pH-Responsive Zwitterionic Nucleotides for Membrane Permeability
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Solution Overview
Problem
The challenge of achieving effective cellular uptake of nucleic acids across biological membranes remains due to their hydrophilic and charged nature, despite various modifications, such as chemical alterations and lipophilic conjugation, which have not significantly improved penetration.
Innovation Solution
The development of pH-responsive zwitterionic nucleotides and nucleic acids, comprising anionic internucleoside linkages and cationic moieties in close proximity, which form zwitterionic structures that undergo a hydrophilic-hydrophobic transition in response to pH changes, enhancing membrane permeability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If nucleic acids are chemically modified to reduce hydrophilicity (e.g., methylphosphonates, phosphorothioate bonds), then membrane permeability is improved, but nuclease resistance and catalytic action are compromised
Solution Approach 1:
The patent changes the charge parameter of nucleic acids by introducing zwitterionic modifications that create pH-responsive charge transitions. At physiological pH, the modifications maintain negative charge for stability, while at endosomal pH they transition to neutral or positive charge for membrane permeability, without compromising nuclease resistance or catalytic function
Solution Approach 2:
The patent creates composite nucleic acid structures combining zwitterionic modifications with pH-responsive elements. These composite structures integrate multiple functional properties: nuclease resistance from the backbone modification, pH-responsive charge transition from zwitterionic groups, and membrane permeability enhancement from the combined effect
2Stability of the object's composition
If lipophilic conjugation is used to improve cellular uptake, then membrane permeability increases, but the hydrophilic nature required for solubility and biological activity is reduced
Solution Approach 1:
The patent introduces dynamic pH-responsive zwitterionic modifications that allow the nucleic acids to change their hydrophilicity dynamically. In the cytoplasm at physiological pH, they remain hydrophilic for solubility and activity, while in endosomes at lower pH they become less hydrophilic to facilitate membrane permeability and cellular uptake
3Stability of the object's composition
If carboxylate charge groups are eliminated by esterification to achieve cellular penetration, then membrane permeability improves, but nuclease resistance and catalytic function are lost
Solution Approach 1:
The patent uses pH-responsive zwitterionic modifications that change the effective charge state of the nucleic acid backbone based on environmental pH. At endosomal pH, the modifications reduce negative charge to improve membrane penetration, while at physiological pH they restore negative charge to maintain nuclease resistance and catalytic function, eliminating the need for permanent esterification
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
This approach significantly reduces the log D values of nucleic acids, making them less polar and more permeable, thereby improving cellular uptake and transfection efficiency, especially in slightly acidic environments like endocytic compartments.
Implementation Method 1
The elements are pH sensitive in terms of charge and hydrophilicity and undergo a polar-apolar transition when exposed to low pH
Data Source
AI summary
This invention provides pH-responsive zwitterionic nucleotides and nucleic acids comprising said nucleotides, wherein said zwitterions are constituted from one or more anionic internucleoside linkages and one or more cationic moieties and said zwitterionic nucleotides further comprise either one or more hydrophobic moieties or one or more TEE's with the general structure (I) Hydrophobic element-pH-responsive hydrophilic elements (I).