pH-Sensitive Hydrogel for Oral siRNA Delivery
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Solution Overview
Problem
Current methods for the oral delivery of siRNA face significant challenges due to extracellular and intracellular barriers such as proteolytic degradation, harsh pH environments, and the need for intracellular delivery and endosomal escape, with limited effective strategies for systemic delivery, particularly for therapeutic proteins and nucleotides.
Innovation Solution
Development of pH-sensitive polymers crosslinked with an enzymatically cleavable peptide linker, specifically designed to be cleaved by enzymes present in the small intestine, such as trypsin, to control the release of therapeutic compounds like siRNA or proteins, using polymers like poly(methacrylic acid-co-N-vinylpyrrolidone) (P(MAA-co-NVP) with a peptide linker that enhances therapeutic release in the small intestine.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If pH-sensitive polymers are used for oral delivery of therapeutics, then protection from gastric conditions is improved, but control over release in the small intestine is insufficient
Solution Approach 1:
The patent combines pH-sensitive polymeric materials with enzyme-cleavable peptide crosslinkers to create a composite hydrogel system. This composite structure provides dual functionality: pH-responsive swelling for gastric protection and enzyme-triggered degradation for controlled intestinal release, thereby resolving the contradiction between protection and controlled release.
Solution Approach 2:
The patent utilizes changes in pH parameters to trigger polymer swelling and degradation. The pH-sensitive polymer network undergoes conformational changes and swelling at intestinal pH conditions, which accelerates the degradation of peptide crosslinkers by proteases, thereby enabling controlled release of therapeutics in the small intestine.
2Ease of operation
If peptide crosslinkers are used to enhance therapeutic release, then release control is improved, but device complexity increases
Solution Approach 1:
The patent employs self-degrading peptide crosslinkers that automatically break down in response to proteases present in the intestinal environment. This self-service mechanism eliminates the need for external control systems or complex activation mechanisms, achieving controlled release while maintaining relatively simple polymer structure.
3Productivity
If hydrogel swelling is increased at neutral pH, then therapeutic release is improved, but structural stability during gastric transit is reduced
Solution Approach 1:
The patent creates a dynamic hydrogel system that adapts its structural properties in response to environmental pH changes. The hydrogel remains compact and stable in acidic gastric conditions, then dynamically swells and becomes more permeable at neutral intestinal pH, enabling timed therapeutic release while maintaining structural integrity during gastric transit.
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 approach enables improved control over the release of therapeutics in the small intestine, protecting them from gastric conditions and ensuring effective delivery by utilizing pH-responsive behavior and enzymatic degradation, thereby enhancing the efficacy of oral drug delivery systems.
Implementation Method 1
Polyanionic hydrogels such as poly(methacrylic acid) (PMAA) exhibit complexation via hydrogen bonding at low pH conditions, such as that of gastric fluid, and undergo increased swelling due to ionization of the carboxylic groups at neutral pH conditions, such as that of the intestine
Implementation Method 2
there are many extracellular and intracellular barriers to oral siRNA delivery such as proteolytic degradation
Data Source
AI summary
In some aspects, methacrylate co-polymers crosslinked with an enzymatically cleavable peptide linker are provided and may be used for the oral delivery of a therapeutic. The peptide linker may be cleavable by an enzyme in the small intestine and may allow for the delivery of a therapeutic protein or nucleic acid to the small intestine. Also provided are methods of using the polymers for the treatment of a disease.