Smart hydrophilic/ hydrophobic switches for targeted membrane delivery

The cell membrane acts as a barrier that regulates the movement of molecules into and out of our cells. The lipid bilayer that makes up the membrane contains a hydrophobic interior, and as such polar, hydrophilic molecules such as ions and some drug molecules cannot cross this barrier unaided. This means that new drug targets need to be hydrophobic enough to enter cells and tissues by crossing the cell membrane, but also hydrophilic enough to dissolve in the blood in order to be carried by the circulation to the intended site of action. Achieving this balance is a significant challenge in drug design. Nearly 90% of molecules in the discovery pipeline are poorly water-soluble, and drug candidates with poor solubility carry a higher risk of failure.

The challenge of balancing hydrophilicity and hydrophobicity is particularly difficult when designing therapeutics to localise and function inside a cell membrane. Examples of potential drug targets that function in this environment include small molecule ion carriers. Ion carriers could be used as channel replacement therapies for diseases such as Cystic Fibrosis, a life-shortening genetic disorder that impairs the function of naturally occurring ion channels. However, in order to function inside a lipid bilayer (rather than just passing through), the ion carriers need be extremely hydrophobic. As a result they are rarely water soluble, and hence their delivery into cells and tissues is extremely challenging. This limits their potential application as treatments for disease.

To address this problem, we propose to develop small molecules that can reversibly switch between hydrophilic and hydrophobic on the application of a triggering stimulus (light or heat). These switches will be designed as "tags" that can be easily appended to small therapeutic and imaging agents. This will enable us to control the hydrophilic-to-hydrophobic balance of the appended molecules in real time by applying triggering stimuli, and allow us to deliver hydrophobic cargoes into lipid bilayers where they can function. We will firstly demonstrate that we can deliver appended hydrophobic cargoes into simple models of cell membranes, which will help us to optimise the molecular design of the "tags" and gain precise control of their switching capabilities. We will then perform experiments in real cells to demonstrate the delivery and function of the hydrophobic cargoes into cell membranes in response to stimuli.

Overcoming the problem of delivering these hydrophobic molecules to cells will pave the way for their development as viable drug candidates in the future. Additionally, the "tags" will also become valuable tools in the development of new and existing pharmaceuticals and diagnostic agents, as well as agrochemicals and fragrances, in which understanding and controlling the distribution of chemicals in physiological and ecological systems is crucial.

Academic impact beyond the supramolecular community:
The tags developed in this proposal will be initially applied to progress supramolecular approaches to molecular medicines towards clinical application. However, this work will benefit researchers beyond the supramolecular community. The partitioning of substrates between hydrophilic and hydrophobic phases is fundamentally important in many fields and industries in which scientists need to understand and predict the delivery, distribution or separation of chemical species. This includes drug discovery, which is discussed in this proposal, but also includes agrochemistry, in which the impact of new fungicides and herbicides on the waterways, plants and animals is closely related to their bioavailability. Strategies towards environmental remediation often involve separations based on extractions between immiscible phases. Partitioning between aqueous media and lipids is also thought to influence flavor and fragrance perception and hence is highly relevant to the development of new food and perfume additives. Chemical technology that allows scientists to control and direct the partitioning of substrates could therefore be beneficially applied in these diverse fields.

Healthcare and the economy:
The scientific goals of this project are to produce chemical technology that aid the progress of classes of membrane localising drug candidates, such as ion carriers, towards clinical development as therapies for diseases including Cystic Fibrosis, cancer and microbial infections. This will benefit both patients and the UK economy.

Cystic Fibrosis is a life-shortening genetic condition affecting around 100,000 people world-wide. It has been well publicised that new Cystic Fibrosis therapies, such as the drug 'Orkambi', are prohibitively expensive and therefore cannot be provided to patients by the NHS (see for example https://www.bbc.co.uk/news/health-47115039). The development of new, affordable treatments for this incurable condition would therefore be extremely beneficial. Meanwhile, cancer treatments will cost the NHS an estimated £13 billion by 2020/21 and will affect 1 in 2 people in the UK (https://www.cancerresearchuk.org/sites/default/files/achieving_world-class_cancer_outcomes_-_a_strategy_for_england_2015-2020.pdf). The rise in antibiotic resistance is a spiralling crisis in modern healthcare that must be tackled by tackling the overuse of existing antibiotics in combination with the development of new antibiotic targets. Public Health England have estimated that a failure to tackle antibiotic resistance could result in 10 million deaths every year globally by 2050 at a cost of £66trillion in lost productivity to the global economy (https://www.gov.uk/government/publications/health-matters-preventing-infections-and-reducing-amr/health-matters-preventing-infections-and-reducing-antimicrobial-resistance).

Training:
The PDRA recruited through this project will receive targeted training in cell biology handling and imaging techniques, and perform specialised cell-based assays in collaboration with the co-I. They will also gain practical experience of synthetic and soft matter chemistry. This practical experience will yield an excellent skill set and perspective of performing impactful science at the interface of physical and biological fields. The PDRA will also gain project management and supervisory experience from contributing to the supervision of a PhD student and summer students, and communication skills from co-authoring papers and presenting at conferences/ outreach events. They will be encouraged to seek out additional training and development opportunities in consultation with a dedicated departmental mentor in order to achieve their future career ambitions.