Anionic Polyplexes for Nucleic Acid Delivery via Calcium Crosslinking
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Solution Overview
Problem
Current nucleic acid therapeutics face challenges in systemic application due to short half-life in the bloodstream and inability to cross cell membranes, limiting their effectiveness for disseminated diseases like metastasized tumors and inflamed tissues.
Innovation Solution
The development of anionic polyplexes formed from alginate sulfate or hyaluronan sulfate and nucleic acids, mediated by electrostatic interactions with calcium ions, which facilitate efficient cellular uptake and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cationic lipid or polymer formulations are used to protect nucleic acid therapeutics and facilitate cellular uptake, then cellular uptake and protection against enzymatic degradation are improved, but severe cytotoxicity and serum inactivation occur due to cationic charge
Solution Approach 1:
The patent inverts the conventional approach by using anionic polymers (alginate sulfate, hyaluronan sulfate) instead of cationic polymers to form polyplexes with nucleic acids. This charge reversal eliminates cytotoxicity while maintaining delivery efficiency through calcium ion-mediated crosslinking that creates stable, biocompatible complexes for cellular uptake
Solution Approach 2:
The patent introduces calcium ions as intermediary crosslinking agents that bridge the anionic polymer and nucleic acid. The calcium ions form coordinate bonds with both the carboxylate groups of the polymer and phosphate groups of the nucleic acid, creating stable polyplexes without requiring cationic charges, thus avoiding cytotoxicity while enabling efficient delivery
2Adaptability or versatility
If nucleic acid therapeutics are administered systemically to treat disseminated diseases, then treatment coverage is improved, but half-life in bloodstream is very short due to degradation
Solution Approach 1:
The patent applies preliminary protection by forming nucleic acid polyplexes with anionic polymers before systemic administration. The calcium ion-mediated crosslinking creates stable complexes that protect the nucleic acid from enzymatic degradation in the bloodstream, extending half-life and enabling successful systemic delivery to disseminated disease sites
Solution Approach 2:
The patent creates composite polyplex materials combining anionic polymers (alginate sulfate or hyaluronan sulfate), calcium ions, and nucleic acids. This composite structure provides both protection against degradation and facilitates cellular uptake, enabling systemic administration with extended circulation half-life for treating metastasized tumors and inflamed tissues
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 anionic polyplexes effectively deliver nucleic acids into cells, providing stable protection against degradation and enabling targeted gene silencing or expression, with demonstrated efficacy in various disease models, including cancer and inflammatory conditions.
Implementation Method 1
forming polyplexes with the nucleic acid via electrostatic interactions with calcium ions
Data Source
Figure 1A~1D
Figure 2A~2B
Figure 2C~3A
AI summary
The present invention provides an anionic polyplex formed from a nucleic acid and an anionic polymer and further comprising a cation, which can be in the form of a nanoparticle or a microparticle and compositions comprising the anionic polyplex. The present invention further provides uses of the anionic polyplex such as delivery of the nucleic acid into cells and methods of treating a disease, disorder or condition selected from cancer or metabolic, neurodegenerative, cardiovascular, infectious or inflammatory diseases or disorders. The present invention also provides complexes comprising a divalent cation and a nucleic acid lacking an anionic polymer in the form of nanoparticles that is capable of forming a colloidal suspension, and methods for its production.