Nanoscale, pH-responsive polycationic networks for targeted delivery of anionic biologic therapeutics

This technology involves nanoscale, pH-responsive polycationic hydrogels for delivering anionic biologic therapeutics like siRNA. These hydrogels, made from crosslinked copolymers, trap therapeutics at physiological pH and release them in lower pH environments, enhancing biocompatibility and targeted delivery.

Background

The delivery of small interfering RNA (siRNA) and microRNA (miRNA) has emerged as a promising therapeutic strategy, due to their ability to silence specific genes implicated in various diseases. However, the clinical application of RNA interference (RNAi) is hampered by the problem of efficiently delivering these molecules to their target cells.

Existing delivery methods, such as naked siRNA, conjugated polymers, and lipid carriers, rely primarily on topical and intravenous administration, which are not optimal for targeting the gastrointestinal (GI) tract. These approaches often fail to provide the necessary stability and protection for siRNA in the harsh GI environment, leading to rapid degradation and poor cellular uptake. Also, the lack of specificity in delivery systems can result in off-target effects and toxicity. Therefore, there is a critical need for innovative delivery platforms that can protect siRNA from degradation, facilitate its transport across cellular membranes, and release it in a controlled manner at the desired site of action.

Technology description

The technology involves nanoscale, pH-responsive polycationic networks specifically engineered for the delivery of anionic biologic therapeutics such as siRNA. These networks are made from crosslinked copolymers that include a cationic monomer, 2-(diethylamino)ethyl methacrylate (DEAEMA), and a methacrylamide-derivatized hydrophobic amino acid, N-methacryloyl L‑phenylalanine methyl ester (MAPA). The hydrogels are methacrylate-based and can incorporate poly(ethylene glycol) (PEG) or polyoxazoline (POZ) polymers on their exterior to enhance biocompatibility and colloidal stability. These hydrogels exhibit a volume phase transition in response to pH changes, collapsing at physiological pH (7.4) to trap therapeutic agents and swelling in lower pH environments (such as endosomes) to release them. The synthesis method includes UV-initiated photoemulsion polymerization, and the hydrogels are designed to be cytocompatible with a positive surface charge at pH 7.4, making them suitable for targeted delivery in various biological contexts, including gastrointestinal diseases.

This technology is differentiated by its tunable response to pH changes, which allows for precise control over the release of therapeutic agents. The inclusion of PEG or POZ polymers on the hydrogel’s exterior enhances its biocompatibility and colloidal stability, making it more suitable for in vivo applications. The use of DEAEMA and MAPA in the copolymer network provides a balance of hydrophilic and hydrophobic properties, optimizing the hydrogels for both trapping and releasing therapeutic agents under specific physiological conditions.

The ability to undergo a volume phase transition in response to pH changes is particularly advantageous for targeting environments like endosomes, where the pH is naturally lower than the physiological pH. This specificity in response enhances the efficiency of drug delivery and reduces potential side effects, making the technology highly effective for treating diseases that require targeted delivery of anionic biologic therapeutics.