Dr Kogularamanan (Rama) Suntharalingam and Dr Robert Britton
Cancer relapse and metastasis, the leading cause of cancer-associated deaths, is strongly linked to the existence of cancer stem cells (CSCs), a small sub-population of cancer cells defined by their ability to self-renew, differentiate, and form secondary tumours. Conventional chemotherapy and radiotherapy coupled with surgery effectively reduces primary tumour size by removing the bulk of cancer cells, however, CSCs can survive treatment and regenerate secondary tumours with higher metastatic propensity. To improve clinical outcomes, treatments must have the ability to eradicate the entire population of cancer cells, including CSCs, otherwise CSC-mediated relapse could occur. Although progress has been made in the identification of potential CSC therapeutic targets, there are still no clinically approved drug formulation that can completely remove CSCs. Part of the reason for this is the ineffective delivery of CSC-active agents to CSCs.
Nanoscale technologies offer a method to unambiguously deliver chemotherapeutics to their site of action. Nano-systems increase drug solubility, bioavailability, and extend drug half-life. Nanoparticles can passively target tumours by taking advantage of the enhanced permeability and retention (EPR) effect. Several nanoparticle formulations exist for drug delivery, including those based on iron oxide, carbon nanotubes, gold, liposomes, and polymers. Nanoparticles comprising of polymers are of particular interest due to their synthetic versatility and tuneable properties. Most polymer-based nanoparticles are spherical, however, biometric studies have shown that non-spherical constructs benefit from higher circulation times and drug loading. This project will develop “worm-like” nanoparticles (filomicelles), based on naturally occurring viruses like Ebola and Marburg, to delivery CSC-active agents to CSCs. The filomicelles will be made up of biocompatible and biodegradable polymers functionalised with different permutations and ratios of antibodies specific for receptors on the membrane of CSCs. This will enable pattern based recognition of CSCs, and facilitate safe, selective, and personalised delivery. The streamline nature of the filomicelles will also enable deeper penetration into tumours. As CSCs are thought to reside in deep tumour pockets, this approach could provide access to CSC microenvironments unlike current state-of-the-art nano-delivery systems. The long-term outcomes of this project will inform (and potentially revolutionise) the way cancer drugs are administered to patients.
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