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4-3 Progress in siRNA Delivery Using Multifunctional Nanoparticles
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CreativeBiolab Science Channel is a contract research organization specializing in mRNA studies. They offer solutions for mRNA synthesis, modification, and therapeutics development. In their podcasts, they discuss topics related to mRNA technology. In one episode, they talk about small interfering RNA (siRNA) delivery using different carriers, such as viral carriers and non-viral carriers like liposomes, nanoparticles, and polymer materials. They also discuss the difference between passive and active targeting in siRNA delivery, and the use of targeted ligands like monoclonal antibodies, antibody fragments, short peptides, transferrin, protein transduction domains, and aptamers. These ligands can be coupled with siRNA to improve delivery efficiency and reduce adverse effects. They also mention the use of small molecules like folic acid and lactose as targeted ligands. Welcome to CreativeBiolab Science Channel. CreativeBiolabs is a specialized contract research organization supporting mRNA studies with all-round solutions covering mRNA synthesis, modification, and mRNA therapeutics development. With an unwavering pursuit of innovation and lifelong learning, we keep on producing podcast series related to mRNA technology based on our knowledge and practical experience gained through years of exploration in this area. Subscribe to our channel and keep updated with our podcasts. Good evening, dear friends. Thanks for joining us again. In our previous episode, we talked about polymer nanoparticles for small interfering RNA delivery and the essence of effective small interfering RNA encapsulation and subsequent release. Nanoparticles not only need to carry small interfering RNA, but also need to protect small interfering RNA from degradation. We discussed how to package small interfering RNA with conventional cationic polymers and how to design cationic polymers reasonably. In addition, Professor B had also introduced small interfering RNA delivery using non-cationic polymers. In today's podcast, our old friend David is here to share with us targeting in small interfering RNA delivery. Welcome, David. Thank you for your invitation. I'm very excited to be here. And let's get started right away. At present, siRNA is mainly transmitted through viral carriers and non-viral carriers. Viral carriers mainly include retroviral carrier, lentiviral carrier, and adenoviral carrier. Non-viral carriers mainly include liposomes, nanoparticles, and polymer materials. After systemic administration, nanoparticles can target the diseased cells or tissues passively or actively. What is the difference between passive targeting and active targeting? Can you give us a specific example? In passive targeting, drug carriers accumulate in the interstitial compartments of diseased tissues by enhancing permeability and retention. For active targeting, drug carriers penetrate cell compartments by targeting ligand-cell receptor interactions. Between the two, which is more concerned? I have to say active targeting is because it can improve the drug delivery efficiency and also reduce the adverse effects on normal tissues. At present, various targeted ligands have been designed and applied in siRNA delivery. What are the most studied targeted ligands? You must be referring to monoclonal antibodies and antibody fragments. Monoclonal antibodies are a class of molecules commonly used for targeting purposes. Although monoclonal antibodies can achieve high specific targeting, their large and complex molecular structure and high production cost often hinder the application of drug delivery. You also mentioned antibody fragments. Are they better compared to monoclonal antibodies? Yes. The antibody fragment retains the high antigen binding specificity of the antibody and its small molecular size helps to enhance tissue permeability and is easy to design as a multifunctional delivery system. In fact, it has become an attractive alternative for targeting. Tell us the relationship among monoclonal antibodies, antibody fragments, and cationic polymers. Monoclonal antibodies and antibody fragments can be coupled to cationic polymers as targeted ligands for gene delivery. You summarized it in one sentence. Perfect. Is there any report on the use of polymer antibody conjugates for siRNA delivery? Only a few to my knowledge. Some researchers reported the development of antibody protein fusion protein as a receptor-directed siRNA carrier. In that study, a fusion protein was designed as a protein coding sequence linked to the C-terminal of the fab fragment of HIV-1 envelope antibody and further combined with siRNA. Their design successfully silenced HIV-1 capsid gene and inhibited HIV replication in HIV-infected primary T cells that were difficult to transfect. I've heard that monoclonal antibody modified with siRNA was designed to cross the blood-brain barrier, so it was like a molecular Trojan horse. Can you tell us more about this experiment? Yes. A team of researchers conjugated B7 integrin antibodies to polymeric nanoparticles. And targeted specific leukocyte subsets involved in gut inflammation. They loaded nanoparticles with cyclin D1 siRNA. Then they reversed experimentally induced colitis in lice by suppressing leukocyte proliferation and T helper 1 cytokine expression. Great design. And besides monoclonal antibodies and antibody fragments, what else can be used as targeted ligands? Targeting molecules based on small peptides are also considered. Short peptides have also been successfully used to bind to targets with high specificity and affinity. Because