Modified cyclodextrins for the targeted delivery of siRNA for prostate cancer therapy

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Evans, James C.
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University College Cork
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Prostate cancer is the most common non-cutaneous cancer in men of the western world. When the disease is confined to the prostate gland there are many effective treatment options for the disease, some of which are even curative. In contrast, the metastatic disease is far more difficult to treat, with current therapies offering only a modest increase in overall survival and significant morbidity. In light of this, an effective therapy for metastatic prostate cancer is an unmet clinical need. RNA interference (RNAi) has emerged in recent years as a potential therapy for a wide range of disease states including cancer. However, the clinical application of RNAi is challenging. The main barrier to an effective therapy is the lack of a suitable delivery vector. Cyclodextrins are cyclic oligosaccharides that have emerged in recent years as highly effective gene delivery vectors. The main aim of this thesis was to develop a range of formulations containing modified cyclodextrins that are targeted to prostate cancer and to assess the effect of silencing therapeutically relevant genes on the metastatic potential of prostate cancer cells. A series of modified targeted cyclodextrins were assessed in various models of prostate cancer. These include 2D-cell monolayers, 3D collagen-based scaffold cultures, spheroid models and in vivo models. The resulting formulations resulted in superior delivery of siRNA to prostate cancer cells. In addition, it was shown that the inclusion of the cell-penetrating peptide, octaarginine or the fusogenic peptide, GALA into the formulations led to a superior level of knockdown of the target genes. In conclusion, we have successfully developed a range of cyclodextrin formulations that exhibit receptor mediated targeting in prostate cancer cell lines and that have potential for use in vivo.
Prostate cancer , RNAi , Nanoparticles , Cyclodextrin , Targeted therapy
Evans, J. C. 2017. Modified cyclodextrins for the targeted delivery of siRNA for prostate cancer therapy. PhD Thesis, University College Cork.
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