A New System for DNA/RNA Delivery in Cancer Therapeutics
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Cancer immunotherapies and viral vaccines that are nucleic acid-based can be challenging to formulate and require highly specific delivery systems. Commonly adopted delivery systems, such as lipid nanoparticles and viral vectors, can have limited efficacy, associated risks, or in some cases, may have unknown long-term safety profiles.
N4 Pharma have been developing an alternative approach: Nuvec® – silica nanoparticles, a unique and non-viral adjuvant delivery system.
Technology Networks recently spoke with Nigel Theobald, CEO and Founder of N4 Pharma, to learn more about nanoparticle drug delivery, the Nuvec® platform and its progress towards clinical trials.
Laura Lansdowne (LL): Could you tell us about the history and mission of N4 Pharma?
Nigel Theobald (NT): N4 Pharma was founded in 2014 with the goal of creating a unique, non-viral, delivery system that could potentially revolutionize the development of vaccines and cancer treatments. Nucleic acid-based cancer immunotherapies and viral vaccines are challenging to formulate and rely on specific delivery systems. Currently, lipid nanoparticles are the most common approach, but they suffer some significant limitations. We wanted to produce an alternative, safe and effective delivery system to enable commercialization of cancer immunotherapies and viral vaccines based on mRNA and pDNA.
At the time, researchers at the University of Queensland (UQ) in Australia were working with a mesoporous silica particle that resembled a practice golf ball (a hollow particle with pores) – these holes would allow a vaccine inside but slowed down its release from the particle. UQ were experimenting with the size of these pores to allow subunit vaccines such as bovine diarrhea or hepatitis B to get inside the nanoparticle. This worked well for subunit vaccines but, at the time, didn’t work with DNA, RNA or SiRNA, as they are negatively charged. So, we took this technology and developed our silica nanoparticle, Nuvec®, to grow spikes over the particle to allow DNA and mRNA to be attached to the outside of the nanoparticle, rather than in the core, and delivered safely into a cell.
Molly Campbell (MC): What challenges currently exist in the delivery of immunotherapy drugs and vaccines?
NT: A key challenge exists with lipid nanoparticles, although it is the most common delivery vehicle, is they can result in undesired hepatic extraction. This causes the loss of critical tumor targeting and – if used in long-term treatment – can result in lipid-induced liver injury.
Viral vectors have also been used but present a challenge as they carry a risk of recombination with endogenous viruses. Viruses are produced in mammalian cells and the process involves specialized biotechnology facilities with strict containment and cross-identification procedures. This process is costly and carries associated supply and safety risks. Similarly, polymeric delivery systems being developed have an unknown long-term safety profile and may lack capacity for full length mRNAs and plasmids.
While inert and safe, most silica systems tested to date have been smooth mesoporous particles, which meant that the nucleic acid was attached inside the particle, limiting the amount that would make it into the cell. The greater surface area of Nuvec® increases loading of oligonucleotides and thus improves transfection compared with smooth silica nanoparticles.
LL: Could you explain what is meant by “nanoparticle drug delivery” and what are the benefits of delivering therapeutics in this way?
NT: A nanoparticle is broadly defined as a particle up to 500 nm in size. For example, Nuvec® is approximately 200 nm in size. The size of the particle is critical in terms of its uptake by the cell. Following interaction of the particle with the cell membrane, the particle is encapsulated and taken into the cell intact. Once inside the cell, a number of processes take place which result in the release of the payload.
Traditionally, liposomes were the favored delivery system and several small molecule drugs were introduced to the market in this dosage form. Today, however, the discussion, as well as the technology and target, has advanced significantly. Now, most activity focuses on developing improved vaccines and cancer therapeutics using DNA, RNA, and other "large molecule" approaches.
Generally, everyone developing drug vaccines involving nucleic acids are looking to achieve successful delivery to the target site of action, as well as protection of the drug substance from early or rapid degradation in the body. An ideal delivery system also needs to demonstrate a combination of high loading capacity, controlled release with extended half-life, no leakage and no interference with the stability of the attached payload.
Good biocompatibility, low toxicity and biodegradability, as well as a clear understanding of the mode of action of the delivery system are also desirable factors. In order to achieve this, many believe that nanoparticle delivery is critical to enabling these drugs to be used effectively in a therapeutic setting.
LL: Can you highlight some of the unique properties and key features of Nuvec® silica nanoparticles?
NT: What’s unique about Nuvec® is that its silica nanoparticles have an irregular (spiky) surface structure which creates a high surface area. The surface is coated with a charged molecule, PEI, which attracts and binds DNA/RNA. This simply and effectively traps and protects mRNA/pDNA before it has time to enter the target cells. Once inside the cell, the DNA/RNA is released to produce the antigenic protein which results in activation of the immune system.
Silica nanoparticles have been demonstrated to have adjuvant properties and this may increase the level of the immune response. Specifically, Nuvec® has also been shown to generate a strong cytokine response, which is a key component of the immune response.
The crucial feature is that, compared to existing lipid-based delivery systems, Nuvec® doesn’t exhibit any unwanted systemic side effects. Our data has shown that the trapped drug remains at the site of injection, doesn’t produce unwanted inflammatory responses and, very importantly, doesn’t track to the liver.
MC: What are the next steps for N4 Pharma and the Nuvec® platform?
NT: We are continuing with our formulation work through further preclinical research. Once this has been completed, we will repeat our in vivo studies and undertake an oncology efficacy study. This work will give us a full data pack to share with prospective partners with the aim of getting Nuvec® into clinical trials in 2021.
Our recent partnership with Nanomerics Limited to produce and test two candidate formulations using Nuvec® will be an exciting opportunity for us to accelerate the development of the particle and gain access to scientists and labs with considerable experience in the field of nanotechnology delivery. Overall, it is an exciting time for us at N4 Pharma and we look forward to this next chapter!
Nigel Theobald, CEO and Founder N4 Pharma, was speaking to Laura Elizabeth Lansdowne and Molly Campbell, Science Writers, Technology Networks.
About the author
Nigel Theobald has over 25 years’ experience in healthcare and in building businesses, strategy development and its implementation and a strong network covering all aspects of pharmaceutical product development and commercialization. He was the head of healthcare brands at Boots Group plc in 2002 before leaving to set up a series of successful businesses, including Oxford Pharmascience Group plc, which he grew over five years into an AIM quoted company with a market capitalization of £40 million upon departure. Nigel formed N4 Pharma in 2014.