Therapy & Delivery
Current ACN projects focussed on Therapy & Delivery
Synthesis of novel flavonoid hybrids and development of their delivery system
Natural products such as flavonoids have attracted wide interest for the treatment of cancer. These compounds provides potent biological active scaffold that can be hybridized to further improve its overall activity. In this study, the isoflavene phenoxodiol, and flavanol (+)-catechin were selected as the scaffolds for a novel dual action hybridized anti-tumor molecule due to their already potent anti-cancer properties. Given the key role of metals such as copper in the proliferation of cancer cells, it is anticipated that the hybrids will possess superior anti-cancer activities compared to the parent compounds alone. Hence, a copper-chelating motif will be hybridized onto these scaffolds.
Natural products sometimes suffer from low bioavailability in the human body, which reduces their effectiveness as therapeutic agents. In order to overcome this barrier, the attachment of (+)-catechin to the drug carrier β-cyclodextrin will be investigated as a means of developing a novel drug delivery system for flavonoids. A variety of linker groups will be explored, including pH-sensitive linkers that could potentially selectively release (+)-catechin inside the acidic interior of cancer cells. These novel dual action hybrids and its delivery system will be analyzed for its physical properties such as copper chelation and nitric oxide releasing abilities, and biological activity such as anti-proliferative and anti-angiogenic properties.
Targeted delivery of chemotherapeutic drugs for the treatment of neuroblastoma
In collaboration with EnGeneIC and Dr David Ziegler
Neuroblastoma is the most common extra-cranial solid tumour in children, accounting for 6-10% of all childhood cancers. The majority of children are diagnosed with advanced stage disease (metastatic) and despite intensive therapy that includes highly toxic chemotherapy and bone marrow transplantation, neuroblastoma has the lowest overall survival rates of all the common childhood cancers (40-50%). Due to the toxic side effects of chemotherapy, the limited number of long-term survivors have lifelong health issues due to the late effects of treatment. There is an urgent need to develop effective treatments that not only to improve survival, but also minimise the late effects of treatment. The Kavallaris laboratory is collaborating with EnGeneIC and our clinical collaborator Dr David Ziegler to identify the mechanism of action and efficacy of drug loaded minicells in a preclinical model of neuroblastoma. The longer term aim is to obtain proof of concept data for acceleration of the minicells to clinical trial for the treatment of drug refractory neuroblastoma.
Self-assembled gels for drug release
This project is concerned with developing a new class of materials for drug release and localised delivery, namely self-assembled gels. These materials are formed from small molecules that self-assemble into macroscopic structures yet chemically well-defined structure. Key research questions include issues such as stability, drug release properties, ease of synthesis and biological compatibility.
Self-assembled gels for 3D cell cultures and tissue engineering
Related to the self-assembled gels for drug release project above, we are also investigating the use self-assembled gels for 3D cell cultures and tissue engineering but self-assembled gels appear to be excellent mimics of the Extra-Cellular Matrix (ECM).
Understanding and controlling protein interaction, assembly and ligand (drug) binding
Using approaches from small-molecule-based supramolecular chemistry this project aims to shed a new light on how we can control how proteins interact with each other and other ligands but these interactions underpin various signal processes including those that play a major role in cancers. Additionally, this work could also allow for the development of novel system for drug delivery targeting particular over-expressed protein (receptors) in cancer cells.
Design of multimodal polymeric nanoparticles as targeted carriers for the co-delivery of therapeutic molecules
Nitric oxide (NO) plays a key role in the development of different diseases. The chronic deficiency of NO results in severe problems such as cardiovascular diseases, liver fibrosis, diabetes, cancer, Alzheimer’s diseases, etc. This project will describe a new method to deliver specifically nitric oxide using macromolecules. This project will greatly enhance the tools available to oncologists by providing new treatment options, minimising side-effects to conventional chemotherapy approaches. In this project, the design of next generation of drug delivery will be developed using the most recent advances in materials sciences.
Preclinical development of nanoparticles as RNAi delivery agents for the treatment of cancer
Gene silencing is an evolutionarily conserved mechanism of gene control. We are exploiting gene silencing to target abnormally expressed genes driving cancer growth and chemosensitivity in cancer. This cross disciplinary collaboration of chemists and cancer biolologists has enabled the development of nanoparticles that can silence genes in cancer cells in both cell line models and preclinical animal models of cancer.
Development of a ddRNAi therapeutic for lung cancer
In collaboration with Benitec Biopharma
Intellectual property arising from the Kavallaris lab on specific β-tubulin isotypes in lung cancer (Cancer Res 2007, 2008 and 2010) and their diagnostic and therapeutic utility has led to the filing of several patents. The IP has been assigned to New South Innovations (NSi), including a patent that has been licensed to Benitec (Biopharma) for the therapeutic aspects of suppression of specific β-tubulins. We are working in partnership with Benitec Biopharma Ltd to develop a lung cancer therapeutic based on their proprietry dsRNAi technology and our patent on β-tubulin isotype targeting. During the proof-of-concept stage we demonstrated potent in vivo silencing of β-tubulin in a clinically relevant model of non-small cell lung cancer developed in our laboratory that chemosensitised tumours and significantly prolonged the lifespan of mice compared with that of control animals. Based on this highly promising proof-of-concept data, Benitec have continued their support of our preclinical studies, and will be advancing this discovery to clinical trial. This transition from discovery (basic research) to preclinical research, to translation, to a therapeutic product highlights our ability to ultimately move discovery to the bedside.