Preparation and analysis of novel tumour-targeted delivery systems for prostate cancer therapy

• Main Author: Al Robaian, Majed
• Published: University of Strathclyde 2014
• Subjects: 610
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.667569

Cancer is a major public health problem worldwide. It is considered a major cause of death around the world. The World Health Organization estimates that 84 million people will die of cancer between 2005 and 2015, and the incidence is expected to increase continuously as the world population ages (Danhier et al., 2010). Prostate cancer is one of the most commonly diagnosed cancers in men and remains the second leading cause of cancer-related deaths in industrial countries. To date, there is still no efficacious treatment for patients with advanced prostate cancer with metastases. New treatments are therefore critically needed for these patients. Gene therapy holds great promise for the intravenous treatment of prostate cancer. Non-viral gene delivery is emerging as potential safer alternative to the use of viral vectors for the treatment of various gene related diseases including cancer. Although non-viral vectors may not be as effective as the viral ones, the continuous research on rationally designing multifunctional non-viral polymeric gene delivery carriers resulted in improved delivery. This study is carried out to prepare and evaluate the efficacy of tumour- targeted transferrin, lactoferrin and lactoferricin conjugated polypropylenimine dendrimer as a novel gene delivery system able to improve the delivery of the therapeutic gene to cancer cells, in a safe and targeted way. We demonstrated that new tumour-targeted therapeutic systems recognizing receptors specifically overexpressed on prostate tumours, were able to improve the in vitro therapeutic efficacy on PC-3, DU145 and LNCaP prostate cancer cells when compared to the non-targeted delivery system, by up to 100-fold in LNCaP cells. In vivo, the intravenous administration of the tumour-targeted therapeutic system encoding Tumour Necrosis Factor (TNF) α resulted in tumour suppression for 60% of PC-3 and 50% of DU145 tumours. The dendriplex encoding TRAIL led to tumour suppression of 10% of PC-3 tumours. IL-12 mediated gene therapy resulted in tumour regression of 20% of both types of prostate tumours. By contrast, all the tumours treated with DAB-Tf, naked DNA or left untreated were progressive for both tumour types. The treatment was well tolerated by the animals, with no apparent signs of toxicity. The treatment of cancer cells with lactoferrin- and lactoferricin-bearing dendriplexes in vitro, led to an anti-proliferative activity enhanced by up to 5-fold for lactoferricin-bearing DAB in T98G cancer cells compared to the unmodified dendriplex. In vivo, the conjugation of lactoferrin and lactoferricin to the dendrimer significantly increased the gene expression in the tumour while decreasing the non-specific gene expression in the liver. Consequently, the intravenous administration of the targeted dendriplexes encoding TNFα led to the complete suppression of 60% of A431 tumours and up to 50% of B16-F10 tumours over one month. The treatment was well tolerated by the animals, with no apparent signs of toxicity. To our knowledge, it is the first time that an intravenously administered non-viral gene therapeutic system led to growth inhibition and even complete tumour suppression for prostate tumours. In conclusion, these tumour-targeted therapeutic systems therefore hold great potential as a novel approach for the gene therapy of prostate cancer.