Nanoparticles hold significant potential as an effective drug-delivery system. They typically range in sizes less than 100 nm in at least one dimension and can consist of different biodegradable substances, such as natural or synthetic polymers, lipids, or metals. According to a study by S.S. Suri et al., nanoparticles are taken up by cells “more efficiently than larger micromolecules and, therefore, could be used as effective transport and delivery systems” (1). By incorporating nanoparticles, drugs can either be integrated into the particle matrix or be attached to the particle surface.
Though a relatively newer science, “nanomedicine” and nano-delivery systems are nevertheless rapidly developing. Nanotechnology offers multiple benefits in treating chronic human diseases with its ability to provide site-specific and target-oriented delivery of precise medicines. There have recently been a number of applications of nanomedicine (e.g., chemotherapeutic agents, biological agents, immunotherapeutic agents) in treating various diseases (2).
Today, companies such as N4 Pharma, a UK-based pharmaceutical company specializing in a novel silica nanoparticle delivery system for vaccines and therapeutics, and Nanoform, a Finland-based company that offers services in nanotechnology and drug particle engineering, are pushing forward with their respective technology development using nanotechnology in drug delivery applications. Nigel Theobald, founder and CEO of N4 Pharma, and Gonçalo Rebelo de Andrade, chief of business operations at Nanoform, shared with BioPharm International the inroads these companies are making and how nanotechnology can enhance the therapeutic effects of biologic-based drugs as well as traditional small-molecule drugs.
BioPharm: What is nanotechnology, and how is it suited to be a platform or vehicle for drug delivery?
Theobald (N4 Pharma): People started talking about nanotechnology in the context of drug delivery more than 10 years ago. However, back then it was all about legacy drug delivery technology that happened to be in the nano-size range—generally accepted to be 1 nm to 1000 nm—being applied to improve the bioavailability or negate toxicity challenges with existing small-molecule drugs. Liposomes were the hot topic, and several drugs came to market in this new dosage form.
Fast forward to today, and the discussion—as well as the technology and targets—have moved on considerably, with the majority of activity concentrated on developing improved vaccines and cancer therapeutics using DNA, RNA, or other large-molecule approaches.
Andrade (Nanoform): Nanotechnology is the science that manipulates, generates, and utilizes submicron sized materials. In the pharmaceutical space, nanotechnology is associated with the manipulation and generation of excipients. This includes silicon-based nanoparticles, lipid nanoparticles, and liposomes, which are used as formulation adjuvants and dissolution enhancers of drug substances. Through the manipulation and generation of API nanoparticles, drug molecules can become more soluble, thus enabling a faster onset, a larger therapeutic window, and reduced side effects.
In recent years there have also been initiatives to generate intelligent biomaterials (e.g., with sensors and nanotech circuits) that can be used for sustained release, adding to the already long line of existing enhanced performance biomaterials (e.g., biomaterials with silver nitrate nanoparticle deposition at the surface for medical device and implant infection reduction).
BioPharm: What is the biggest hurdle to overcome?
Andrade (Nanoform): While developing any new and innovative technology, scientists and companies alike are faced with not only the uncertainty of the success of its delivery platform (technology development risk), but also the adoption barrier associated with a lack of previous experience with the technology (market risk). In addition, given the nature of drug delivery within the pharmaceutical industry, there are safety and toxicology requirements that scientists and companies will need to comply with (regulatory risk) to obtain market approval.
Theobald (N4 Pharma): At present, our work is specific to vaccines and cancer therapeutics, and in this scenario, the drug delivery system must cope with the specific challenges of delivering nucleic acids (DNA/RNA).
A DNA/RNA drug may have relatively poor immunogenicity, and they are unstable in vivo. So, the goal in the body is to protect the messenger RNA/plasmid DNA (mRNA/pDNA) from the immune system and deliver it to the site of action before releasing it to stimulate an immune response, whereby the body’s own systems either attack the target tumor or produce enough antibodies against it.
If you’ve got a DNA/RNA-based active, therefore, you’re going to have to develop it together with a delivery system. In fact, there are a range of technologies that can be considered, such as drug-protein conjugates and virus-like vectors, but lipid nanoparticles (LNPs) have emerged as the most common approach to date.
LNPs meet many of the criteria mentioned above for a good drug delivery system. However, they exhibit some well-known limitations, most notably: stimulating the release of systemic inflammatory cytokines; accumulation in the liver and spleen, with resulting possibility of toxicity; low drug payload for hydrophilic molecules; drug expulsion; and reticuloendothelial system (RES) clearance for systemic drug delivery (3).
Importantly, LNPs also suffer from suboptimal cellular penetration; it is interesting to note that currently, of 23 cancer vaccines in Phase II/III trials, 18 showed low clinical effect, probably due to insufficient presentation of the tumor-associated antigens.
BioPharm: What regulatory hurdles have to be overcome, and what kind of guidance does the industry have—or lack—from regulatory authorities?
Theobald (N4 Pharma): Neither FDA nor the European Medicines Agency (EMA) place specific barriers on a company using nanotechnology as part of its drug delivery modality, but at the same time they have not yet come to a firm view on its use because it is so novel and varied. FDA—in draft guidance for industry, published late in 2017 (4)—provides a risk-based framework that covers safety; preclinical studies such as absorption, distribution, metabolism, excretion, and toxicity; and clinical trials.