of their small size, low immunogenicity, high stability, and easy manufacture, they are considered attractive target molecules. We know that all great technologies somehow complement each other's advancement. In recent years, peptide phage library, bacterial peptide display library, plasmid peptide library, and new screening technology have all been developed rapidly. Does this benefit short peptides as targeted ligands? Definitely. The development of these technologies makes the selection of short peptides easier, enabling them to be widely used as targeted ligands. Can a short peptide chain be directly coupled with a siRNA? Yes, the two can be combined directly. In another recent study, a team used a short peptide of rabies virus glycoprotein as a targeted ligand to cross the blood-brain barrier. The peptide composed of 29 amino acids was found to specifically bind to acetylcholine receptors expressed in nerve cells. In that study, the chimeric peptide was synthesized by adding nonamer arginine residues at the C-terminus of rabies virus glycoprotein for small interfering RNA conjugation. The rabies virus glycoprotein relative peptide can bind to nerve cells in vitro and transduce small interfering RNA, showing specific gene silencing in vivo. It seems that transferrin can also be used as a targeted ligand. As far as I know, it's a glycoprotein that transports iron to cells. What is the reason that transferrin can be studied in this field? Due to the overexpression of transferrin receptors in tumor cells, transferrin has been used as a ligand for tumor-targeted delivery and has been verified in human clinical trials. It is worth noting that human transferrin can bind to transferrin receptors in rodents and non-human primates. Therefore, they can be extracted from preclinical studies of human patients without lengthy reconstitution steps. What about the protein transduction domain? Is it also playing an important role in this field? Right. Protein transduction domains, also known as cell-penetrating peptides, are a class of small cationic peptides with a length of about 10 to 30 amino acids. They can interact with the cell surface and induce cell internalization through a variety of mechanisms. Peptides with arginine-glycine aspartate sequence can target integrin receptors that mediate cell adhesion to the extracellular matrix. Polyethylene amine nanoparticles have been used to deliver small interfering RNA at the distal end and polyglycolation of arginine-glycine aspartate peptide. Does this polyethylene amine nanoparticle have a certain effect on tumor treatment? Of course, they can effectively target integrin expressed in tumor angiogenesis and successfully inhibit tumor angiogenesis by silencing vascular endothelial growth factor 2 gene. And here is another one, oligonucleotide aptamers. Can they also be used to bind to target genes? Aptamers are single-stranded nucleic acids which can be folded into unique conformations and bind to targets with high affinity and specificity. They are selected through an in vitro process of systemic evolution of ligands by exponential enrichment against specific targets. With the development of systemic evolution of ligands by exponential enrichment, more than 200 aptamers have been isolated and used in various applications. And these applications include to be used as drugs? Yeah, for example, polylactic co-glycolic acid, polyethylene glycol co-polymer nanoparticles were used as aptamers to deliver chemotherapeutic drugs in vivo. What about their application mediating the siRNA delivery? Aptamer-mediated siRNA delivery is mainly focused on the use of direct aptamer siRNA conjugates. For example, siRNAs targeting PLK1 and BCL2 in prostate cancer cells are directly coupled with aptamers that specifically bind to prostate-specific membrane antigens. And how do these conjugates kill cancer cells? They are internalized by prostate-specific membrane antigen-positive cells resulting in target protein knockdown and cell death. In contrast, prostate cancer cells with negative prostate-specific antigens do not internalize the conjugates. A prostate cancer xenograft mouse model was used to confirm their inhibition of tumor growth. Interesting. Any other substances that can be used as targeted ligands? I would say small molecules as a kind of targeted molecule have attracted much attention due to their unique advantages like cost-effective, robust, and can tolerate harsh chemical synthesis processes. Aren't they a relatively large category? You know specifically which ones can be used as tools to assist siRNA targeting? Let me give you a couple of examples. Folic acid is a widely studied small molecule that is widely used to target ligands against folate receptors overexpressed in human tumors. In one study, folic acid coupled with polyethylene imine differentially targeted tumors in healthy tissues. In addition, lactose is also used as a target ligand and cells expressing salivary glycoprotein receptors can recognize compounds containing galactose terminals. Another small molecule, N-acetylgalactosamine, was used in the conjugates. N-acetylgalactosamine can target liver cells, right? You are right. Previous studies have shown that N-acetylgalactosamine contributes to the preferential accumulation of multiple conjugates in hepatocytes. Only minimal correlation was observed with the non-parenchymal cells in hepatic sinusoids. That's it for today's program. David introduced us to a variety of targeted ligands that have been designed and applied in siRNA delivery. Thank you, David, for the very helpful introduction. Thank you all for listening. We will be back with more content on siRNA next time.
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