̽��ֱ�� of Cambridge - David Fairen-Jimenez

Cambridge spin-out receives £2.2 million to help improve cancer treatments

skbf2 — Wed, 01 Mar 2023 09:45:06 +0000

̽��ֱ��spinout from the ̽��ֱ��’s Department of Chemical Engineering and Biotechnology has been awarded this funding by the European Innovation Council’s (EIC) ‘Transition Challenge’ investment programme which supports the development and commercialisation of innovative technologies.

This capital will allow Vector to develop its novel RNA delivery platform, increasing the safety, specificity and effectiveness of RNA therapies. ̽��ֱ��technology builds on more than 15 years of research in innovative materials and drug delivery by Professor David Fairen-Jimenez and his team.

Fairen-Jimenez, who is also Chief Executive Officer at Vector Bioscience, says: “RNA-therapies are, potentially, the most powerful cancer drugs. However, their targeted delivery remains a challenge. Our preliminary studies in vitro and in vivo have showcased the outstanding possibilities of our platform, leading to excellent efficacies with outstanding biocompatibility. Now, the EIC ‘Transition Challenge’ funds will help us take these discoveries to the clinic.”

Vector’s platform improves the targeted delivery of macromolecules – particularly RNA delivery. ̽��ֱ��technology is based on metal-organic frameworks (MOFs), nanoparticles that carry RNA molecules to their targets. MOFs have a number of advantages as a delivery mechanism: they offer controlled release of the RNA macromolecules, improving safety and selectivity. They also protect the RNA from degradation and increase their solubility and bioavailability.

Vector’s technology has shown promising results treating complicated cancers, including hard-to-treat tumours in the brain, lung and pancreas.

Established in 2021, Vector Bioscience has already been awarded £500k from Innovate UK. Now, with the additional investment from the EIC, it is in a position to design and develop its RNA delivery platform, with applications across different diseases.

Lluna Gallego-Segrelles, Chief Operating Officer at Vector Bioscience, adds: “Within just 18 months, we have attracted over £3 million in funding to commercialise our technology. This demonstrates there’s an immense interest around our drug delivery platform, which will bring the latest innovations in materials science to the pharmaceutical industry and the clinic. Now, our objective is to push our pioneer treatments into pre-clinical phases.”

Vector Bioscience has received a £2.2 million investment to help it take forward its drug delivery platform designed to make RNA cancer therapies more effective.

Scanning electron microscopy of highly crystalline metal-organic framework nanoparticles

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Yes

Nanoparticles used to transport anti-cancer agent to cells

erh68 — Tue, 17 Sep 2019 09:35:26 +0000

Research led by Dr David Fairen-Jimenez, from the Cambridge Department of Chemical Engineering and Biotechnology, indicates metal-organic frameworks (MOFs) could present a viable platform for delivering a potent anti-cancer agent, known as siRNA, to cells.

Small interfering ribonucleic acid (siRNA), has the potential to inhibit overexpressed cancer-causing genes, and has become an increasing focus for scientists on the hunt for new cancer treatments.

Fairen-Jimenez’s group used computational simulations to find a MOF with the perfect pore size to carry an siRNA molecule, and that would breakdown once inside a cell, releasing the siRNA to its target. Their results were published today in Cell Press journal Chem.

Some cancers can occur when specific genes inside cells cause over-production of particular proteins. One way to tackle this is to block the gene expression pathway, limiting the production of these proteins.

SiRNA molecules can do just that – binding to specific gene messenger molecules and destroying them before they can tell the cell to produce a particular protein. This process is known as ‘gene knockdown’. Scientists have begun to focus more on siRNAs as potential cancer therapies in the last decade, as they offer a versatile solution to disease treatment – all you need to know is the sequence of the gene you want to inhibit and you can make the corresponding siRNA that will break it down. Instead of designing, synthesising and testing new drugs – an incredibly costly and lengthy process – you can make a few simple changes to the siRNA molecule and treat an entirely different disease.

