Lipid-PEGylated Solid Supports for Oligonucleotide Synthesis

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Solution Overview

Problem

Current methods for synthesizing lipid-oligonucleotide conjugates (LONs) face challenges such as limited solubility and stability issues during solid-phase oligonucleotide synthesis, particularly when introducing hydrophobic moieties. Additionally, existing delivery methods for oligonucleotide drugs like siRNAs struggle with efficient cellular uptake and prolonged circulation times due to their polyanionic and hydrophilic nature.

Innovation Solution

The development of lipid-PEGylated solid supports and phosphoramidites, which incorporate fatty acid moieties and shorter PEG chains, allows for improved drug distribution after injection. These compounds can be used in both pre-synthetic and post-synthetic approaches for synthesizing LONs, enhancing solubility and stability, and facilitating better pharmacokinetic properties.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of manufacture

If hydrophobic moieties are introduced directly into solid-phase oligonucleotide synthesis, then purification is easier, but solubility and stability requirements are challenging

Engineering Contradiction:

Improvepurification easeVSAvoidsolubility and stability

Core Design Contradiction:

Ease of manufactureVSStability of the object's composition

Solution Approach 1:

The hydrophobic moiety is segmented into separate components: a solid support component and a linker component. The solid support contains the hydrophobic moiety (e.g., fatty acid or cholesterol derivative), while the linker contains the PEG chain and reactive groups. This segmentation allows the hydrophobic moiety to be incorporated during solid-phase synthesis for easy purification, while the PEG linker maintains solubility and stability requirements.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The linker acts as an intermediary between the hydrophobic moiety on the solid support and the oligonucleotide. It contains both PEG chains (providing solubility and stability) and reactive groups (enabling conjugation). This intermediary structure resolves the contradiction by allowing hydrophobic incorporation during synthesis while maintaining aqueous solubility through the PEG linker.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Adaptability or versatility

If siRNAs are used as oligonucleotide drugs, then targeted treatment is achieved, but cellular uptake is poor due to polyanionic and hydrophilic nature

Engineering Contradiction:

Improvetargeted treatment capabilityVSAvoidcellular uptake efficiency

Core Design Contradiction:

Adaptability or versatilityVSEase of operation

Solution Approach 1:

The conjugate is a composite structure combining siRNA (polyanionic, hydrophilic) with lipid-PEG moieties (hydrophobic). The lipid component provides hydrophobic character that enhances cellular membrane permeation, while the PEG component maintains solubility. This composite structure resolves the contradiction by combining the targeted treatment capability of siRNA with the cellular uptake efficiency of lipid-conjugated compounds.

Inventive Principle:

Principle #40Composite materials

3Duration of action of stationary object

If PEG chains are used to increase circulation lifetime, then enzymatic degradation is prevented, but solubility control becomes critical

Engineering Contradiction:

Improvecirculation lifetimeVSAvoidsolubility control

Core Design Contradiction:

Duration of action of stationary objectVSStability of the object's composition

Solution Approach 1:

The patent systematically varies parameters including the number of PEG chains, PEG chain length, and hydrophobic moiety structure to optimize the balance between circulation lifetime and solubility. By changing these parameters, the conjugate achieves prolonged circulation while maintaining appropriate solubility for biological activity.

Inventive Principle:

Principle #35Parameter changes

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 use of lipid-PEGylated solid supports and phosphoramidites improves the solubility and stability of LONs, leading to enhanced drug distribution and prolonged circulation times. This results in improved therapeutic efficacy for oligonucleotide drugs, including increased cellular uptake and sustained action.

Implementation Method 1

PEG's high flexibility is believed to lead to the creation of a hydration layer, which not only increases overall solubility but also increases the hydrodynamic volume

Methodology Applied

Scientific EffectHydration layer formation: Solvation

Implementation Method 2

The lipidation of oligonucleotides significantly increases their hydrophobic character and provides for longer circulation times

Methodology Applied

Scientific EffectHydrophobic interaction: Hydrophobe

Data Source

PatentUS20250027091A1Lipid-pegylated compounds, preparations and uses thereof

Publication Date: 2025.01.23 HONGENE BIOTECH CORPORATION

AI summary

Embodiments of the present disclosure relate to lipid-PEGylated solid support and phosphoramidites derivatives, methods for preparing the same, and their uses in the delivery of oligonucleotide drugs to the cellular targets.