June 24, 2022

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A sharp tool for silencing cancer genes: Peptide siRNA carriers

A sharp tool for silencing cancer genes: Peptide siRNA carriers

 

 

A sharp tool for silencing cancer genes: Peptide siRNA carriers.  Researchers have discovered a modified peptide carrier that can deliver siRNA drugs by adhering to and possibly moving along the cell’s silk feet, thereby entering cells more efficiently and improving gene silencing.

  
Researchers at Musk Hollins Cancer Center are exploring the use of peptide carriers to deliver small RNA drugs as a new way to treat cancer.

The latest research results of the research team were published in Molecular Therapy on March 19, laying the foundation for the development of clinically relevant peptide carrier RNAi-based drug treatment strategies. It is estimated that the risk of oral cancer in the United States is one in 60 for men and one in 140 for women. Cancer treatment faces multiple challenges, including targeted side effects and inefficiency. RNAi-based treatment methods have great potential in overcoming these special treatment challenges.

 

Dr. Andrew Jakymiw is an associate professor in the Department of Oral Health Sciences at MUSC, focusing on RNA interference (RNAi)-based oral cancer treatment research. RNAi is a method of gene silencing that specifically targets the degradation of messenger RNA (mRNA). mRNA contains the genetic code needed to make proteins. Small interfering RNA (siRNA) is an RNA fragment that binds to a specific region on mRNA that prevents protein production. Scientists are studying how to use this to lock in and silence disease-causing genes. Decades of research have shown that certain proteins are overexpressed in cancer and promote the growth of cancer cells. The goal of RNAi drug treatment strategies is to “turn off” proteins that promote cancer development.

Jakymiw said that although this principle is biologically reasonable, the delivery of siRNA still faces many technical challenges. For example, rapid renal excretion, RNase degradation, low intracellular uptake, endosome embedding, and low release of siRNA cargo from the delivery platform are all challenges that we must consider when modifying peptide siRNA carriers.

To take advantage of the gene silencing ability of siRNA, scientists must allow the siRNA to enter the appropriate cells. The siRNA must be attached to a larger molecule to protect it when it is delivered to the desired location. Peptide carriers are an attractive tool for delivering siRNA because they are affordable and easy to modify.

In early research, the Jakymiw laboratory discovered that the original peptide carrier they designed, called 599, can deliver siRNA cargo to cancer cells and shut down targeted oncogenes. “Our original 599 peptide can help siRNA cargo It is easier to penetrate the cell and escape the endosome. However, by observing the three-dimensional arrangement of the amino acids in the 599 peptide, especially their stereochemistry, we can make additional changes that are beneficial to affect the function of the peptide carrier,” Jakymiw said.

A student in Jakymiw’s laboratory used a confocal fluorescence microscope to observe a modified 599 siRNA peptide carrier, called RD3AD, arranged in a clear pattern around cancer cells. This was his original 599 peptide carrier. What I haven’t seen.

The modified RD3AD peptide carrier delivers siRNA drugs by adhering and possibly moving along the cell surface protrusions (called silk feet). Entering cells through silk feet is an effective way for small biological complexes to enter cells; some viruses and bacteria also use this import method. Because the RD3AD peptide carrier loaded with siRNA can enter cancer cells more efficiently, the research team found that gene silencing was improved. Jakymiw explained that this means that peptide carriers have higher cancer treatment potential.

The next step will be to test the RD3AD peptide in animal cancer models. In addition, researchers hope to have a more comprehensive understanding of the mechanisms associated with this form of drug delivery. For example, an open question is, what protein does the peptide carrier interact with on the filament? If this molecule is overexpressed in cancer, it may be a valuable therapeutic target, especially for aggressive cancers, where the number of filaments usually increases.

Cancer cells are biological targets for improving this drug delivery system. Peptide carriers, such as RD3AD, have more applications not only in cancer treatment. In fact, in any situation where gene silencing is needed to treat diseases, peptides such as RD3AD can be used to deliver siRNA.

The Jakymiw laboratory understands how to use specific amino acid stereochemical modifications in peptide design, and the capabilities of carriers are not limited to siRNA. Other nucleic acid cargoes can be delivered through these peptide carriers, which opens up new options for more targeted delivery of other forms of therapeutic molecules to treat challenging diseases in the future.

“I look forward to working with members of the Hollins Cancer Center to explore how to use silk pods to enhance drug delivery in future studies, especially in the treatment of aggressive cancers.

 

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