Despite the selectivity of oligonucleotides, they still face challenges such as short serum stability, low membrane permeability and lack of tissue selectivity. Cleavable linkers are essential in the field of oligonucleotide therapeutics as they facilitate efficient coupling of the therapeutic payload to the oligonucleotide while maintaining stability during circulation and enabling controlled release from the target site. This drug release mechanism is highly effective in oligonucleotide applications. At IntegrateRNA, we offer comprehensive services to support your oligonucleotide coupling program. We can provide different cleavable linkages to help researchers choose their oligonucleotide coupling method based on the compatibility of downstream applications.
What We Offer?
Suitable linkers are critical to the success of oligonucleotide therapy. Typically, the linker must remain stable in circulation and ensure safe release of the payload in the cell. Cleavable linkers are by far the most commonly used connectors in oligonucleotide design and play an important role in improving plasma stability, water solubility, target release efficiency, oligonucleotide drug distribution, and pharmacokinetics of oligonucleotide-based therapies. IntegrateRNA can provide various safe, cleavable linkers with different drug release mechanisms and stability in the circulation, including but not limited to:
pH-sensitive linkers are essential in designing oligonucleotide couplers as they control the release of the oligonucleotide payload in response to pH changes. These linkers are stable in alkaline environments but highly sensitive to acidic environments, such as perylene. The low pH of endosomes (pH=5-6) and lysosomes (pH=4.8) is utilized to trigger hydrolysis of acid-unstable stilbene junctions and subsequent release of the payload. pH-sensitive linkers have several main functions, including enhanced intracellular delivery, targeted therapeutic treatment, protection from nuclease enzymes, and tunable release kinetics.
A disulfide bond consists of two sulfur atoms covalently bonded to form a disulfide bond (-SS-). The disulfide bond is relatively stable in the environment and can be doped into specific positions within the oligonucleotide sequence, allowing precise control of the affixation site, but can be cleaved by intracellular glutathione reduction to release the payload. This controlled release mechanism enhances therapeutic efficacy and minimizes off-target effects. It has multiple applications in siRNA delivery, ADCs, oligonucleotide-protein affixes, and imaging agents.
