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PEGylated Drug Delivery Systems for siRNA Drug Development in Cancer Therapy .pdf

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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

Advantages of siRNA and barriers to siRNA in cancer
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



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
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
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



(∼13 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

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



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

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