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Prostate cancer is the second most common cancer affecting men in Ireland and worldwide. Due to limitations with existing therapies there is still a clinically unmet need for a more effective treatment option. Recent knowledge in the area of cancer has shown that certain genes can regulate the growth and development of the disease and the controlled destruction of these may be viewed as a potential therapy. siRNAs (small interfering RNAs) are a new class of exciting drugs that can be tailor made to stop cells from producing a specific cancer causing protein without affecting other normal functioning genes. They have therefore huge potential for cancer therapy. However, siRNAs face a number of obstacles that can limit their efficacy. They are prone to degradation in the body and therefore require protection on the journey towards the tumour. Also, there is a need to achieve targeted selective entry of siRNA into prostate cancer cells and avoid delivery to healthy tissue. Data from our laboratory has demonstrated that these problems can be tackled with cyclodextrins. Cyclodextrins (CDs) are sugar molecules with a proven safety record that can be modified to allow wrapping of the siRNA, protecting it from degradation in the body. We have also previously achieved selective uptake of cyclodextrin wrapped siRNA by prostate cancer cells using a homing/targeting mechanism which allowed recognition only by the cancer cells. This CD based delivery siRNA system reduced tumour size in a mouse prostate cancer model and reduced the levels of a cancer related gene. However, while hugely encouraging, a high dose of CD was required to wrap siRNA. To tackle this issue, we now plan to use one CD to wrap the siRNA and another CD to coat these particles with the anisamide 'homing' molecules that enables selective attack of the prostate cancer. This treatment may be used alone or allied with current approaches e.g. as a means of reducing tumour size prior to surgery or as a means of targeting any remaining cancer cells after surgery.We aim to improve efficacy and lower the dose of both CD and siRNA needed to treat the tumour. To achieve this we plan to utilise a number of strategies that allow the efficient complexation of siRNA at low doses of CD, and the subsequent attachment of the stabilising and targeting elements. This differs from our previous approach where all elements of the delivery system (i.e. complexation, stabilisation, and cancer targeting) were present upon siRNA complexation. Our new improved vectors will be tested both in cells (previously isolated from prostate cancer tumours) and in 2 mouse prostate cancer models. The effectiveness and the safety profile of these cancer treatments will be assessed. The distribution pattern of the delivery system in the body will also be determined to ensure selective localisation to the cancer sites and therefore avoidance of side effects. It is hoped that at the end of this project, through improvements in quality, stability, safety, and efficacy we will have a prostate cancer specific CD based siRNA delivery system ready to enter clinical trials in patients.
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