Bottlebrush Polymer-Oligonucleotide Conjugates for Stability

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Solution Overview

Problem

Oligonucleotides, such as aptamers, face challenges as therapeutics due to poor in vivo stability and difficult pharmacological properties, including short blood circulation times and non-specific binding.

Innovation Solution

A bottlebrush polymer-oligonucleotide conjugate is developed, comprising a sequence-defined polymer backbone with side chains and oligonucleotides linked to the monomers, enhancing stability and pharmacological properties.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If oligonucleotides are used as therapeutics, then they can bind with high affinity to targets, but they exhibit poor in vivo stability and short blood circulation times

Engineering Contradiction:

Improvebinding affinityVSAvoidblood circulation time

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent creates a composite material by conjugating oligonucleotides to bottlebrush polymers. The oligonucleotide portion maintains target binding affinity while the polymer portion provides stability and extended circulation time. This composite structure combines the advantages of both components to overcome their individual limitations.

Inventive Principle:

Principle #40Composite materials

Solution Approach 2:

The bottlebrush polymer acts as an intermediary carrier that connects the oligonucleotide therapeutic to the biological environment. This polymer mediator protects the oligonucleotide from degradation while maintaining its binding function, effectively bridging the gap between the therapeutic agent and the in vivo environment.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If oligonucleotides are administered therapeutically, then they can exert antisense activity, but they require high dosages due to rapid clearance

Engineering Contradiction:

Improveantisense activityVSAvoiddosage requirement

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The bottlebrush polymer conjugate enables continuous presence of the oligonucleotide in the bloodstream by preventing rapid clearance. The polymer structure maintains the oligonucleotide in circulation for extended periods, ensuring continuous therapeutic action at lower dosages rather than requiring repeated high-dose administrations.

Inventive Principle:

Principle #20Continuity of useful action

3Ease of manufacture

If oligonucleotides are used as therapeutics, then they offer better production scalability, but they face poor in vivo stability

Engineering Contradiction:

Improveproduction scalabilityVSAvoidin vivo stability

Core Design Contradiction:

Ease of manufactureVSStability of the object's composition

Solution Approach 1:

The therapeutic agent is segmented into two functional parts: the oligonucleotide segment that provides therapeutic activity and the polymer segment that provides stability. This segmentation allows each component to be optimized independently - the oligonucleotide for manufacturability and binding, while the polymer for stability and circulation.

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS20250049935A1Bottlebrush conjugates for use as oligonucleotide enhancers

Publication Date: 2025.02.13 NORTHEASTERN UNIV (US)

AI summary

Provided herein are, in various embodiments, are bottlebrush polymer-oligonucleotides conjugates. In certain embodiments, the conjugates are potent in vivo, have improved biopharmaceutical properties, enhanced transfection efficiency, and/or an unconventional biodistribution profile. Also provided herein are pharmaceutical compositions, methods of treatment, and methods of making bottlebrush polymer-oligonucleotide conjugates.