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Chitosan covalently linked with small molecule integrin antagonist for targeted delivery

a technology of integrin antagonist and chitosan, which is applied in the field of chitosan polymer derivatives, can solve the problems of increasing the risk of metastasis, affecting the cytoplasm of cells,

Inactive Publication Date: 2013-08-01
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention is about a type of polymer made from three different components that are connected by a single oxygen atom. The polymer can be used to deliver small molecules, peptides, and nucleic acids to target specific cells in the body. This polymer can also be modified to create new polymers that can have different functions and can be used for therapeutic purposes. The invention also includes methods for making and using these polymers.

Problems solved by technology

Certain cancer cells may also express VLA-4 which bind to VCAM-1 adhering to the endothelium (increasing the risk of metastasis).
One of the problems in using nucleic acids such as siRNA in therapeutic applications (especially for systemic administration in humans) has been in delivering the nucleic acids to: (1) particular target tissues or cell types and (2) to the cytoplasm of those cells (i.e., where the mRNA is present and translated into protein).
Part of the delivery problem is based on the fact that nucleic acids are negatively charged and easily degraded (especially if unmodified), efficiently filtered by the kidney, and cannot be easily transported to the cytoplasm of the cells by themselves.
However, clinical trials using lipid-based nanoparticles (LNPs) have been somewhat limited by safety concerns, antibody opsonization and phagocytosis, and an inability to deliver nucleic acids, such as siRNA, to organs other than the liver and lung after intravenous administration.

Method used

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  • Chitosan covalently linked with small molecule integrin antagonist for targeted delivery
  • Chitosan covalently linked with small molecule integrin antagonist for targeted delivery
  • Chitosan covalently linked with small molecule integrin antagonist for targeted delivery

Examples

Experimental program
Comparison scheme
Effect test

example 1

Cs(NM)-αvβ3 Ligand 3 (0.3% Loading) (RO5544717 Chitosan Derivative D)

Step 1: Cs(NM)-Pr—S-Ac (0.26%)

[0240]

[0241]In an Erlenmeyer flask was added Protosan (novamatrix (NM) (200 mg, 1.13 mmol), 1H-benzo[d][1,2,3]triazol-1-01 (153 mg, 1.13 mmol, Eq: 1.0), 3-(acetylthio)propanoic acid (836 μg, 5.64 μmol, Eq: 0.005), and water (50 mL). The mixture was stirred until a clear colorless solution formed, and then was diluted with Acetonitrile (50.0 mL). To this was added EDC (3.25 mg, 16.9 μmol, Eq: 0.015) and the reaction was stirred at RT for 13 hr. The reaction was partially acidified with 1 mL of 0.1M HCl, concentrated, transferred to a dialysis bag (10K MWCO, Thermo Scientific, Snake Skin), and dialyzed against 4 L of 2.5% NaCl solution for 3 h, 2% for 5 h, 1% for 6 h, 0.5% 12 h, water 12 h 4 times. The dialysate was lypholized yielding off white fibrous solid, 158 mg. The loading was determined by 1H NMR integration of the methyl of the thioacetate at 2.21 ppm as compared to the methyl o...

example 2

Cs(NM)-αvβ3 Ligand 3 (0.6% Loading) (RO5544719 Chitosan Derivative E)

Step 1: Cs(NM)-Pr—S-Ac (0.47%)

[0246]The product (clear to opaque off white film / sheet solid, 176 mg) was prepared by a similar procedure as Cs(NM)-Pr—S-Ac (0.26%) from Protosan (200 mg, 1.13 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (153 mg, 1.13 mmol, Eq: 1.0), 3-(acetylthio)propanoic acid (1.67 mg, 11.3 μmol, Eq: 0.01), and EDC (6.49 mg, 33.9 μmol, Eq: 0.03). (0.47%, N 4.30 nmol / mg).

Step 2: Chitosan(NM)-Pr—SH (0.47%)

[0247]The product (clear to opaque off white film / sheet solid) was prepared by a similar procedure as Cs(NM)-Pr—SH (0.26%) from Cs(NM)-Pr—S-Ac (0.47%) (47.5 mg). The material was used as is (0.47%, 23.7 nmol / mg).

