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Shear controlled release for stenotic lesions and thrombolytic therapies

A thrombus and anti-thrombotic technology, which can be applied to medical preparations without active ingredients, medical preparations containing active ingredients, sexual diseases, etc., and can solve the problems that have not been proposed or developed.

Active Publication Date: 2013-07-24
PRESIDENT & FELLOWS OF HARVARD COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these methods, or alternatives, have not been suggested or developed for the targeted delivery of drugs to narrow sites in blood vessels or other fluid-filled passages in the body

Method used

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  • Shear controlled release for stenotic lesions and thrombolytic therapies
  • Shear controlled release for stenotic lesions and thrombolytic therapies
  • Shear controlled release for stenotic lesions and thrombolytic therapies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0452] PEG-PLGA (50:50MW4:17kDA) or PLGA (50:50MW17kDa) nanoparticles were prepared as follows. Using maleimide-PEG-NH 2 Linkers, COOH-PEG-PLGA or COOH-PLGA polymers were conjugated to binding peptides (CREKA (SEQ ID NO: 1) or CRKRLDRNK (SEQ ID NO: 3)). First, the cysteine ​​terminus of the peptide was conjugated to the maleimide terminus of the PEG linker in PBS buffer at pH 6.5. Second, the carboxyl-functionalized PEG-PLGA polymer was preactivated with 1-ethyl-3-(3-dimethylaminopropyl) (EDC) and N-hydroxysuccinimide (NHS), followed by the corresponding The PEG-modified peptides were reacted in PBS / DMSO mixture for about 4 hours at room temperature. The final product was purified by dialysis and a lyophilized powder was obtained. conjugation reaction by 1 Confirmed by H NMR. The peptide-conjugated polymer was then dissolved with coumarin (a hydrophobic dye) in ethyl acetate or DMSO, and the nanoparticles were prepared by w / o / w emulsion method or simple solvent displaceme...

Embodiment 2

[0457] Example 2: Shear-Activated Platelet Mimetics for Targeting Drugs to Obstruct Blood Vessels

[0458] Materials and methods

[0459] Nanoparticle preparation: Nanoparticles (NP) were prepared from PLGA (50:50, 17 kDa, acid-terminated; Lakeshore Biomaterials, AL) using a simple solvent exchange method (C.E. Astete & C.M. Sabliov, Journal of Biomaterials Science, Polymer Edition 17, 247( 2006)). The fluorescent hydrophobic dye coumarin was included in the NPs to enable visualization and quantification in this study. Briefly, 1 mg / ml of polymer was dissolved with coumarin in dimethylsulfoxide (DMSO, Sigma, MO), dialyzed against water at room temperature, and the nanoparticles were formed by solvent displacement. The size distribution and morphology of the formed NPs were characterized using dynamic light scattering (DLS), scanning electron microscopy (SEM) and transmission electron microscopy (TEM).

[0460] Manufacture of platelet mimics - PLGA NPs were centrifuged and...

Embodiment 3

[0494] Example 3: Shear Stress Controlled Release from RBCs

[0495] Red blood cell ghost cells were prepared using hypotonic hemolysis. Briefly, RBCs were centrifuged from blood (2000 g, 10 min) and resuspended in calcium / magnesium-free diluted PBS (1:10 volume ratio of PBS to DD water). The cells were incubated at 4°C for 15 minutes and then centrifuged (12,000 g, 10 min). This process was repeated four times. The cells were subsequently loaded with FITC-dextran by incubating the cells with 5 mg / ml of dextran in diluted PBS for 1 hour at 4°C. The cells were centrifuged, suspended in PBS buffer containing calcium / magnesium, and allowed to reseal over two hours in a 37°C incubator. After the reclosure procedure, the cells were washed four times in PBS to remove any residues in solution. Figure 8 Fluorescence images of FITC-dextran-loaded RBC ghost cells are shown, imaged 5 days after preparation of the FITC-dextran-loaded RBC ghost cells.

[0496] Inject a suspension of ...

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Abstract

The invention provides compositions and methods for treating or imaging stenosis, stenotic lesions, occluded lumens, embolic phenomena or thrombotic disorders. The invention further provides compositions and methods for treating internal hemorrhage.

Description

[0001] Cross References to Related Applications [0002] Pursuant to 35 U.S.C. §119(e), this application claims priority to U.S. Provisional Patent Application No. 61 / 378,057, filed August 30, 2010, and U.S. Provisional Patent Application No. 61 / 478,700, filed April 25, 2011 Right to incorporate the entire contents of both into this article by reference. [0003] governmental support [0004] This invention was made with Government support under Grant No. R01ES016665 awarded by the National Institutes of Health and Grant Nos. BC074986 and 81XWH-08-1-0659 awarded by the Department of Defense. The US Government has certain rights in this invention. technical field [0005] The present invention relates to compositions and methods for the treatment or imaging of stenosis, stenotic lesions, and thrombolytic therapy. The invention also relates to compositions and methods for the treatment or imaging of internal bleeding. Background technique [0006] Selective drug delivery t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48
CPCA61K47/48A61K9/1617A61K9/5153A61K38/49A61K31/721A61P1/04A61P15/00A61P19/00A61P21/00A61P25/00A61P7/02A61P7/04A61P7/06A61P9/00A61P9/10A61P9/12Y02A50/30A61K47/50A61K9/16A61K47/30A61K48/00A61K38/02
Inventor 唐纳德·E·英格贝尔内塔尼尔·科林马图迈·卡纳帕斯皮尔来
Owner PRESIDENT & FELLOWS OF HARVARD COLLEGE
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