PEGylated Drug Delivery Systems for siRNA Drug Development in Cancer Therapy

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PEGylated Drug Delivery Systems for siRNA Drug Development in Cancer Therapy PEGylated drug delivery system is the leading application field of polyethylene glycol in the pharmaceutical field, especially the application potential in siRNA drug delivery.

Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA non-coding RNA molecules, 20-25 base pairs in length, similar to miRNA, and operating within the RNA interference (RNAi) pathway. It interferes with the expression of specific genes with complementary nucleotide sequences by degrading mRNA after transcription, preventing translation. siRNA was first discovered by the team of David Baulcombe in the United Kingdom and was part of the phenomenon of post-transcriptional gene silencing (PTGS) in plants. The results of the study were published in Science.

In 2001, Thomas Tuschl's team discovered that synthetic siRNA can induce RNAi in mammals, and the results were published in Science. This discovery triggered the use of controllable RNAi for biomedical research and drug development.

Advantages of siRNA and barriers to siRNA in cancer therapeutics Compared to chemotherapeutic anti-cancer drugs, there are a lot of advantages of siRNA drug.

1. The first is its high degree of safety. siRNA acts on the post-translational

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stage of gene expression, so it does not interact with DNA and thereby avoids the mutation and teratogenicity risks of gene therapy.

2. The second advantage of siRNA is its high efficacy. In a single cancer cell, siRNA can cause dramatic suppression of gene expression with just several copies.

3. The greatest advantages of siRNA are the unrestricted choice of targets and specificity determined by the principle of complementary base pairing.

4. Last, the comprehensive nucleotide sequence databases have been established, including human genomic databases, cDNA databases and disease gene databases, which have laid a solid foundation for siRNA drug development.

However, several barriers still exist on the road to siRNA clinical use for cancer therapy.

1. Firstly, siRNA is unstable under physiological conditions.

2. Secondly, free siRNA, which is a type of anionic and hydrophilic double-stranded small RNA, is not readily taken up by cells.

3. The third barrier is the off-target effects of siRNA, which lead to unanticipated phenotypes that complicate the interpretation of the therapeutic benefits of siRNA, including siRNA-induced sequence-dependent regulation of unintended transcripts through partial sequence complementarity to their 3′ UTRs, as well as widespread effects on miRNA processing and function through saturation of the endogenous RNAi machinery by exogenous siRNA. 4. Lastly, siRNA is not as safe as expected. High levels of siRNA have been known to result in the activation of innate immune responses and the production of cytokines in vitro and in vivo.

To apply siRNA into cancer therapy, the delivery barriers of siRNA in vivo are the predominant problems to be solved. As siRNA molecules are too large

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(âˆź13 kDa) and too negatively charged, they are not easy to pass through the cell membrane of specific cells, and are easily endocytosed by cells to form endosomes and develop into lysosomes, which are then degraded by a large amount of enzymes and acids. Therefore, developing new drug delivery system to deliver siRNA into target cells and promote endosomal escape is a major challenge facing researchers. PEGylated poly-nanoparticles can increase the efficiency of gene penetration, increase the concentration of gene drugs in cells, enhance the ability of gene binding, and increase the escape efficiency of endosomes. For example, in vitro anti-tumor experiments show that PEGylation can form a stable 300 nm and 80% complexation efficiency siRNA complex, which can significantly reduce the intracellular BLIMP- 1 protein level when applied to silence the BLIMP-1 protein gene of lymphoma cells.

A schematic image of LNPs siRNA showing a nanostructured core, image source: https://www.ncbi.nlm.nih.gov/

Although a number of reports have demonstrated the great potential of siRNA in cancer treatment, challenges remain in bringing the full potential of siRNA to

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the clinic, and most siRNA drug delivery systems are still in preclinical studies.

In recent years, siRNA drug development has experienced highs and lows.

The attitude of big pharmaceutical companies to RNAi drugs has also become over-optimistic. In summary, a good delivery system is key to siRNA drug development. Once research into siRNA drug delivery systems makes a significant breakthrough, siRNA will occupy a strong position in the drug market, especially the anti-cancer drug market.

Biochempeg provides PEGylation services up to pre-clinical stage, and custom synthesis of PEGylated conjugates. Its dedicated and experienced PEGylation group offers two service models to meet your unique PEGylation needs for proteins, peptides, oligonucleotides, and small molecules.

Reference: Delivery systems for siRNA drug development in cancer therapy, Cong-fei Xu, Jun Wang Small interfering RNA, Wikipedia