Oligonucleotide Conjugates

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Oligonucleotide Conjugates

Oligonucleotide conjugates are powerful molecular-engineering materials where oligonucleotides links with ligands such as peptides, antibodies, carbohydrates, or other small molecules. With the breakthroughs in linker chemistry and drug delivery technologies, these chimeric molecules offer the opportunity to deliver the oligonucleotide to specific cells and tissues and thus modulate the disease-causing targets and further treat the diseases. By conjugating oligonucleotides with various types of ligands, the pharmacokinetic properties of oligonucleotides are improved and the scope of applications in therapeutic cell targeting and protein diagnostics are expanded.

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Galnac Oligonucleotides

Asialoglycoprotein receptor (ASGPR) is an endocytic receptor specifically expressed by hepatocytes. In recent years, using the high-affinity ligand N-acetylgalactosamine (GalNAc) of ASGPR as the targeting molecule, a breakthrough has been made in the liver targeted delivery of oligonucleotide drugs (siRNA, ASO, microRNA). We can provide various oligonucleotides and GalNAc conjugates according to customer needs.

GalNAc siRNA is a single conjugate formed by carbohydrate compounds and siRNA. GalNAc is a targeted ligand of the sialic acid receptor (ASGPR). It has high affinity and rapid internalization ability with liver surface cells so that this kind of siRNA conjugate can specifically bind membrane proteins and then get into cells. It was found that when the single dose of GalNAc siRNA conjugate was 1 mg/ml, the subcutaneous injection could effectively silence specific target genes in the liver, and the silencing efficiency was higher than that of siRNA encapsulated in lipid nanoparticles. These siRNA conjugates have good application potential in the treatment of liver-related diseases involving gene overexpression.

In the early application research, researchers have applied GalNAc to the delivery of antisense oligonucleotide (ASO). It was found that the conjugation modification of GalNAc can improve the efficiency of the second generation ASO in mouse liver by 6-10 times. Compared with the previous generation of 2'- MOE modified ASO, combining GalNAc conjugation with the next generation of cEt modified ASO can improve the efficiency of ASO by 60 times.

In addition to the above siRNA and ASO, GalNAc is also applied to the delivery of microRNA antagonistic nucleic acid. GalNAc-microRNA has already been used for the treatment of hepatitis C. The core molecule of the drug is the antagonistic nucleic acid of miRNA-122. The antagonistic nucleic acid is connected with a GalNAc, which can be efficiently uptaken by hepatocytes and inhibit the expression of miRNA-122, so as to achieve a good anti-hepatitis C therapeutic effect (miRNA-122 is very important for HCV virus replication).

Peptide Oligonucleotides

Oligonucleotides can be used not only as the key raw materials of diagnostic reagents but also as gene therapy drugs. Because of its high specificity and good selectivity, it is considered to be an effective cancer treatment drug. However, after decades of research, oligonucleotides have not become a common and effective drug for cancer treatment. The main reasons are poor cell permeability, easy degradation by enzymes, off-target effect, and so on. The research of peptides is earlier than that of oligonucleotides, and the mechanism is relatively clear. It has better membrane permeability and a strong anti-degradation ability. Therefore, coupling oligonucleotides with peptides with various biological functions can not only improve the biological activity of oligonucleotides but also improve their cell permeability. We can provide conjugates of various oligonucleotides and peptides, such as peptide-siRNA, peptide-DNA, peptide-RNA, RGD-siRNA, etc.

PEG Oligonucleotides

The half-life of oligonucleotide drugs (aptamer, siRNA, Aso, microRNA) in vivo is very short. And the structure of oligonucleotide drugs is also easy to be damaged by various enzymes. Besides, the clearance by the kidney is also very fast, which is not conducive to the maintenance of a certain concentration of drugs. At the same time, oligonucleotides themselves have a strong negative charge and are not easy to get close to the same negatively charged cell membrane, so as to reduce their chances of uptake by cells and reduce the efficacy. The above points limit the clinical application of oligonucleotides. Although the modification of the oligonucleotide drug skeleton and the modification of the phosphodiester bond into thiophosphodiester bond can increase its resistance to nuclease, the in vivo half-life of oligonucleotide drugs still can not reach an ideal length of time, which limits the clinical application.

