Developing the next generation of drug delivery technologies
Medicines are changing. In laboratories across AstraZeneca, we aim to target any novel biology we uncover. To do this, we are developing an array of new modalities.
These potential new therapies are different from the traditional small molecules and current large molecules which are often aimed at targets on the cell surface or delivered without a specific molecular-targeting strategy. As a result, we need advanced drug delivery systems for targeted and controlled release of our novel molecules in tissues and cells in an attempt to optimise their potential benefits for patients.
Our scientists are committed to breaking down the barriers between our most promising new drug candidates and their targets in tissues and cells. They are developing a broad range of nanoparticles* that aim to deliver our new modalities to previously undruggable targets and precisely control their release in formulations that are easy to use and convenient for patients. They are also investigating innovative ways of getting oral formulations of biologic drugs across the intestinal wall – something which has eluded generations of drug designers.
Our biologists are advancing understanding of cellular transport mechanisms while our chemists, mathematicians and pharmaceutical scientists are using those insights to optimise the design, properties, analysis, formulation and delivery of our potential new medicines.
Together, they are developing the next generation of drug delivery technologies, setting us on a course that aims to translate the scientific progress underpinning our exciting new modalities into clinical benefits for patients.
*Nanoparticles are microscopic particles with at least one dimension less than 100 nm
From the earliest stages of drug discovery right through to clinical trials, we are focusing on the delivery of potential new medicines to their targets in a way that is right for the drug and right for the patient.
Our drug delivery research focuses on four key areas:
- Cell-targeted delivery – to access targets previously thought undruggable in specific cells. We focus on the potential use of mRNA to produce therapies directly in the cell, turning the cell into ‘biological factories’ that produce the therapeutic proteins, antigens and/or antibodies to treat diseased organs and tissues.
- Tissue-targeted delivery – to achieve therapeutic concentrations of our medicines at their targets, while minimising undesirable side effects. We are developing a range of formulations and approaches, such as nanoparticles armed with the right targeting elements, including antibodies, aimed at making better tolerated medicines that have the potential to reduce side effects and increase patient adherence
- Controlled release – to reduce the need for frequent dosing, making treatment easier and enhancing the patient experience. We are using a range of polymer, silica and other small particles, and in situ gel and liquid crystal formulations, to extend the half-life of our medicines and optimise the time they stay at their target
- Alternative routes of administration – to simplify the way biologics are given we are working to develop oral products with potential to improve outcomes for patients. Our research aims to protect oral biologics from destruction in the stomach and gut, as well as facilitating their absorption from the gut into the bloodstream. To enable this, we are custom making synthetic peptides such that they are stable in the gastric environment to be able to deliver orally
Drug delivery is overcoming absorption barriers both systemically and at target sites. We use a multitude of molecular engineering and novel delivery science to achieve that, with the aim of enhancing patient adherence and experience.
To be effective, it is critical that medicines reach the site of action in the patient – in the right concentration, at the right time. As our biological understanding of disease increases and we seek to make every target we uncover druggable, we are developing the next generation of drug delivery technologies to turn our most promising molecules into the medicines of the future.
By advancing the science of drug delivery, we want to improve the way patients experience our medicines. With our next generation delivery technologies we are aiming to make medicines that are easier to use, require less frequent dosing and are more convenient – enabling patients to spend less time managing their disease.
Up to 80% of the targets we are seeking to reach are inside cells where they can be hard to access. Through a balanced approach of internally developed technologies and external collaborations, we are making progress in addressing the challenges of intracellular targeting of therapies.
We focus on the potential use of mRNA to produce therapies directly in the cell, turning the cell into ‘biological factories’ that produce the therapeutic proteins, antigens and/or antibodies to treat diseased organs and tissues.
RNA therapeutics offer potential to specifically modulate cellular pathways in ways not previously possible. However, we need to get the RNA molecules into the cytosol of the cell.
We are investigating lipid nanoparticles (LNPs) as a promising vehicle for intracellular delivery of mRNA for production of protein therapeutics in cells. LNPs have a successful track record of delivering nucleic acids and they are by far the most advanced delivery approach for mRNA delivery. As such, they are the natural choice as delivery vehicle in this research front.
We have shown that mRNA encapsulated in LNPs can deliver mRNA inside cells and initiate cellular protein production after intravenous, subcutaneous and lung administration. We are now focusing our research on enhancing the efficacy and safety profile of this drug delivery system.
