Polyaminated PGA Polyplexes for Stable Oligonucleotide Delivery

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Solution Overview

Problem

Existing siRNA/miRNA delivery systems face challenges such as aggregation in aqueous media, short in vivo circulation time, fast renal clearance, high immunogenicity, non-specific body distribution, poor intracellular uptake, and difficulty in escaping endosomes, limiting their effectiveness in gene silencing therapies.

Innovation Solution

Development of PGA-based polymers with pendant amine-containing moieties for conjugating oligonucleotides, utilizing electrostatic interactions to form polyplexes that enhance intracellular delivery and cytoplasmic localization, leveraging the enhanced permeability and retention effect for tumor targeting and endosomolytic release.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If siRNA/miRNA are delivered using conventional methods, then gene silencing activity is achieved, but aggregation in aqueous media occurs and stability is poor

Engineering Contradiction:

ImprovestabilityVSAvoidaggregation

Core Design Contradiction:

Stability of the object's compositionVSReliability

Solution Approach 1:

Cationic polymers serve as intermediaries that complex with anionic siRNA/miRNA to form polyplexes, preventing aggregation in aqueous media while maintaining stability during circulation

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

Changing the physical-chemical parameters of the delivery system by forming polyplexes with cationic polymers, which alters the charge and solubility characteristics to prevent aggregation and enhance stability

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If siRNA/miRNA are administered systemically, then broad distribution is achieved, but non-specific body distribution and fast renal clearance occur

Engineering Contradiction:

ImprovedistributionVSAvoidcirculation time

Core Design Contradiction:

Adaptability or versatilityVSLoss of time

Solution Approach 1:

The polymeric carriers provide local quality enhancement at the tumor site through passive targeting via EPR effect, concentrating the therapeutic agent where needed while reducing systemic clearance

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

Composite polymeric carriers combining cationic polymers with siRNA/miRNA create particles with optimized size and charge characteristics that extend circulation time and enable tumor-specific accumulation

Inventive Principle:

Principle #40Composite materials

3Ease of operation

If naked siRNA/miRNA are used for delivery, then simplicity is maintained, but poor intracellular uptake and difficulty in escaping endosomes occur

Engineering Contradiction:

Improveintracellular uptakeVSAvoiddelivery system complexity

Core Design Contradiction:

Ease of operationVSDevice complexity

Solution Approach 1:

Cationic polymers act as intermediaries that facilitate intracellular uptake through electrostatic interaction with cell membranes and enable endosomal escape via the proton sponge effect, overcoming the limitations of naked oligonucleotide delivery

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

Changing the charge and physicochemical properties of the delivery system by using cationic polymers, which enhances cellular internalization and promotes endosomal disruption for cytoplasmic release

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 PGA-based polyplexes demonstrate improved stability, specificity, and efficacy in gene silencing by effectively delivering oligonucleotides to cells, reducing tumor growth, and inhibiting metastasis in preclinical models.

Implementation Method 1

utilizing electrostatic interactions to form polyplexes that enhance intracellular delivery

Methodology Applied

Scientific EffectElectrostatic interactions: Electrostatics

Implementation Method 2

leveraging the enhanced permeability and retention effect for tumor targeting

Methodology Applied

Scientific EffectEnhanced permeability and retention effect: Permeation

Implementation Method 3

endosomolytic release

Methodology Applied

Scientific EffectEndosomolytic release:

Data Source

PatentUS12527834B2Polyaminated polyglutamic acid-containing compounds and uses thereof for delivering oligonucleotides

Publication Date: 2026.01.20 RAMOT AT TEL AVIV UNIVERSITY LTD

AI summary

Polymers useful for associating therewith oligonucleotides and for delivering the oligonucleotides into a cell, conjugates comprising these polymers and an oligonucleotide associated therewith, and compositions comprising same are provided. Also provided are uses of these conjugates in, for example, gene therapy, and particularly gene silencing. The disclosed polymers feature a PGA backbone, and amine-terminated pendant groups attached to at least 40% of the backbone units, and optionally further comprise alkyl pendant groups and/or other nitrogen-containing pendant groups attached to other one or more portions of the backbone units. The disclosed polymers can be cross-linked or can form a part of a block-copolymer.