Multivalent Oligonucleotide Assemblies for Targeted Drug Delivery
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Solution Overview
Problem
Current targeted drug delivery systems face challenges with the rapid excretion and weaker binding of smaller aptamers, as well as systemic toxicity and serum degradation, limiting their effectiveness in delivering therapeutic agents specifically to targeted sites.
Innovation Solution
Development of multifunctional, self-assembling, customizable double-stranded oligonucleotide molecules with a tetravalent core, comprising two partially complementary oligonucleotide strands that form a double-stranded nucleic acid core, allowing for the attachment of moieties and enhanced stability, enabling targeted delivery of therapeutic agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If smaller aptamers are used for targeted delivery, then ease of manufacture and tissue penetration are improved, but excretion rate increases and binding affinity decreases
Solution Approach 1:
The patent combines multiple aptamer units (typically 2-10 aptamers) into a single multivalent oligonucleotide assembly, where each aptamer unit is separated by spacer sequences. This merging approach maintains the ease of manufacture through in vitro transcription while significantly enhancing binding affinity through cooperative binding effects and increased target engagement time.
Solution Approach 2:
The invention creates composite oligonucleotide structures comprising multiple aptamer sequences linked by spacer sequences, forming a composite material that integrates the advantages of small aptamers (ease of production, tissue penetration) while overcoming their limitations (weak binding, rapid excretion) through the collective action of multiple binding units.
2Length of moving object
If smaller aptamers are used for targeted delivery, then tissue penetration is improved, but duration of action decreases due to faster excretion
Solution Approach 1:
By merging multiple aptamer units into a single multivalent oligonucleotide molecule, the effective size for tissue penetration remains comparable to single aptamers, while the multivalent structure increases molecular weight and complexity, thereby reducing renal clearance and extending circulation half-life and duration of action.
3Reliability
If conventional drugs are used for targeted delivery, then therapeutic effect is achieved, but systemic toxicity increases
Solution Approach 1:
The multivalent oligonucleotide assemblies serve multiple functions: they provide targeted binding to cancer cells through multiple aptamer units, enable selective drug delivery to the target site, and reduce systemic exposure of the therapeutic agent. This multi-functionality allows the system to achieve therapeutic effects while minimizing systemic toxicity.
4Reliability
If nanoparticles conjugated to targeting ligand are used, then binding to surface receptors is improved, but device complexity increases
Solution Approach 1:
The invention extracts and eliminates the need for separate nanoparticle carriers and conjugation chemistry by directly designing multivalent oligonucleotide assemblies that inherently provide both targeting functionality through multiple aptamer units and structural stability, thereby simplifying the overall drug delivery system while maintaining or enhancing receptor binding.
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 double-stranded oligonucleotide molecules provide improved stability and specificity for targeted delivery, overcoming the limitations of smaller aptamers by forming a stable core with functional overhangs for moiety attachment, enhancing therapeutic agent delivery and reducing systemic toxicity.
Implementation Method 1
two partially complementary oligonucleotide strands that form a double-stranded nucleic acid core
Data Source
AI summary
Provided herein, inter alia, are double stranded oligonucleotide molecules and methods of making the molecules. The double stranded oligonucleotide molecules include a first oligonucleotide strand comprising a first nucleic acid sequence bound to a second nucleic acid sequence through a first spacer, wherein said second nucleic acid sequence is bound to a third nucleic acid sequence through a second spacer and a second oligonucleotide strand comprising a fourth nucleic acid sequence bound to a fifth nucleic acid sequence through a third spacer, wherein said fifth nucleic acid sequence is bound to a sixth nucleic acid sequence through a fourth spacer, wherein the second nucleic acid sequence and the fifth nucleic acid sequence are hybridized to form a double stranded nucleic acid core of said double stranded oligonucleotide.