Step 3: Cs(NM)-αvβ3 Ligand 3 (0.6% Loading) (RO5544719 Chitosan Derivative E)

[0248]The product (a white fibrous solid, 20 mg) was prepared by a similar procedure as Cs(NM)-Pr—S-αvβ3 Ligand 3 (0.3%) from Cs(NM)-Pr—SH (0.47%) (42 mg, 23.7 nmol / mg, 0.995 mop and αvβ3 Ligand 3 (3.7 mg, 2.99 μmol, Eq. ...

example 3

Cs(NM)-αvβ3 Ligand 3 (1.9% Loading) (RO5544720 Chitosan Derivative F)

Step 1: Cs(NM)-Pr—S-Ac (1.9%)

[0249]The product (clear to opaque off white film / sheet solid, 226 mg) was prepared by a similar procedure as Cs(NM)-Pr—S-Ac (0.26%) from Protosan (200 mg, 1.13 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (153 mg, 1.13 mmol, Eq: 1.0), 3-(acetylthio)propanoic acid (5.02 mg, 33.9 μmol, Eq: 0.03), and EDC (19.5 mg, 102 μmol, Eq: 0.09). (1.9%, N 4.20 nmol / mg).

Step 2: Cs(NM)-Pr—SH (1.9%)

[0250]The product (clear to opaque off white film / sheet solid) was prepared by a similar procedure as Cs(NM)-Pr—SH (0.26%)) from Cs(NM)-Pr—S-Ac (1.9%) (48 mg). The material was used as is (1.9%, 95.3 nmol / mg).

Step 3: Cs(NM)-αvβ3 Ligand 3 (1.9% Loading) (RO5544720 Chitosan Derivative F)

[0251]The product (a white fibrous solid, 28 mg) was prepared by a similar procedure as Cs(NM)-Pr—S-αvβ3 Ligand 3 (0.3%) from Cs(NM)-Pr—SH (1.9%) (45 mg, 95.3 nmol / mg, 4.29 μmol) and αvβ3 Ligand 3 (15.9 mg, 12.8 μmol, Eq 3). (1.9%, 89...

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Abstract

The invention relates to the chitosan polymer derivatives of formula I:and pharmaceutically acceptable salts and esters thereof, wherein Y, X1, X4, R1, R2, and n are defined in the detailed description and claims. The chitosan polymer derivatives of formula I bind to or associate with alpha-4-beta-1 (α4β1) and alpha-V-beta-3 (αVβ3) integrin dimers and can be used in delivery formulations to deliver drugs, nucleic acids, or other therapeutic compounds to tissues or cells expressing such integrins.

Description

PRIORITY TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Patent Application No. 61 / 670,665, filed Jul. 12, 2012, and U.S. Provisional Application No. 61 / 591,293, filed Jan. 27, 2012, the disclosures of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION[0002]The present invention relates to chitosan polymer derivatives that are covalently linked to small molecule integrin antagonists for targeted delivery. Some of these small molecule integrin antagonists bind to the VLA-4 (Very Late Antigen-4) dimer (also referred to as the Integrin alpha-4-beta-1 dimer or α4β1). Other small molecule integrin antagonists of the present invention bind to the alpha-V-beta-3 (αVβ3) dimer. Such chitosan linked integrins can be used as targeting ligands for the delivery of other small molecules, peptides, and nucleic acids. For example, such chitosans may be used for the formation of oligonucleotide or siRNA nanoparticles which aid in ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K47/48
CPCA61K47/48215A61K47/4823A61K47/60A61K47/61A61K31/722A61P29/00A61P3/00A61P35/00A61K47/50C08B37/003
Inventor CHIN, JAYNEGOODNOW, JR., ROBERT A.HAMILTON, MATTHEW MICHAELSIDDURI, ACHYUTHARAO
Owner F HOFFMANN LA ROCHE & CO AG
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