Aptamer-Drug Complexes via pH-Sensitive Covalent Linkage
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Solution Overview
Problem
Current RNA aptamers for targeted cancer therapy are costly to produce, require modified nucleotides for stability, and have non-covalent toxin complexes with limited stability, making them unsuitable for optimal in vivo activity due to rapid dissociation.
Innovation Solution
Development of aptamers covalently linked to cytotoxic compounds like doxorubicin via a pH-sensitive geminal diamine linkage, forming dimeric complexes that selectively target cancer cells, ensuring stability and efficient drug delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If RNA aptamers are used for targeted cancer therapy, then cell-specific delivery of cytotoxic drugs is achieved, but the complexes have limited stability and rapid dissociation occurs
Solution Approach 1:
The patent combines RNA aptamers with cytotoxic compounds through covalent bonding to create a composite structure. This composite material integrates the target-specific binding capability of RNA aptamers with the cytotoxic activity of the attached compounds, while the covalent linkage provides the necessary stability to prevent rapid dissociation in vivo.
2Reliability
If covalent linkage is used to enhance stability, then drug delivery stability is improved, but drug release after cell binding may be inhibited
Solution Approach 1:
The patent applies different bonding characteristics to different parts of the drug delivery system. The RNA aptamer portion uses covalent bonding for stable attachment of cytotoxic compounds during circulation, while the interaction with the target cell receptor relies on non-covalent binding that can be reversed, enabling drug release at the destination.
3Reliability
If modified nucleotides are used to improve stability, then in vivo stability is enhanced, but production cost increases
Solution Approach 1:
The patent employs standard, unmodified nucleotides in the RNA aptamer sequence, avoiding the need for expensive modified nucleotides. This approach uses readily available, cost-effective building blocks while achieving the required stability through the covalent linkage strategy and optimized aptamer design.
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 covalent linkage enhances the stability and specificity of drug delivery, reducing systemic toxicities and maintaining cytotoxicity primarily in targeted cancer cells, even in co-culture environments with non-malignant cells.
Implementation Method 1
aptamers covalently linked to cytotoxic compounds like doxorubicin via a pH-sensitive geminal diamine linkage
Implementation Method 2
The covalent linkage enhances the stability and specificity of drug delivery, reducing systemic toxicities and maintaining cytotoxicity primarily in targeted cancer cells
Data Source
AI summary
Provided herein are aptamers and pharmaceutical compositions comprising the same. In some embodiments, the aptamer selectively binds a protein of interest such as an extracellular receptor protein of interest (e.g., a cancer cell extracellular receptor protein, which may be differentially expressed in some embodiments). In some embodiments, the aptamer is directly linked by covalent bonding (e.g., via a geminal diamine linkage) to from 2 to 10 toxin compounds. Also provided herein is a method of selecting an aptamer that specifically binds to a protein expressed by a cell of interest, wherein in some embodiments the aptamer comprises at least one binding site for one or more active compounds. In some embodiments, primer regions flanking the variable region of the aptamers in the pool contains from 1 to 10 mismatches with respect to said forward or reverse primer.