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Chitosan covalently linked with small molecule integrin antagonist for targeted delivery

a small molecule integrin and covalent linking technology, which is applied in the direction of biocide, drug composition, metabolic disorder, etc., can solve the problems of increasing the risk of metastasis, affecting and unable to be easily transported to the cytoplasm of cells by themselves, so as to improve the delivery effect of small molecules

Inactive Publication Date: 2015-10-29
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The chitosan polymer derivatives enhance the delivery of therapeutic agents to target cells, improving knockdown capability and tissue specificity, while being biodegradable and safer than lipid-based systems, with potential applications in treating cancer and inflammatory diseases.

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) (Chitosan Derivative D)

Step 1: Cs(NM)-Pr-S-Ac (0.26%)

[0248]

[0249]In an Erlenmeyer flask was added Protosan (novamatrix (NM) (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 (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 0.1 M 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 lyophilized 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 of the N...

example 2

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

Step 1: Cs(NM)-Pr-S-Ac (0.47%)

[0253]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%)

[0254]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) (Chitosan Derivative E)

[0255]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 pimp and αvβ3 Ligand 3 (3.7 mg, 2.99 μmol, Eq. 3). (0.6% (29 nmol / ...

example 3

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

Step 1: Cs(NM)-Pr-S-Ac (1.9%)

[0256]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%)

[0257]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) (Chitosan Derivative F)

[0258]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 nmol / mg, N 3.7 μmo...

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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

[0001]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 the selective delivery of such oligonucleotides or siRNA to cells which express such integrin receptors, thereby altering or preventing the expression of target genes through RNA interference (RNAi) or other mechanisms.[0002]VLA-4 (Very Late Antigen-4, also called α4β1) is an integrin dimer. It is comprised of two subuni...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/722C08B37/08
CPCC08B37/003A61K31/722A61K47/60A61K47/61A61P29/00A61P3/00A61P35/00A61K47/50
Inventor CHIN, JAYNEGOODNOW, JR., ROBERT ALANHAMILTON, MATTHEW MICHAELSIDDURI, ACHYUTHARAO
Owner F HOFFMANN LA ROCHE & CO AG
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