Perfluoroalkyl-Modified Nucleic Acids for Cell Membrane Uptake
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Solution Overview
Problem
Nucleic acid drugs face challenges with low cell membrane permeability, hindering their ability to reach target molecules within cells, particularly siRNA due to its larger molecular weight and negative charge, necessitating inefficient drug delivery systems with potential toxicity concerns.
Innovation Solution
Introduce a C2-10 perfluoroalkyl group with 1 to 5 ether-bonding oxygen atoms into nucleic acids, either directly or indirectly, to enhance cell membrane permeability using phosphoramidite chemistry.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If nucleic acid drugs (especially siRNA) are used as therapeutic agents, then high specificity for target molecules and low side effects are achieved, but cell membrane permeability is low, making it difficult to reach target molecules within cells
Solution Approach 1:
The patent introduces perfluoroalkyl groups with ether bonds into the nucleic acid structure, fundamentally changing the chemical and physical parameters of the molecule. This modification alters the hydrophobicity, charge distribution, and steric properties of the nucleic acid, enabling it to interact with and permeate cell membranes more effectively while preserving its target binding capability
Solution Approach 2:
The invention creates a composite structure by combining nucleic acid backbone with perfluoroalkyl ether side chains. This composite approach integrates the high specificity of nucleic acids with the membrane-permeating properties of perfluorinated compounds, achieving both target recognition and cellular entry
2Reliability
If siRNA is used as a nucleic acid drug, then high specificity is achieved, but molecular weight and negative charge increase, resulting in lower cell membrane permeability compared to antisense RNA
Solution Approach 1:
The perfluoroalkyl ether modification changes the mass-to-volume ratio and charge density of the siRNA molecule. The fluorinated groups add significant molecular weight but also increase hydrophobicity and reduce overall charge, improving the balance between molecular size and membrane interaction capability
3Object-affected harmful factors
If carrier-based drug delivery systems are used to deliver nucleic acid drugs, then cell membrane permeability is improved, but toxicity concerns arise and delivery efficiency needs improvement
Solution Approach 1:
The patent extracts and eliminates the need for separate carrier systems by incorporating membrane-permeating perfluoroalkyl ether groups directly into the nucleic acid structure. This self-sufficient approach removes the carrier component that causes toxicity, allowing the nucleic acid to deliver itself into cells
Solution Approach 2:
The modified nucleic acid becomes self-delivering through the intrinsic membrane-permeating properties of the perfluoroalkyl ether groups. The molecule autonomously overcomes the cell membrane barrier without requiring external carrier assistance, reducing complexity and toxicity
Data Source
AI summary
To provide a nucleic acid excellent in cell membrane permeability and a method for its production.A nucleic acid containing a C2-10 perfluoroalkyl group having from 1 to 5 ether-bonding oxygen atoms between carbon atoms; said nucleic acid wherein said perfluoroalkyl group is directly or indirectly bonded to the 5′- or 3′-end of the nucleic acid, or said perfluoroalkyl group is indirectly introduced between two nucleotides; or a nucleic acid medicine comprising, as an active ingredient, a nucleic acid containing a C2-10 perfluoroalkyl group, which may have from 1 to 5 ether-bonding oxygen atoms between carbon atoms.