One of the problems with using siRNAs to treat disease is that the molecules are very unstable and are often broken down by the cell’s natural defence mechanisms before they can reach their targets. SiRNA molecules can be modified to make them more stable, but this compromises their ability to knock down the target genes. It’s also difficult to get the molecules into cells – they need to be transported by another vehicle acting as a delivery agent.

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

Fairen-Jimenez leads research into advanced materials, with a particular focus on MOFs: self-assembling 3D compounds made of metallic and organic building blocks connected together.

There are thousands of different types of MOFs that researchers can make – there are currently more than 84,000 MOF structures in the Cambridge Structural Database with 1000 new structures published each month – and their properties can be tuned for specific purposes. By changing different components of the MOF structure, researchers can create MOFs with different pore sizes, stabilities and toxicities, enabling them to design structures that can carry molecules such as siRNAs into cells without harmful side effects.

“With traditional cancer therapy if you’re designing new drugs to treat the system, these can have different behaviours, geometries, sizes, and so you’d need a MOF that is optimal for each of these individual drugs,” says Fairen-Jimenez. “But for siRNA, once you develop one MOF that is useful, you can in principle use this for a range of different siRNA sequences, treating different diseases.”

“People that have done this before have used MOFs that don't have a porosity that's big enough to encapsulate the siRNA, so a lot of it is likely just stuck on the outside,” says Michelle Teplensky, former PhD student in Fairen-Jimenez’s group, who carried out the research. “We used a MOF that could encapsulate the siRNA and when it's encapsulated you offer more protection. ̽��ֱ��MOF we chose is made of a zirconium based metal node and we've done a lot of studies that show zirconium is quite inert and it doesn't cause any toxicity issues.”

Using a biodegradable MOF for siRNA delivery is important to avoid unwanted build-up of the structures once they’ve done their job. ̽��ֱ��MOF that Teplensky and team selected breaks down into harmless components that are easily recycled by the cell without harmful side effects. ̽��ֱ��large pore size also means the team can load a significant amount of siRNA into a single MOF molecule, keeping the dosage needed to knock down the genes very low.

“One of the benefits of using a MOF with such large pores is that we can get a much more localised, higher dose than other systems would require,” says Teplensky. “SiRNA is very powerful, you don't need a huge amount of it to get good functionality. ̽��ֱ��dose needed is less than 5% of the porosity of the MOF.”

A problem with using MOFs or other vehicles to carry small molecules into cells is that they are often stopped by the cells on the way to their target. This process is known as endosomal entrapment and is essentially a defence mechanism against unwanted components entering the cell. Fairen-Jimenez’s team added extra components to their MOF to stop them being trapped on their way into the cell, and with this, could ensure the siRNA reached its target.

̽��ֱ��team used their system to knock down a gene that produces fluorescent proteins in the cell, so they were able to use microscopy imaging methods to measure how the fluorescence emitted by the proteins compared between cells not treated with the MOF and those that were. ̽��ֱ��group made use of in-house expertise, collaborating with super-resolution microscopy specialists Professors Clemens Kaminski and Gabi Kaminski-Schierle, who also lead research in the Department of Chemical Engineering and Biotechnology.

Using the MOF platform, the team were consistently able to prevent gene expression by 27%, a level that shows promise for using the technique to knock down cancer genes.

Fairen-Jimenez believes they will be able to increase the efficacy of the system and the next steps will be to apply the platform to genes involved in causing so-called hard-to-treat cancers.

“One of the questions we get asked a lot is ‘why do you want to use a metal-organic framework for healthcare?’, because there are metals involved that might sound harmful to the body,” says Fairen-Jimenez. “But we focus on difficult diseases such as hard-to-treat cancers for which there has been no improvement in treatment in the last 20 years. We need to have something that can offer a solution; just extra years of life will be very welcome.”

̽��ֱ��versatility of the system will enable the team to use the same adapted MOF to deliver different siRNA sequences and target different genes. Because of its large pore size, the MOF also has the potential to deliver multiple drugs at once, opening up the option of combination therapy.

̽��ֱ��research is part of a wider project, funded by the EPRSC and European Commission, into treatments for hard-to-treat cancers.

