Poly-ion Complex Micelle Hydrazone Crosslinking

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Solution Overview

Problem

Conventional poly-ion complex micelles easily collapse at physiological conditions due to disruption of polymer-drug ionic interactions, leading to premature release of encapsulated negatively-charged molecules and non-selective cytotoxicity from free polymers.

Innovation Solution

A poly-ion complex micelle is developed using a block copolymer with a hydrophilic block, a cationic hydrophobic block, and a crosslinking block with a hydrazone bond, which crosslinks to stabilize the encapsulation of anionic molecules, preventing leakage unless triggered by physiological conditions like low endosomal pH.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If simple ionic interaction between polymer and drug is used, then micelle formation is achieved, but micelle stability deteriorates at physiological conditions

Engineering Contradiction:

Improvemicelle stabilityVSAvoidpolymer-drug interaction reliability

Core Design Contradiction:

Stability of the object's compositionVSReliability

Solution Approach 1:

The patent uses a composite block copolymer structure containing hydrophilic PEG blocks, cationic polylysine blocks, and crosslinkable aspartic acid blocks. This composite structure provides both the ionic interaction needed for micelle formation and the crosslinking capability for enhanced stability, resolving the contradiction between easy micelle formation and stable encapsulation.

Inventive Principle:

Principle #40Composite materials

Solution Approach 2:

The patent incorporates crosslinkable functional groups (aspartic acid residues) into the polymer structure before micelle formation. These groups are preliminarily prepared to enable subsequent crosslinking under physiological conditions, which stabilizes the micelle structure and prevents premature drug release.

Inventive Principle:

Principle #10Preliminary action

2Quantity of substance

If conventional poly-ion complex micelles are used, then encapsulation is achieved, but premature drug release occurs due to ionic interaction disruption

Engineering Contradiction:

Improvedrug encapsulationVSAvoiddrug release control

Core Design Contradiction:

Quantity of substanceVSDuration of action of moving object

Solution Approach 1:

The polymer is preliminarily equipped with crosslinkable aspartic acid blocks that remain dormant during micelle formation but become activated under physiological conditions to form crosslinks, thereby stabilizing the encapsulated drug and preventing premature release while maintaining controlled release over time.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent exploits changes in physiological parameters (pH, temperature, presence of glutathione) to trigger crosslinking of the aspartic acid blocks. This parameter-based activation transforms the micelle from a simple ionic complex to a crosslinked stable structure, ensuring sustained drug release rather than premature release.

Inventive Principle:

Principle #35Parameter changes

3Ease of manufacture

If free polymer is present in the system, then micelle formation is facilitated, but non-selective cytotoxicity increases

Engineering Contradiction:

Improvemicelle formation easeVSAvoidcytotoxicity

Core Design Contradiction:

Ease of manufactureVSObject-affected harmful factors

Solution Approach 1:

The polymer is preliminarily designed with crosslinkable functional groups that enable in-situ crosslinking under physiological conditions. This preliminary design allows easy micelle formation initially, followed by automatic stabilization that prevents free polymer from causing cytotoxicity while maintaining the beneficial micelle structure.

Inventive Principle:

Principle #10Preliminary action

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 micelle effectively stabilizes the encapsulation of negatively-charged molecules, enhancing cellular uptake and maintaining drug stability, with improved release control and reduced cytotoxicity compared to conventional methods.

Implementation Method 1

the crosslinking block portion has a hydrazone bond, the block copolymer includes the first block copolymer chain and the second block copolymer chain crosslinked to each other in the crosslinking block portion

Methodology Applied

Scientific EffectHydrazone bond formation: Chemical Bonding

Implementation Method 2

conventional poly-ion complex micelles have been used for nucleic acids (e.g., pDNA, mRNA, siRNA, ASO), and negatively-charged, large molecules that has ionic interactions with cationic polymers

Methodology Applied

Scientific EffectIonic interaction: Ion Repulsion/Attraction

Data Source

PatentUS20240075148A1Poly-ion complex micelle

Publication Date: 2024.03.07 KAWASAKI INST OF IND PROMOTION

AI summary

A poly-ion complex micelle comprising: a block copolymer having a hydrophilic block portion, a cationic hydrophobic block portion and a crosslinking block portion positioned between the hydrophilic block and the cationic hydrophobic block, and an anionic molecule drug encapsulated by the block copolymer, wherein the crosslinking block has a hydrazone bond, the block copolymer comprises the first block copolymer chain and the second block copolymer chain, the first block copolymer chain and the second block copolymer chain crosslinked to each other in the crosslinking block portion, the hydrophilic block portion comprises the first hydrophilic block of the first block copolymer chain and the second hydrophilic block of the second block copolymer chain, and the cationic hydrophobic block portion comprises the first cationic hydrophobic block of the first block copolymer chain.