Alongside research into LNP structure and function, we are collaborating with scientists at Gothenburg University to find out how LNPs deliver their mRNA cargo inside the cell and how it is then released. In a recent publication in Nature Communication, led by Lennart Lindfors, Principal Scientist, Advanced Drug Delivery, Pharmaceutical Sciences, R&D, and Adjunct Professor at the University of Gothenburg, Sweden, we have shown that when cells are exposed to LNPs, they secrete small vesicles (exosomes) containing the mRNA cargo. Furthermore, during in vivo studies, such exosomes could deliver functional RNA to a range of tissues and elicit a lower inflammatory response than current approaches – a finding that could offer an attractive alternative for delivery of RNA-based therapeutics in the future.
Our highly productive collaborations have been essential to our progress in developing next generation drug delivery systems. Our own drug delivery specialists come from all areas of academia and industry – attracted by our diverse, creative and rigorous research, and the knowledge that they are contributing to help target any novel biology we uncover for the benefit of patients.
By targeting delivery of a medicine precisely to the tissue where it is needed, we want to achieve a therapeutic concentration while minimising the potential for unwanted off-target activity at other sites that could cause side effects and prevent patients staying on the treatment they need.
Using nanoparticles to deliver promising drug candidates to their site of action has the potential to help us improve the therapeutic index of small molecules and new modalities. Combining drugs with carefully selected nanoparticles and functionalising the nanoparticles with targeting ligands has the potential to change their distribution in the body, target the tissues of interest and control their release – increasing their concentration in diseased tissue relative to healthy tissue.
In pre-clinical and clinical programmes, we are currently focusing on a number of different nanoplatforms – polymeric nanoparticles, polymer conjugates and inorganic nanoparticles.
In the case of polymeric nanoparticles, drug compounds are encapsulated in a polymer matrix while, in polymer conjugates, they are chemically linked to branched polymers. Our goal is to ‘load’ these different types of nanoparticles with drugs as efficiently as possible, ensure their release rate is controlled, and fully understand the critical factors that affect nanoparticle performance and hence their impact in the body.
Ultra-small (<8 nm) silica particles are renally-clearable inorganic nanoparticles with a unique bio-distribution. The nanoparticle can be linked to a drug molecule, imaging labels and an antibody for active targeting to the tissues of interest. In collaboration with Memorial Sloan Kettering and Cornell University we have shown that these nanoparticles containing engineered antibody fragments attached to it for imaging and detection of HER2-overexpressing breast cancer penetrated the tumour and showed large accumulation within the tumor tissues.1
Marianne Ashford, Senior Principal Scientist, Pharmaceutical Sciences, R&D, AstraZeneca, explains that we are working to carefully ‘tune’ our nanoparticles so only limited release of their cargo occurs when they are still in the bloodstream and the majority occurs when they reach their target tissue. This requires a deep understanding of both the biology and the chemistry of the interactions between nanoparticles and tissues.
As nanoparticles prolong the circulation time of drugs in the body, it is important to ensure they are not seen as ‘foreign’ by the immune system and eliminated before they have a chance to release their cargo. ‘Stealth coatings’ have been designed into both our polymeric nanoparticles and polymer conjugates so they have the potential to travel under the immune radar.
Over the next few years, we hope to enhance our targeting and specificity of our novel nanoparticle delivery systems and expand our routes of administration, with the potential patient benefit always in mind.
Collaborating with leaders in nanoparticle technology has been key to the initial promise of our nanomedicine approach. We are working with Starpharma’s DEP? dendrimer technology to enable the delivery of potential innovative cancer medicines by active and passive targeting approaches, with scientists at the University of Manchester on novel production methods for polymeric nanoparticles and methods to enhance the specificity with which they reach their targets, and with researchers at the University of Tokyo to achieve cell-specific nanoparticle delivery to cancer cells using antibody-based ligands2,3
We are using advanced analytical characterisation technique to fully understand the physicochemical properties of our nanoparticles and ensure we control those factors which impact on their in vivo performance; this is critical for the successful pharmaceutical development and translation of these delivery systems into clinical practice.
Novel drug delivery tools and platform technologies have the potential to change the way we develop medicines in the near future. In addition to internal platforms and technologies, we collaborate to bringing innovation from external companies, start-ups and entrepreneurs into AstraZeneca to create a thriving R&D atmosphere percolating with new concepts and ideas.