Read the full paper, published in Cell Press journal Chem.

Reference:
Teplensky et al., Chem 5, 1–16 November 14, 2019 ª 2019 Elsevier Inc. https://doi.org/10.1016/j.chempr.2019.08.015

Scientists from the ̽��ֱ�� of Cambridge have developed a platform that uses nanoparticles known as metal-organic frameworks to deliver a promising anti-cancer agent to cells.

We focus on difficult diseases such as hard-to-treat cancers for which there has been no improvement in treatment in the last 20 years

David Fairen-Jimenez

Cells with MOFs carrying siRNA

Yes

Machine learning predicts mechanical properties of porous materials

sc604 — Wed, 15 May 2019 15:00:44 +0000

Researchers have used machine learning techniques to accurately predict the mechanical properties of metal-organic frameworks (MOFs), which could be used to extract water from the air in the desert, store dangerous gases or power hydrogen-based cars.

̽��ֱ��researchers, led by the ̽��ֱ�� of Cambridge, used their machine learning algorithm to predict the properties of more than 3000 existing MOFs, as well as MOFs which are yet to be synthesised in the laboratory.

̽��ֱ��results, published in the inaugural edition of the Cell Press journal Matter, could be used to significantly speed up the way materials are characterised and designed at the molecular scale.

MOFs are self-assembling 3D compounds made of metallic and organic atoms connected together. Like plastics, they are highly versatile, and can be customised into millions of different combinations. Unlike plastics, which are based on long chains of polymers that grow in only one direction, MOFs have orderly crystalline structures that grow in all directions.

This crystalline structure means that MOFs can be made like building blocks: individual atoms or molecules can be switched in or out of the structure, a level of precision that is impossible to achieve with plastics.

̽��ֱ��structures are highly porous with massive surface area: a MOF the size of a sugar cube laid flat would cover an area the size of six football fields. Perhaps somewhat counterintuitively however, MOFs make highly effective storage devices. ̽��ֱ��pores in any given MOF can be customised to form a perfectly-shaped storage pocket for different molecules, just by changing the building blocks.

“That MOFs are so porous makes them highly adaptable for all kinds of different applications, but at the same time their porous nature makes them highly fragile,” said Dr David Fairen-Jimenez from Cambridge’s Department of Chemical Engineering and Biotechnology, who led the research.

MOFs are synthesised in powder form, but in order to be of any practical use, the powder is put under pressure and formed into larger, shaped pellets. Due to their porosity, many MOFs are crushed in this process, wasting both time and money.

To address this problem, Fairen-Jimenez and his collaborators from Belgium and the US developed a machine learning algorithm to predict the mechanical properties of thousands of MOFs, so that only those with the necessary mechanical stability are manufactured.

̽��ֱ��researchers used a multi-level computational approach in order to build an interactive map of the structural and mechanical landscape of MOFs. First, they used high-throughput molecular simulations for 3,385 MOFs. Secondly, they developed a freely-available machine learning algorithm to automatically predict the mechanical properties of existing and yet-to-be-synthesised MOFs.

“We are now able to explain the landscape for all the materials at the same time,” said Fairen-Jimenez. “This way, we can predict what the best material would be for a given task.”

̽��ֱ��researchers have launched an interactive website where scientists can design and predict the performance of their own MOFs. Fairen-Jimenez says that the tool will help to close the gap between experimentalists and computationalists working in this area. “It allows researchers to access the tools they need in order to work with these materials: it simplifies the questions they need to ask,” he said.

̽��ֱ��research was funded in part by the Royal Society and the European Research Council.

Reference:
Peyman Z. Moghadam et al. ‘Structure-Mechanical Stability Relations of Metal-Organic Frameworks.’ Matter (2019). DOI: 10.1016/j.matt.2019.03.002

Machine learning can be used to predict the properties of a group of materials which, according to some, could be as important to the 21st century as plastics were to the 20th.

We can predict what the best material would be for a given task

David Fairen-Jimenez

Crystalline metal–organic framework

Yes