Establishing a Design Blueprint for Nanomedicines for Oral Drug Delivery

Oral administration is by far the most preferred way of taking medicines. Other drug administration routes are associated with decreased patient acceptability and compliance, as well as pain, high costs and risks (e.g. injections). Patient preference for oral administration is reflected in drug development processes, whereby a new drug compound is almost always aimed for oral delivery (exceptions exist in the case of drugs for local treatment such as creams for skin conditions and inhalers for asthma). However, currently it is not possible to deliver all drugs through the oral route. This is largely because some drugs are 1) prone to degradation in the stomach environment and 2) do not cross the intestinal wall in sufficient levels to show clinical benefit (drugs need to be in the blood to exert systemic therapeutic effect). A good example is insulin: patients requiring insulin therapy usually need between 2-5 injections per day as lifelong therapy. This project's ambition is to establish a design blueprint for engineering drug carriers that enable or improve oral drug delivery. Drug carriers considered in this project are based on extremely small particles (diameters equivalent to 1/1000th of the thickness of a human hair) or nanoparticles with the ability to cross the intestinal epithelium, carrying the drug cargo across the intestinal wall.

The use of nanoparticles to enable oral drug delivery has been proposed before. However, a key problem is that nanoparticles, similarly to some drugs such as insulin and antibody-based medicines, do not readily cross the intestinal wall or epithelium. This is because of the anatomy of the intestinal epithelium, which consists of a layer of closely packed and interconnected cells forming a fence which presents a formidable barrier to the movement of material from the intestinal lumen to blood. Central to this project is rational design and fabrication of nanoparticles that readily cross the intestinal epithelium. To this end, we will first create a number of compounds (peptides) designed to cross the intestinal tissue barrier (epithelium) through receptors that normally transport biological molecules. We will then attach these 'transport enabling peptides' in varying amounts to the surface of nanoparticles of different size. The resulting systems will be evaluated in an intestinal model based on human intestinal epithelium cells grown in the lab, mimicking the intestinal tissue.

In previous work the applicant has identified a number of key technological advances that underpin the current application. The proposed project is therefore based on the applicant's long-standing efforts - including prior work pertinent to the current proposal - to improve oral drug delivery. We will create a number of different systems, using a rational design approach based on previous experience and preliminary data, and test them in a robust way. This will enable us to identify nanoparticles 'decorated' with transport enabling peptides that readily cross the intestinal tissue barrier. The characteristics of these systems (e.g. nanoparticle size and identity of transport enabling peptide) that enable transport across the intestinal tissue will result in a design blueprint for nanoparticles with the ability to carry drug cargo across the intestinal wall, enabling oral administration of drugs that currently cannot be taken by this route.

Delivery of drugs via the oral route is considered a panacea in terms of administration routes owing to patient acceptability and compliance, which is increasingly important with multiple drug regimens due to increased life expectancy. But, poor drug absorption is a hurdle to developing orally delivered therapy against major disease burdens such as cancer, coronary heart disease and inflammatory disease.

Multidisciplinary researchers working in areas related to the proposal will benefit through methodological and theoretical advances achieved by the proposed research, which relate to rational (bioinformed) engineering of nanomaterials designed to overcome transport across biological tissue barriers. Such advances will be of interest to all researchers working on biomaterials for healthcare applications. The outcomes of the project are likely to start benefiting other scientists within the lifetime of this project.

Enabling oral delivery of 'difficult to deliver' drugs is a key challenge in the pharmaceutical industry. The project's outcomes could therefore significantly impact the current state of art in drug development, as a nanoformulation blueprint that enables or improves oral drug delivery would increase the number of orally delivered drugs. The pharmaceutical industry (and UK economy) will benefit from the proposed research through a carefully planned commercialisation strategy as a route to eventual clinical translation of the project's findings. This strategy constitutes 1) development of intellectual property and 2) the possibility of setting up of a spin out company, with subsequent interaction with the pharmaceutical industry, with the view to achieving outcomes akin to the multimillion dollar deals of BIND Therapeutics with large Biopharma companies.

Overall, establishing a design blueprint for nanomedicines that enables oral delivery of therapeutics such as biologics would eventually translate into benefits for healthcare providers (e.g. cost and risk reduction achieved through a move from injections to oral dosage forms) and more importantly, patients. Indeed, central to UK economy and societal benefits is the proposal's potential to contribute (following successful translation) to development of safer medicines that patients are more likely to take, which could achieve a reduction in medicine wastage that currently costs the NHS an estimated £300 million every year.