EMA’s position, as presented in their Reflection Paper on Nanotechnology-Based Medicinal Products for Human Use (5), is also clear: ‘As for any medicinal product, the [European Union] EU-competent authorities will evaluate any application to place a nanomedicinal product on the market, utilising established principles of benefit/risk analysis, rather than solely on the basis of the technology per se.’
In practice, both regulatory agencies are pleased to engage with a company early in the drug development process to ensure that any specific nanotechnology aspects are appropriately dealt with ahead of an application.
Andrade (Nanoform): As with every other technology that is incorporated into a drug product, the use of nanotechnology needs to provide sufficient evidence of its safety, tolerability, and the control of its manufacturability. In the spirit of collaboration with the industry that the regulatory authorities have long demonstrated, FDA’s nanomaterials guidance provides additional information to the industry as to how the agency will review an application that incorporates nanotechnology into the developed drug product.
BioPharm: What therapeutic advantage does nanotechology offer?
Andrade (Nanoform): Nanotechnology has been traditionally associated with the pursuit of improved solubility and dissolution for poorly soluble small-molecule drugs and the generation of sustained drug release formulations. Recent advances in the generation of nanoparticles, however, have demonstrated increased biologic membrane permeability associated with nanoparticles. Greater permeability enables deeper penetration in the tumor microenvironment, leading to its increased application in oncology and the generation of more effective drug product formulations.
Nanotechnology-driven drug products have shown to have a faster onset in terms of therapeutic action, due to the increased solubility of the nanosized API. It offers a potential reduction of the daily dose required for a therapeutic effect, while also enabling a decrease in side effects associated with the drug uptake.
Theobald (N4 Pharma): In general, everyone developing drug vaccines consisting of nucleic acids is looking to achieve some or all of the following benefits from delivery systems:
- Protection of the drug substance from early or rapid degradation in the body
- Preferential delivery to the target site of action
- A combination of high loading capacity, controlled release with extended half-life, no leakage, and no interference with the stability of the encapsulated product.
In addition, good biocompatibility, low toxicity, and biodegradability, as well as a clear understanding of the mode of action of the delivery system, are desirable factors. To achieve this, many believe that nanoparticle delivery is critical to enabling these drugs to be used effectively in a therapeutic setting.
Technology in development
BioPharm: Can you briefly walk us through your brand of nanotechology and where in the manufacturing process it is implemented?
Theobald (N4 Pharma): Our approach has been different and our technology—called Nuvec—is a delivery system with differentiated physical and structural properties specifically adapted to carry mRNA, pDNA, and other therapeutic proteins. Nuvec nanoparticles are hollow silica spheres covered in thin silica structures that are functionalized with polyethyleneimine (PEI) to enhance binding of macromolecules. The nanoparticles are 180 nm but can be made available from 120 nm to 500 nm in size. Its unique ‘spikey’ surface traps and protects the looped structure of nucleic acids.
Nuvec has been designed to deliver the cargo directly into the cells, and its properties have the potential to overcome many of the challenges of other approaches. The technology works by simply and effectively trapping and protecting nucleic acid (such as mRNA/pDNA) as it travels to the cells. It does not totally encapsulate the DNA or RNA, but rather binds and protects enough to deliver good transfection. The high surface area of the nanoparticle, due to the spikes, allows for high levels of material to be loaded onto the particle.
Once inside the cell, the cargo load is released to activate the immune system. Nuvec is also a natural adjuvant, so it attracts a large number of innate immune cells, which, in turn, leads to more activation of the adaptive immune system (T and B cells), thus increasing the level of immune response against the target cancer cells.
The Nuvec system offers the advantage of not posing unwanted systemic sideeffects. Our data show 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. Nuvec is provided as PEI-loaded nanoparticles that can then have the relevant DNA or mRNA loaded onto them via a simple mixing process. The final drug product will involve the combination of the Nuvec particle with the DNA or mRNA itself. Nuvec is an intermediate step in the final drug product manufacture.
Andrade (Nanoform): At Nanoform, we have developed a technology called Controlled Expansion of Supercritical Solutions (CESS) to engineer API particles to the nanosized scale that will give failed drug candidates a second chance and enable more successful drug product development. CESS elevates particle engineering, and we focus on the generation of crystalline nanoparticles, typically with a Dv50 (i.e., median volume distribution) below 200 nm, directly from solution and with a high-yield (over 90%). We take any API and study its physical and chemical properties to define the process parameters to apply CESS to the molecules for which we want to generate nanoparticles. We start by preparing a suspension in carbon dioxide, turning it into a solution, and then controlling the nucleation step by controlled pressure and temperature drops that are coupled to a final atomization step. The process is used to obtain the crystalline nanoparticle dry powder. As it is a recrystallization step, Nanoform’s technology is part of drug-substance manufacturing and can seamlessly be integrated into any drug product development supply chain. As Nanoform’s technology does not require excipients or surfactants, the free-flowing nanoparticles generated are compatible with any drug product development strategy. We anticipate that our work will double the number of molecules that enter the market.