PEG modification can effectively solve the problem of such drugs. In the study of antisense oligonucleotide (ASO), it was found that the half-life of PEG-modified ASO with thiophosphate diester bond as the skeleton was prolonged, which was ten times that of ordinary ASO. At the same time, macromolecular PEG can increase the molecular weight and volume of oligonucleotide drugs, making it difficult for them to pass through the glomerular filtration membrane and reduce the excretion rate of the kidney, so as to effectively prolong the retention time of drugs in the circulatory system and improve their biological activity. In addition, PEG can also form a three-dimensional protective film in water, which is wound on the surface of oligonucleotide drugs to shield the negative charge on the surface, which is conducive to the uptake of oligonucleotide drugs by corresponding cells and improve the effect. We can provide various conjugates of oligonucleotides (PEG-Aptamer, PEG-siRNA, PEG-ASO) and PEG (mPEG, DSPE PEG, Branched PEG, Biotin PEG, FITC PEG, DBCO PEG, Azide PEG, etc.)

Radiolabelled Oligonucleotides

At present, PET with high sensitivity and high spatial resolution is a leading technology in the field of molecular imaging. PET combined with probes that can specifically bind to molecular targets can qualitatively and quantitatively study the process of tumorigenesis and development at the cellular and molecular level, with the advantages of in vivo, noninvasive, repetitive, and real-time. Aptamers have a strong affinity at low concentrations and can be chemically modified and labeled. Therefore, the use of radiolabeled high specific aptamer probes has unique advantages in tumor diagnosis.

In addition, the application of siRNA in vivo also faces some urgent problems to be solved, such as the off-target effect of siRNA in vivo treatment, non-specific transport and distribution, and the potential risk of activating the immune response. The in vivo distribution of siRNA is very important for RNAi technology to play a role. Therefore, the development of appropriate methods to evaluate the in vivo distribution of siRNA has attracted more and more attention. The methods used to evaluate the distribution in vivo include invasive measurement and noninvasive imaging. Invasive measurement refers to the evaluation of the distribution of probes by measuring the concentration of probes in isolated organs after killing experimental animals. Noninvasive imaging technology mainly includes radionuclide imaging, fluorescence imaging, and optical imaging technology. These technologies provide feasibility for noninvasive tracking of siRNA in vivo. Radionuclide tracing, as a widely used imaging technology in clinical and scientific research, has the characteristics of noninvasive, high sensitivity, and strong specificity. Compared with fluorescence and optical imaging technology, radionuclide imaging is non-toxic and safe, especially for large animals and even human body imaging. The application of radioactive tracer technology in siRNA in vivo imaging provides technical support for radionuclide therapy based on siRNA in the future. It can not only directly evaluate the therapeutic effect, but also achieve the dual therapeutic effect of RNAi gene therapy and radiotherapy, which is conducive to promoting the development of RNAi technology in vivo application. We can provide oligonucleotide conjugates with common radioactive markers (99mTc, 111In, 64Cu, 18F, etc., and chelating agents can be NOTA, DOTA, MAG, HYNIC, DTPA, TETA, etc.).

Oligonucleotide Fluorophores in the NIR

Fluorescence imaging technology is widely used in various biomedical research. Compared with the commonly used fluorescence imaging technology, the near-infrared fluorescence probe can significantly reduce the influence of light scattering and self fluorescence effect when penetrating blood and tissue, and make the detection depth deeper and the spatial resolution higher. The near-infrared fluorescence probe is hopeful to play an important role in the fields of in vivo imaging, early tumor diagnosis, and manual navigation in the future. We can provide oligonucleotides (siRNA, DNA, aptamer, ASO) labeled with near-infrared fluorescence (Cy7, Cy7.5, ICG, etc.), and can provide development and synthesis services of various near-infrared fluorescent nucleic acid probes according to the needs of customers

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