ORIGINALLY PUBLISHED:
23 December 2021
Medicines are changing. Across our laboratories, our ambition is 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 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.
Ultimately, these next generation drug delivery technologies aim to translate the scientific progress underpinning our innovative new modalities into clinical benefits for patients.
Cell-targeted delivery of therapies with lipid nanoparticles (LNPs)
Up to 80% of the targets we are seeking to reach are inside cells, making them challenging to access for large-charged molecules such as nucleotide-based therapies. Through a balanced approach of internally developed technologies and external collaborations, we are making progress to develop therapies and delivery agents that can reach these elusive intracellular targets.
Specifically, we are investigating lipid nanoparticles (LNPs) as a promising and innovative vehicle for intracellular delivery of nucleotide-based therapeutics 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 approach for mRNA delivery. We have shown that LNPs can deliver mRNA into cells to initiate cellular protein production after intravenous, subcutaneous and pulmonary administration. We are now focusing our research on enhancing the efficacy and safety profile of this drug delivery system.
Hear more from Drug Delivery scientists about LNPs as a promising drug delivery technology
Our Advanced Drug Delivery teams have an ongoing collaboration with Fredrik Höök’s and Elin Esbjörner’s teams at Chalmers University of Technology, resulting in a publication in ACS Nanotechnology in 2022. Together, the team used surface-sensitive fluorescence microscopy to analyse single ionisable lipid-containing LNPs one at a time as they interacted with a synthetic membrane that mimicked the endosomal membrane environment. In a follow-up experiment, Audrey Gallud, Senior Scientist, Advanced Drug Delivery, Pharmaceutical Sciences, AstraZeneca and team incubated the LNPs in serum to simulate the effects of proteins binding to the surface as the LNPs travel through the body. This new technique provides a deeper understanding of how protein accumulation on the surface of the LNPs – called a protein corona – influences the way LNPs interact with endosomal membranes.1
Additional research into the protein corona led by Kai Liu, Senior Scientist, Advanced Drug Delivery, Pharmaceutical Sciences and published in Nature Communications in 2023 showed that this surface accumulation of biomolecules affects the targeting, delivery, and ultimate destination of LNPs. Using high-throughput screening and proteomic analysis followed by in vivo studies, the team discovered that high-density lipoprotein (HDL) rich LNP coronas were most efficient for targeted delivery to the liver. Now, the team aims to use this as a framework to control corona composition, thereby improving LNP therapeutic efficacy.2
Alongside research into LNP structure and function, we are collaborating with scientists at Gothenburg University with key contributions from Lennart Lindfors, Senior Principal Scientist, Advanced Drug Delivery, Pharmaceutical Sciences, AstraZeneca. The team aimed to determine how LNPs deliver mRNA into the cell and how it is then released. Research findings published in a 2019 publication in Nature Communications showed that cells exposed to LNPs secrete small vesicles (exosomes) containing the mRNA cargo.3 More recent findings from the same collaboration published in Advanced Science in 2023 and led by Sepideh Hagvall, Associate Director Patient Safety Scientist, AstraZeneca add to this data and show that in heart cells and preclinical models, these mRNA containing exosomes travel to neighbouring cells resulting in local production of protein.4
Learn more about a new approach to deliver RNA into cells in the animation below.
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.
Tissue-targeted delivery to expand druggable targets
By targeting delivery of a medicine precisely to the tissue where it is needed, we aim to achieve a therapeutic concentration while minimising the potential for off-target activity at other sites that could lead to side effects.
Nanoparticles are microscopic particles with at least one dimension less than 100 nm. Using nanoparticles to deliver 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 tissues of interest and control their release – increasing their concentration in diseased tissue relative to healthy tissue.
Discover how nanomedicines could help direct medicines to specific tissues in the body in the animation below
In preclinical 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. The efficient “loading” of these nanoparticles with drugs and the control of their release rate in the body are key challenges that our teams are working to address. Ultimately, our goal is to fully understand the impact of the combination of these particles and our drugs in the body.
Ultra-small (<8 nm) silica particles are inorganic nanoparticles with a unique bio-distribution that are renally cleared. The nanoparticle can be linked to a drug molecule, imaging labels and an antibody to actively target tissues of interest. In collaboration with Memorial Sloan Kettering and Cornell University, we have shown that these nanoparticles containing attached engineered antibody fragments for imaging and detection of HER2-overexpressing breast cancer, penetrated the tumour, and showed significant accumulation within the tumour tissues.5
Over the next few years, we hope to enhance the targeting and specificity of our novel nanoparticle delivery systems and expand our routes of administration – always with the potential patient benefit in mind.
Making treatment more convenient for patients with controlled release
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.
Polymeric particles and implants
Putting medicines into biodegradable polymeric particles, such as PLGA (poly lactic-co-glycolic acid) and polycaprolactone, enables us to control their release according to the diffusion and degradation characteristics of the particles. Biodegradable 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 thereby allowing for less frequent administration.
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.6 More recently, a similar approach with block copolymers, has demonstrated more than five months of continuous release for a monoclonal antibody.
Silica particles
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. To address this issue, we are combining biologics with silica particles, which are created using a water-based process. This process also allows creation of particles with specific sizes and shapes to influence their delivery characteristics. In preclinical experiments, we have already demonstrated the controlled release of an antibody from silica particles for up to two months after a single injection.7 Furthermore, we have been able to reproduce a similar sustained release profile for a peptide,” explains Puneet Tyagi, Associate Director, BioPharmaceuticals Development, AstraZeneca
Atomic layer deposition (ALD) of metal oxides
ALD is a dry, metal oxide film deposition process which enables sustained release over long time periods following the formation of nanoshells on the surface of the particles. The nanoshells are produced directly on particles of an active ingredient. ALD has been extensively evaluated in preclinical development and demonstrated its potential to control drug release.
Alternative routes of administration – turning oral biologics from concept to reality
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 delivery technologies, oral biologics are becoming a reality.
Transient permeation enhancers
Transient permeation enhancers (TPEs) are excipients that can be co-formulated with drug modalities, such as peptides or antisense oligonucleotides, in a tablet to help promote the transport of these macromolecules across the natural barriers of the GI tract. TPEs work to briefly increase the fluidity of the cell membranes within the intestinal epithelium or open the tight junctions between cells to allow macromolecules to pass through. We are also able to design macromolecules so they are better suited for oral delivery when co-formulated with TPEs. This enables improved stability against intestinal enzymes as well as increased half-life to account for the expected variability in oral absorption.
We have recently reported on the potential of these approaches to enable oral delivery of both peptides as well as antisense oligonucleotides.8,9 In addition, we have ongoing collaborations with the University of Uppsala, through the SweDeliver Forum, to better understand how TPEs can safely promote oral absorption of macromolecules as well as how to rationally select the best TPEs for a particular macromolecule.10,11
In collaboration with Uppsala University through the SweDeliver Center, we now better understand how to safely and effectively use TPEs to enable oral absorption of peptides and other macromolecules. As a result, we are in a much better place to develop oral formulations for these types of molecules that are usually administered by injection.
Ingestible injectables
Another emerging technology to enable oral delivery of biologics is “ingestible injectables”. As the name suggests, this aims to move the site of injection from subcutaneous to the gastrointestinal tract, taking advantage of the lack of pain receptors in the intestine. To work, the patient takes a pill which, after ingestion, activates to inject the biologic into the gastrointestinal mucosa using microneedles or liquid jets. The intention of ingestible injectables is to give similar bioavailability to a subcutaneous injection but in a pain-free manner. We are collaborating externally in this exciting space to bring about patient-centric delivery technology for biologics.
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.
