Intro
Chemotherapy revolutionised cancer treatment when it was first applied in the 1940s. Since then, these drugs have been refined into more selective targeted therapies. Despite such advancements, chemotherapy is still associated with significant toxicities towards healthy tissues. This toxicity can be reduced by altering the biodistribution of chemotherapeutics, for example using nanotechnology. Increasing tumour accumulation of drugs while avoiding healthy tissues through nanotechnology is at the core of the ACN drug delivery focus area.
Nano-sized particles are designed to help protect drugs from being broken down or cleared before they can reach the target site, reduce the interaction of drugs with normal tissues and deliver them to the site of action. Both already approved drugs and novel drugs that showed promising preclinical efficacy but failed in clinical trials – for example due to issues with toxicity – can benefit from this approach.
Current Projects
Advancing the treatment of refractory childhood leukaemia through multitargeted delivery of therapy
Each year >200 Australian children are diagnosed with Acute Lymphoblastic Leukaemia (ALL), about 5% will fail to respond to initial treatment and 20% will relapse from treatments their ALL cells initially responded. Children with relapsed/refractory ALL have a poor prognosis and despite high dose chemotherapy and bone marrow transplantation that cause significant toxicity, these treatments have failed to increase survival rates beyond 40% in this high-risk group. Lipid-based nanoparticles (liposomes) are successful vehicles in the clinic to encapsulate and improve tolerability of anticancer drugs. Nevertheless, their lack of selectivity for cancer cells and extensive biodistribution in healthy tissues, causes off-target toxicity and has limited their effectiveness and applicability for paediatric use. Our project will directly impact treatment and improve quality of life of patients by developing a more effective, less-toxic and highly cancer selective treatment approach for relapsed/refractory ALL. Importantly, our approach will offer opportunities for personalised treatment of leukaemia and can be readily customised to treat other aggressive childhood cancers using clinically approved formulations.
Cancer Nanomedicine: Visualising Nanoparticle Delivery
Nanotechnology offers opportunities to develop effective drug delivery vehicle (nanoparticles) that can target cancer cells whilst sparing normal cells, thereby reducing the collateral toxicity associated with current therapies. Recent studies in cell culture have highlighted that the size and shape of nanoparticles can influence how nanoparticles can enter and be retained in cells. What is unclear in a complex, biological context, is how shape and size influences uptake and release of drug-loaded nanoparticles in in vivo cancer models. Our current research aims: 1. Identify how the design (size and shape) of nanoparticles loaded with chemotherapy influences their capacity to penetrate three-dimensional (3D) tumour spheroids and release drug payload to kill cancer cells. 2. Determine how the shape and size of the drug-loaded nanoparticles can influence accumulation of the particles within tumours and normal tissues using intravital microscopy, a powerful tool recently developed to image subcellular structures in live models.
Development of targeted liposomal nanocarriers for chemotherapy and gene silencing against paediatric solid tumours
In spite of the advances in diagnosis and survival achieved during the past years, childhood cancer is still a highly challenging disease that requires further improvements in the form of highly tolerable, minimally invasive & effective therapies. In more detail, about 720 children aged 0-14 years are being diagnosed every year only in Australia, among which 18% will die within 10 years of diagnosis. Low 5-year survival rates reaching <40% are particularly associated with solid tumours and, above all, in those cases in which the nervous system (e.g. neuroblastoma & brain cancer) and/or connective tissues (e.g. sarcoma) are affected. Survivors of childhood cancer can also experience long term side effects as a result of the very treatment designed to save their life. There is an urgent need to develop effective and less toxic therapies that can be targeted against aggressive solid tumours of childhood. Targeted nanotherapies in the form of antibody-conjugated nanocarriers encapsulating anti-cancer agents or gene silencing material offer the opportunity to overcome biological barriers and localize therapy into the solid tumour while sparing healthy tissues. We are developing antibody-targeted liposomal delivery systems that will serve as tumour-specific drug delivery systems to increase drug delivered payloads to tumour cells and enhance treatment efficacy.
Functional precision medicine for aggressive childhood cancers
Predicting response to therapy for recurrent and drug refractory childhood cancers, and avoiding the use of toxic and unnecessary therapies, remains a major obstacle to cure. There is an urgent need to develop strategies to identify the best treatment for individual patients in an accurate and timely manner. Tumouroids, which are developed from tumour cells, accessory cells and extra-cellular matrix (ECM) found within a tumour microenvironment and grown in three-dimensions (3D), are important models for evaluating drug response as they closely mimic the genetics and pathology of human tumours. Current methods to establish 3D tumouroids are labour intensive, suffer variable reproducibility and are not suited to high-throughput (HTP) applications. We have been instrumental in developing an advanced and innovative HTP 3D-bioprinter with an industry partner, and our strong preliminary data of bioprinted spheroids from cancer cell lines and tumouroids from patient samples, demonstrates our ability to screen against anti-cancer drugs in a HTP manner. Our unique 3D bioprinting platform will accelerate the identification of effective therapies for recurrent and drug resistant cancers through the development of high-throughput drug screening and combination therapies of tumours – advancing functional precision medicine approaches for refractory childhood cancers.Â