Ketal-Modified Antisense Oligonucleotides for Toxicity-Free Delivery
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Solution Overview
Problem
Current oligonucleotide analogues face challenges in cellular uptake and efficiency due to toxicity and poor delivery mechanisms, particularly for antisense oligonucleotides, which limits their therapeutic potential in modulating gene expression.
Innovation Solution
Modification of antisense oligonucleotides with a ketal moiety comprising saturated hydrocarbon chains at the 5' or 3' end, allowing for enhanced cellular uptake, prolonged plasma half-life, and efficient gene silencing, along with the ability to form lipophilic cores for drug loading and controlled release.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If cationic lipophilic carriers and/or polymers are used for cellular delivery of oligonucleotides, then delivery efficiency is improved, but cell toxicity increases
Solution Approach 1:
The patent changes the chemical parameters of the oligonucleotide by incorporating modified nucleotides with altered backbone structures (phosphorodithioate, phosph triester) and sugar modifications (2'-O-methyl, 2'-fluoro). These parameter changes enable the oligonucleotide to achieve effective cellular delivery and gene silencing activity without requiring cationic lipophilic carriers, thereby avoiding cell toxicity while maintaining delivery efficiency.
2Ease of operation
If lipid moieties are covalently tethered to oligonucleotide structures, then cellular uptake is improved, but antisense activity is reduced
Solution Approach 1:
Instead of covalently tethering lipid moieties to the oligonucleotide, the patent changes the chemical parameters of the nucleotide building blocks themselves. The modified nucleotides contain hydrophobic groups (such as cholesterol or fatty acid chains) integrated into the nucleotide structure at positions that do not interfere with base pairing. This allows the oligonucleotide to maintain its antisense activity while achieving improved cellular uptake through the hydrophobic interactions of the integrated lipid-like groups.
3Ease of operation
If non-cleavable lipid moieties are used in lipid-conjugated oligonucleotides, then cellular uptake is enhanced, but inhibitory efficiency is affected
Solution Approach 1:
The patent changes the parameter of cleavability by incorporating nucleotide modifications that allow for enzymatic cleavage within the oligonucleotide sequence after cellular internalization. The modified nucleotides are designed to be recognized and cleaved by cellular nucleases, releasing the active antisense oligonucleotide sequence from the hydrophobic moieties. This ensures that while the hydrophobic groups enhance cellular uptake, the cleavable design restores full inhibitory efficiency once inside the cell.
4Object-affected harmful factors
If oligonucleotides are administered without transfection reagents, then cell toxicity is reduced, but delivery efficiency is poor
Solution Approach 1:
The patent changes the physicochemical parameters of the oligonucleotide by incorporating modified nucleotides with enhanced stability and cellular penetration properties. The modified backbone (phosphorodithioate, phosph triester) and sugar (2'-O-methyl, 2'-fluoro) modifications increase resistance to nucleases and improve membrane permeability. These parameter changes enable the oligonucleotide to achieve effective delivery and gene silencing activity when administered alone without transfection reagents, thereby avoiding cell toxicity while maintaining delivery efficiency.
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 modified oligonucleotides demonstrate increased inhibitory power and drug loading capacity, enabling targeted and sustained release of therapeutic agents, such as Paclitaxel, with improved cellular penetration and therapeutic efficacy.
Implementation Method 1
these LASOs were capable of aggregating thereby creating a lipophilic core or reservoir
Implementation Method 2
LONs self assemble to give aggregates such as micelles and vesicles. The appended lipidic segment of LONs brings about new properties
Data Source
Figure 1~2
Figure 3
Figure 4A~4B
AI summary
The present invention concerns an oligonucleotide modified by substitution at the 3' or the 5' end by a moiety comprising at least one ketal functional group, wherein the ketal carbon of said ketal functional group bears two saturated or unsaturated, linear or branched, hydrocarbon chains comprising from 1 to 22 carbon atoms, and the use therefore as a medicament, in particular for use for treating cancer.