Chitosan Polymer Integrin Antagonist siRNA Delivery

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Solution Overview

Problem

Current delivery methods for nucleic acids, such as siRNA, face challenges in targeting specific tissues and cell types, and efficiently reaching the cytoplasm, due to their negative charge and susceptibility to degradation, with existing carriers like lipid nanoparticles having safety concerns and limited organ targeting.

Innovation Solution

Development of chitosan polymer derivatives covalently linked to small molecule integrin antagonists, which act as targeting ligands for the delivery of siRNA and other therapeutic molecules to cells expressing integrin receptors like α4β1 and αVβ3, forming nanoparticles that facilitate selective gene silencing through RNA interference.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If lipid nanoparticles are used as carriers for nucleic acid delivery, then delivery efficiency is improved, but safety concerns and limited organ targeting occur

Engineering Contradiction:

Improvedelivery efficiencyVSAvoidsafety concerns

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the chemical composition parameters of the nanoparticle carrier from lipid-based to chitosan-based polymers. This parameter change maintains delivery efficiency while improving safety profile and enabling integrin-specific targeting through covalent attachment of targeting ligands to the chitosan structure

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite nanoparticle structures by covalently linking integrin antagonist ligands (such as RGD peptides or small molecule integrin antagonists) to chitosan polymer chains. This composite approach combines the biocompatibility of chitosan with the targeting specificity of integrin antagonists, resolving the contradiction between delivery efficiency and safety

Inventive Principle:

Principle #40Composite materials

2Reliability

If nucleic acids are delivered to target cells, then gene silencing efficacy is achieved, but negative charge and susceptibility to degradation hinder delivery

Engineering Contradiction:

Improvegene silencing efficacyVSAvoidsusceptibility to degradation

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent introduces chitosan polymer derivatives as intermediary carriers that protect nucleic acids from degradation. The chitosan forms stable complexes with siRNA through electrostatic interactions, shielding the negatively charged siRNA from nucleases while maintaining its gene silencing activity, thus resolving the contradiction between achieving gene silencing efficacy and overcoming susceptibility to degradation

Inventive Principle:

Principle #24Intermediary (Mediator)

3Ease of operation

If existing carriers are used for nucleic acid delivery, then delivery to cells is achieved, but limited organ targeting and inefficient cytoplasmic delivery occur

Engineering Contradiction:

Improvedelivery capabilityVSAvoidtargeting precision

Core Design Contradiction:

Ease of operationVSMeasurement precision

Solution Approach 1:

The patent segments the delivery system into distinct functional components: chitosan polymer for carrier functions, integrin antagonist ligands for targeting specificity, and siRNA for gene silencing. This segmentation allows each component to be optimized independently, with the integrin antagonist providing precise targeting to specific organs and cell types expressing integrin receptors, thereby improving targeting precision while maintaining delivery capability

Inventive Principle:

Principle #1Segmentation

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The chitosan polymer derivatives enhance the delivery of siRNA to target cells, improving gene silencing efficacy and safety by utilizing integrin-specific targeting, overcoming the limitations of existing delivery methods.

Implementation Method 1

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

Methodology Applied

Scientific EffectReceptor-ligand binding: Adsorption

Implementation Method 2

Chitosan and other cationic polymers and their complexes with polyanions have emerged as attractive alternatives to lipid-based nanoparticles for the delivery of siRNA and other nucleic acids

Methodology Applied

Scientific EffectProton sponge effect:

Implementation Method 3

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)

Methodology Applied

Scientific EffectRNA interference:

Data Source

PatentUS11491178B2Chitosan covalently linked with small molecule integrin antagonist for targeted delivery

Publication Date: 2022.11.08 F HOFFMANN LA ROCHE INC

AI summary

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 (α Vβ3) 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.