Many therapies require frequent dosing to maintain drug concentrations at therapeutic levels. By using controlled release formulations to extend the half-life of our medicines inside the body, we aim to minimise dosing frequency and make treatments easier and more convenient for patients, especially when given by injection.
We are using multiple technologies to precisely control the release of our medicines at their site of action, including PLGA (poly lactic-co-glycolic acid) micro- and nanoparticles and implants, silica particles and in situ gelling formulations and liquid crystals.
Putting medicines into PLGA particles enables us to control their release according to the diffusion and degradation characteristics of the particles. PLGA implants, which are larger (up to 1 mm in diameter) and often injected under the skin, work on the same principle – slowly releasing their contents and degrading over time.
In preclinical studies, we have shown that using PGLA nanoparticles as carriers for anti-cancer drugs increased their anti-tumour activity, reduced their side effects and suggested that weekly therapy could be converted to monthly therapy.4
“These effects are likely to have been due to a combination of increased circulation time and increased biodistribution of the drug in the tumour, followed by sustained release locally,” says Puneet Tyagi, Senior Scientist, BioPharmaceuticals Development, R&D, AstraZeneca.
In 2019, we became the first pharmaceutical company to manufacturer nanoparticles at the International Space Station. We wanted to test the effects of microgravity on perturbations such as sedimentation and convection. In this way, we hope to enhance our understanding of the optimal physicochemical and other properties of these particles in drug targeting and controlled release.
Silica particle based controlled release, though at an earlier stage of development, is another attractive option, particularly for biological molecules, because the body tolerates natural silicon which is widely found in tissues and fluids.
“Biologics are sensitive to changes in their environment and break down if they are exposed to harsh chemicals or solvents. In contrast, silica particles are created using a water-based process and we can change their size and shape to accommodate biologic molecules. We’ve already demonstrated, in pre-clinical experiments, controlled release of an antibody from silica particles for up to two months after a single injection5,” explains Puneet.
Completing our portfolio of next generation controlled-release technologies are in situ gelling and liquid crystal formulations of compounds. These are designed to transform from liquid to gels or crystals on contact with body fluids. As drug carriers, these liquid formulations are easy to inject at room temperature and, after their transformation to solid forms, they gradually release their contents in a controlled and localised way.
As we move forward, we are actively addressing the challenges of ensuring drug stability in these novel formulations, and consistency of controlled release, so that the advantages of these innovative approaches can be fully realised for patients.
Development of oral formulations of biologics has been the ‘holy grail’ for pharmaceutical scientists since insulin became available in the 1920s. Many patients understandably prefer an oral formulation to an injection. Now, through a combination of advances in drug design and protective coatings, and the introduction of transient permeation enhancers (TPEs), oral biologics have the potential to become reality.
TPEs transiently increase the fluidity of the cell membranes of the intestinal epithelium to open-up the tight junctions between cells so that macromolecules can pass through. To do this, TPEs need to be formulated with the active macromolecule, which makes medicines difficult to manufacture, particularly on a large scale. To address this, we are making progress in refining our production process to enable large scale manufacture of oral biologics in tablets of an acceptable size to patients.
“We are designing our biologics to increase their stability in the presence of gastrointestinal enzymes and adding a protective coat to the formulation which breaks down only in the alkaline environment of the small intestine to release the drug cargo. By co-formulating these oral biologics with TPEs, we can modulate the permeability of the intestine to allow effective absorption.” says Principal Scientist, Nigel Davies, Advanced Drug Delivery, R&D, AstraZeneca.
To further improve oral delivery of biologics, considerable effort is going into designing molecules with long half-lives and, through our collaboration with the Swedish Drug Delivery Forum, led by Uppsala University, we are looking for ways to further improve oral bioavailability of macromolecules and reduce variability in absorption.
We are also collaborating with scientists at the University of Greifswald, Germany, to explore more ‘disruptive’ technologies to make oral delivery of biologics more efficient, and allow a wider population to benefit from improved medicines in the future.
Oral biologics really shouldn’t work given how proficient our body is at breaking down molecules of this type, so it’s very exciting to see us achieving encouraging results. This was only possible through an integrated approach including the design of the molecule and design of the dosage formulation.
1. Chen et al. Nature Communications (2018) 9: 4141
2. Florinas S et al. Biomacromolecules (2016) 17(5): 1818-1833
3. Chen S et al. Science and Technology of Advanced Materials (2017) 18(1): 666-680
4. Tyagi et al. J Pharm Sci 2019
5. Tyagi et al. Drug Delivery and Translational Research 2017