Nanoparticles used to transport the anticancer agent to the cells

Scientists at the University of Cambridge have developed a platform using nanoparticles, called metal-organic structures, to provide a promising anti-cancer agent to cells.

Research by Dr. David Fairen-Jimenez, from Cambridge's Department of Chemical Engineering and Biotechnology, suggests that organometallic structures (MOFs) could be a viable platform for delivering a potent anti-cancer agent called siRNA to cells.

Small interfering ribonucleic acid (siRNA), capable of inhibiting overexpressing cancer-causing genes, has become a growing priority for scientists seeking new cancer treatments.

The Fairen-Jiménez group used computer simulations to find an MOF with the ideal pore size to transport an siRNA molecule, which would break down once in a cell, thus releasing the siRNA to its target. Their results were published today in the journal Cell Press, Chem.

Some cancers can occur when specific genes within cells cause overproduction of particular proteins. One way to solve this problem is to block the gene expression pathway, thus limiting the production of these proteins.

SiRNA molecules can do just that: bind to specific gene messenger molecules and destroy them before they can ask the cell to produce a particular protein. This process is known as "knockdown". Scientists have begun to focus more on siRNAs as potential cancer treatments over the last decade, as they offer a versatile solution to disease treatment. All you need to know is the gene sequence you want to inhibit and you can create the corresponding siRNA. will break it down. Instead of designing, synthesizing and testing new drugs, extremely expensive and time-consuming processes, you can make some simple modifications to the siRNA molecule and treat a totally different disease.

One of the problems associated with using siRNAs to treat diseases is that molecules are very unstable and are often degraded by the cells' natural defense mechanisms before they can reach their targets . SiRNA molecules can be modified to make them more stable, but this compromises their ability to destroy target genes. It is also difficult to introduce the molecules into the cells – they must be transported by another vehicle acting as an agent of administration.

Cambridge researchers have used a special nanoparticle to protect and deliver siRNA to cells, where they demonstrate its ability to inhibit a specific target gene.

Fairen-Jimenez leads research on advanced materials, particularly MOFs: self-assembled 3D compounds composed of interconnected metallic and organic building blocks.

Researchers can create thousands of different types of MOFs (the Cambridge Structure Database currently contains over 84,000 MOF structures with 1,000 new structures published each month) and their properties can be adjusted for specific purposes. By modifying different components of the MOF structure, researchers can create MOFs with different pore sizes, stability, and toxicities, allowing them to design structures that can transport molecules such as siRNAs into cells without harmful side effects.

"With traditional cancer therapy, if you are designing new drugs to treat the system, they may have different behaviors, geometries, and sizes, and you would need an optimal MOF for each of these drugs." Says Fairen-Jimenez. . "But for siRNAs, once you've developed a useful MOF, you can basically use it for a whole range of different siRNA sequences, treating different diseases."

"People who have done this before have used MOFs whose porosity is not large enough to encapsulate siRNA, so much of it is probably stuck on the outside," says former PhD student Michelle Teplensky. . student in the Fairen-Jimenez group, who did the research. "We used an MOF that could encapsulate the siRNA and, when it is encapsulated, you offer more protection.The MOF we chose is made of a zirconium-based metal node and we conducted many studies that show that zirconium is quite inert and does not do it. " t cause toxicity problems. "

The use of a biodegradable MOF for siRNA distribution is important to avoid unwanted buildup of structures once their work is done. The MOF selected by Teplensky and his team breaks down into harmless components that are easily recycled by the cell without harmful side effects. The large pore size also means that the team can load a significant amount of siRNA into a single molecule of MOF, maintaining the necessary dosage to destroy the very low genes.

"One of the advantages of using an MOF with such large pores is that we can get a much more localized and higher dose than that required by other systems," he says. explains Teplensky. "SiRNA is very powerful, you do not need a huge amount of it to get good functionality, the required dose is less than 5% of the MOF porosity."

The use of MOF or other vehicles to carry small molecules into cells poses a problem because they are often stopped by cells moving towards their target. This process is called endosomal trapping and is essentially a defense mechanism against unwanted components entering the cell. The Fairen-Jiménez team added additional components to its MOF to prevent them from being trapped in their cell and thus allowing the siRNA to reach its target.

The team used its system to destroy a gene that produces fluorescent proteins in the cell. It has therefore been able to use microscopy imaging methods to measure the comparison of the fluorescence emitted by the proteins between the cells not treated with the MOF and those that were. The group leveraged its in-house expertise and collaborated with professors Clemens Kaminski and Gabi Kaminski-Schierle, specialists in super-resolution microscopy, who also conduct research at the Department of Chemical Engineering and Biotechnology.

With the help of the MOF platform, the team has always been able to prevent gene expression by 27%, a level that looks promising for the use of the technique for destroying cancer genes.

Fairen-Jimenez thinks that they will be able to increase the system's efficiency. The next step will be to apply the platform to the genes involved in the formation of so-called difficult cancers.

"One of the questions we are often asked is:" Why do you want to use an organometallic framework for health care? "Because there are metals in play that could seem harmful to the body," says Fairen-Jimenez. "But we are focusing on difficult diseases, such as hard-to-treat cancers, for which no treatment has been improved in the last 20 years." We need something that can offer a solution; additional life will be welcome. "

The versatility of the system will allow the team to use the same MOF adapted to deliver different siRNA sequences and target different genes. Because of the large size of its pores, the MOF can also administer multiple medications at once, thus opening the possibility of a combination therapy.