Trehalose Nanogel Stabilization of Glucagon Peptides

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Solution Overview

Problem

Glucagon's clinical potential is limited by its insolubility and instability in solution, leading to patient discomfort and significant peptide degradation, which necessitates the development of stable and effective delivery methods.

Innovation Solution

Trehalose-based nanogels are synthesized, comprising copolymers with trehalose side chains and disulfide side chains, which form redox-responsive nanogels through disulfide exchange with thiolated glucagon, providing stabilization and controlled release of the peptide hormone.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If glucagon is dissolved in dilute HCl to increase solubility, then solubility is improved, but patient discomfort occurs upon injection

Engineering Contradiction:

ImprovesolubilityVSAvoidpatient discomfort

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

The patent changes the pH parameter of the glucagon formulation from acidic (dilute HCl) to neutral pH by using trehalose-based nanogels, which maintain glucagon solubility while eliminating the acidity-related patient discomfort upon injection

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The trehalose-based nanogel acts as an intermediary carrier that encapsulates glucagon, allowing the peptide to be delivered at neutral pH without direct contact between the acidic environment and patient tissue, thereby resolving the contradiction between solubility and patient comfort

Inventive Principle:

Principle #24Intermediary (Mediator)

2Ease of operation

If glucagon is kept in solution for administration, then ease of administration is improved, but peptide aggregation and degradation occur rapidly

Engineering Contradiction:

Improveease of administrationVSAvoidpeptide stability

Core Design Contradiction:

Ease of operationVSStability of the object's composition

Solution Approach 1:

The glucagon peptide is nested within the trehalose-based nanogel structure, which provides a protective microenvironment that prevents aggregation and degradation while maintaining the peptide in a soluble, administrable form for extended periods

Inventive Principle:

Principle #7Nested doll (Nesting)

Solution Approach 2:

The patent creates a composite material system where glucagon is conjugated to trehalose-based copolymers forming nanogels, combining the benefits of peptide functionality with polymer stabilization to prevent aggregation and extend solution stability

Inventive Principle:

Principle #40Composite materials

3Stability of the object's composition

If polymer conjugation is used to stabilize glucagon, then stability is improved, but bioactivity may be lost due to steric shielding

Engineering Contradiction:

Improveglucagon stabilityVSAvoidbioactivity

Core Design Contradiction:

Stability of the object's compositionVSReliability

Solution Approach 1:

The trehalose-based nanogel provides localized stabilization at specific sites on the glucagon molecule through conjugation, while leaving other regions of the peptide accessible for receptor interaction, thus maintaining bioactivity while improving stability

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The nanogel-conjugated glucagon system allows dynamic conformational adjustments where the peptide can adopt different orientations, enabling the active site to remain accessible to receptors while the polymer provides stabilization, resolving the contradiction between stability and bioactivity

Inventive Principle:

Principle #15Dynamics

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 trehalose-based nanogels significantly enhance the stability and solubility of glucagon, preventing aggregation and maintaining bioactivity for extended periods, allowing for effective delivery and controlled release of the hormone.

Implementation Method 1

copolymers with trehalose side chains and disulfide side chains, which form redox-responsive nanogels through disulfide exchange with thiolated glucagon

Methodology Applied

Scientific EffectDisulfide exchange: Chemical Bonding

Implementation Method 2

Current research suggests that potentially trehalose stabilization occurs due to a combination of the above hypotheses: vitrification, water replacement, and water entrapment

Methodology Applied

Scientific EffectVitrification: Vitrification

Implementation Method 3

the hydrogen bonding capabilities of trehalose could potentially displace water and stabilize protein structure

Methodology Applied

Scientific EffectWater replacement:

Implementation Method 4

trehalose is able to trap water near the protein surface, stabilizing protein structure

Methodology Applied

Scientific EffectWater entrapment:

Data Source

PatentUS11951176B2Stabilization of glucagon by trehalose glycopolymer nanogels

Publication Date: 2024.04.09 RGT UNIV OF CALIFORNIA

AI summary

Trehalose-based nanogels for stabilizing and controlled releasing biomolecules such as glucagons are disclosed. Specifically, trehalose-based nanogels comprise (a) a copolymer comprising first methacrylate units and second methacrylate units, wherein (i) the first methacrylate units comprise trehalose side chains; and (ii) the second methacrylate units comprise disulfide side chains; (b) dithiol cross-linkers; wherein the dithiol cross-linkers cross link the copolymer through the disulfide side chains of the second methacrylate units.