Cancer is a genetic disease that is associated with mutations, changes in expression or loss of genes.
Approximately 90% of cancer-associated genes cannot be targeted with small molecule inhibitors. However, an evolutionarily conserved mechanism of controlling (“turning off”) gene expression is called RNA interference (RNAi). Short interfering RNA (siRNA) can be chemically synthesised and can turn off specific target genes. A major challenge with using RNAi, however, is that it cannot enter cells without a delivery vehicle.
To address this challenge CBNS researchers have developed a star-polymer-based siRNA delivery system to deliver siRNA and silence cancer genes that affect growth and chemosensitivity.
Pancreatic cancer is one of the most lethal of cancers as it is often diagnosed at advanced stage disease, can rarely be surgically removed and is poorly responsive to chemotherapy or radiotherapy. Five-year overall survival rates are less than 5% and there is an urgent need to identify effective treatments for this cancer.
Pancreatic cancer is a highly stromal tumour and chemotherapy and radiotherapy are poorly effective against these tumours. TUBB3/βIII-tubulin is part of the cytoskeleton of cells and is abnormally expressed in a number of epithelial cancers including pancreatic cancer.
It is strongly linked with aggressive disease and chemoresistant disease. To date, there are no small molecule inhibitors that can target TUBB3/ βIII-tubulin so we developed an RNA interference (siRNA) gene silencing approach.
To address the RNAi delivery challenge, CBNS researchers have developed a star-polymer-based siRNA delivery system to deliver siRNA and silence TUBB3/βIII-tubulin which is overexpressed in cancer cells.
A panel of Star-polymers with different charges and polymer content were developed and evaluated in cancer cells. The Star- siRNA delivery system could effectively silence gene expression, sensitise cells to chemotherapy and inhibit cell growth in pancreatic cancer cells in vitro. Star-polymer siRNA nanoparticles biodistribution studies in tumour-bearing mice showed that the siRNA-loaded nanoparticles could penetrate the complex stromal rich pancreatic tumours in vivo.
However, a key challenge in the design of star polymers is their efficacy in vivo. Using an orthotopic model of pancreatic cancer we demonstrated that the star polymers were biocompatible and were effectively taken up by the tumours resulting in potent gene silencing in vivo. The star polymer siRNA delivery system is an effective therapeutic strategy for the treatment of pancreatic as well as other cancers that aberrantly express this gene or non-targetable genes.
Neuroblastoma is the second-most common solid tumour in children. Neuroblastoma is classified into three risk groups, with the most aggressive high-risk subtype characterised by a significant propensity to metastasise. High-risk neuroblastoma patients represent half of all new neuroblastoma cases each year and have a poor prognosis of less than 50% survival.
Children presenting with high-risk neuroblastoma tumours undergo invasive and toxic medical procedures during treatment, which can severely impact their quality of life. Even if treatment is successful, they often suffer from life-long consequences of the aggressive therapy.
There is, therefore an urgent unmet need for new therapies, which circumvent the biological barriers to deliver therapeutics, enhance conventional treatments specifically at the tumour site, and reduce the non-specific toxicity to healthy tissue.
Our CBNS team has recently developed a unique platform of antibody-coated and drug-loaded porous silicon nanoparticles, which actively target neuroblastoma cells through binding to cell-surface receptors specific to these cancer cells. Building on these results, we have been performing preclinical studies to investigate the targeting and efficacy of drug-loaded and antibody-coated porous silicon nanoparticles in a panel of neuroblastoma cells.
Once these are completed we plan to move our studies to our preclinical models of orthotopic and metastatic human neuroblastoma. These preclinical studies are essential to provide proof-of-concept and advance the clinical development of our antibody-coated and drug-loaded porous silicon nanoparticles.
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