling through PI3K and MAPK (10). However, it is unknown whether the PI3K pathway and the MAPK pathway are activated in 1K1-mediated endothelial cell proliferation. Therefore, the cells were pretreated with LY294002 or PD98059, which inhibited PI3K and MAPK, respectively. As shown in Figures 2A to 2D, both LY294002 and PD98059 inhibited 1...

Embodiment 3

[0169] Example 3. Synthesis and characterization of 1K1-nanoparticles.

[0170] A key challenge in therapeutic angiogenesis is the local and sustained delivery of angiogenic factors at the desired site of action (6). In a previous study, Richardson et al. demonstrated that sustained release of VEGF-165 and PDGF-BB from a single structural polymer scaffold (each with different kinetics) resulted in rapid formation of mature vascular networks (19). Furthermore, controlled intramyocardial delivery of platelet-derived growth factors has been reported to improve ventricular function after infarction with increased vascularization (20). Similarly, in a recent study, intramuscular injection of pivastatin-loaded nanoparticles, which deliver sustained drug release, resulted in enhanced angiogenesis (21). However, no previous studies have demonstrated sustained release formulations of 1K1. Thus, nanoparticles were engineered from polylactic-glycolic acid (PLGA) copolymers, which are...

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Abstract

The invention relates to pharmaceutical compositions and to methods for inducing angiogenesis in conditions associated with insufficient vascularization, e.g. ischemia and diabetic conditions, such as diabetic foot ulcers. In particular, pharmaceutical compositions comprising sustained release nanoparticles that contain 1K1 fragment of Hepatocyte Growth Factor / Scatter Factor are provided.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application Serial No. 61 / 378,968, filed September 1, 2010, and U.S. Provisional Application Serial No. 61 / 306,768, filed February 22, 2010, under 35 U.S.C. § 119(e) , the contents of which provisional application is incorporated herein by reference in its entirety. field of invention [0003] Embodiments of the invention relate to pharmaceutical compositions and methods for inducing angiogenesis in conditions associated with hypovascularization, such as ischemic and diabetic conditions, such as diabetic foot ulcers. Background of the invention [0004] Adult neovascularization has the potential to ameliorate ischemic disease, the leading cause of morbidity and mortality in the United States (1). Ischemic diseases include cardiovascular disorders including angina pectoris, peripheral arterial disease, tissue sores. Ferrara and Kerbel recently articulated 'thera...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/18A61K38/16A61K9/06A61K9/12A61P7/06A61P9/00
CPCA61K9/5153A61K38/1833A61P7/06A61P9/00
Inventor S.森古普塔R.辛哈罗伊S.索尼R.哈富歇
Owner THE BRIGHAM & WOMEN S HOSPITAL INC
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