21ENGBIO: Microenvironment-Responsive Synthetic Cells for Cancer Drug Delivery

Bottom-up synthetic biology aims to reproduce the structures and behaviours of cellular organisms through the self-assembly of molecules that mimic the structural, functional and information containing roles present in biology. These structures are known as synthetic cells, and they can act as a framework to study biological processes (such as movement or replication). Cells are able to undertake many tasks at once and have evolved to change their behaviours in response to the world around them. As we build increasingly complex synthetic cells that can mimic these behaviours, we also create tools that can be applied to societal challenges such as medical therapies and the production of useful chemicals.

Recently, we have demonstrated a synthetic cell (SynCell) technology that can sense specific combinations of protein biomolecules in their local environment, and in response release a molecular cargo. This behaviour has potential applications in the delivery of drugs for diseases that are associated with increased protein levels, such as multiple types of cancer. In this project we propose a feasibility study of SynCells that can respond to prostate cancer tumours as a new delivery system for the treatment of advanced, drug resistant prostate cancer. This roadmap involves modifying the SynCell structure to increase its robustness in the human body, targeting the SynCells to tumours, developing different SynCell release behaviours and testing the ability of SynCells to circulate around the body and be taken up by the prostate.

This project will enable the validation of a new drug delivery vehicle that could overcome a significant limitation of current methods, which do not possess the ability to sense their biological environment. These delivery vehicles could enable new treatments to be developed for prostate cancer, as well as other biochemically similar cancers such as breast, ovarian and pancreatic cancer. Furthermore, if the synthetic cell materials developed here are shown to be effective delivery systems, this could act as the first step for the development of many synthetic cell technologies that could be applied in other aspects of biomedicine such as diagnostics.

Bottom-up synthetic biology aims to reproduce the architectures, functions and behaviours of biological life using self-assembled chemical systems known as synthetic cells (SynCells). Here we present a lipid vesicle-based SynCell technology that uses mechanosensitive channels that indirectly sense enzymes present in the local environment through membrane-mediated protein - protein communication, undertaking different triggered release programmes in response. Rational design of SynCell parts (lipid composition, membrane accessibility and channel density / sensitivity) enables them to respond to a select enzyme combination (phospholipases and proteases) as molecular logic gates, only releasing content after transducing both biochemical signals from their local environment.

We propose to use SynCells as smart delivery systems that can respond to diseases showing overexpression of enzymatic content such as the tumour microenvironment of particular cancers (e.g., prostate / breast / pancreatic). Prostate cancer was chosen as our target, both due to the biochemical signatures associated with its microenvironment as well as its significant societal impact. Prostate cancer is the most diagnosed, and second most lethal cancer found in men in the UK, where there is a pressing need for technologies to treat advanced, treatment-resistant tumours.

Following recent results demonstrating that SynCells can respond to physiological concentrations of key proteins present in prostate cancer microenvironments, here we plot a four-stage feasibility roadmap to develop SynCells as cancer delivery vehicles. By assessing SynCell i) drug loading and serum stability ii) release behaviours iii) in vitro and ex vivo tumour inhibition and iv) in vivo half-life we will establish SynCell technology as a new paradigm in smart drug delivery. This will demonstrate the translational potential of synthetic cell technologies, leading to further interest and development of this promising field.