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

Lead Research Organisation: Imperial College London
Department Name: Chemistry

Abstract

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.

Technical Summary

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.

Publications

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Allen M (2022) Hydrogels as functional components in artificial cell systems in Nature Reviews Chemistry

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Gispert I (2022) Stimuli-responsive vesicles as distributed artificial organelles for bacterial activation in Proceedings of the National Academy of Sciences

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Zhu KK (2024) Magnetic Modulation of Biochemical Synthesis in Synthetic Cells. in Journal of the American Chemical Society

 
Description This award has led to the following breakthroughs:

1) The development of optimised protocols for the production of new, medically-relevant synthetic cell (SynCell) compositions. We can now produce particles of the necessary structure to enable long circulation times in the body, and the ability to localise within the tumour.

2) Development of new drug-loading protocols to SynCells. This enables us to use the compositions in 1) as drug delivery vehicles, for the delivery of front line cancer drugs (e.g., docetaxel).

3) Confirmation of the function of medically-relevant SynCells. Specifically, the effect of surface accessibility and the mechanical properties of the SynCell on enzyme-responsive drug release. This confirms that SynCells could function within the tumour, and leads design rules that enable the development of more advanced SynCells with more protein components.

4) Supporting additional, related projects within the laboratory, as evidenced by three peer-reviewed publications in developing (i) multicompartment synthetic cells (ii) how to integrate hydrogel components (e.g., used in tissue engineering) within synthetic cells and (iii) how to develop light- and heat-responsive synthetic cells that can communicate with living cells.
Exploitation Route The outcomes of this funding will be used to apply for further funding, with the aim of further testing the ability of SynCells to treat solid tumours that contain the necessary biomarkers that SynCells selectively respond to (e.g., prostate and breast cancer). We are also using our current findings to explore clinical application of SynCell technologies.

The design rules that we have generated from this grant will additionally lead to a better understanding of how the structure of the lipid compartment of the SynCell affects communication with the protein component that acts as a gate for molecular release. These rules will help us build new SynCell designs capable of more advanced sense-and-response functions, as well as test how proteins interact through the membrane (lipid compartment), which is critical to the function of natural cells within our bodies.
Sectors Healthcare

Pharmaceuticals and Medical Biotechnology

 
Description We are now exploring clinical applications of SynCells in oncology with relevant clinical and industrial partners.
Sector Healthcare,Pharmaceuticals and Medical Biotechnology
 
Description Cancer Research UK & Prostate Cancer UK Innovation Award
Amount £670,498 (GBP)
Funding ID DRCMDP-May23/100012 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2024 
End 02/2027