Uddannelses- og Forskningsministeriet - FTP - Exploiting secretory phopholipase A2 for enzyme for delivery of bioactive siRNA nano-particles to cancer tissues

The goal of this proposal is to develop a novel liposome-based nano-particle formulation for active and selective delivery of bioactive small interfering RNA (siRNA) to cancer cells. siRNA has the advantage in this context that molecular specificity can be achieved for the selective down-regulation of the translation of any protein of choice in a cancer cell. The proposed nano-particle formulation in this case is based on earlier work in our laboratory on exploiting the over-expression of secretory phospholipase A2(sPLA2) enzyme in cancer cells in order to enable selective drug delivery in tumors in vitroand in vivo(Arouri and Mouritsen (2012) E. J. Pharm. Sci. 45, 408-420; Davidsen et al. (2003) Biochim. Biophys. Acta 1609, 95-101; Pedersen et al. (2010) J. Med. Chem. 53, 3782-3792).A domestic company “LiPlasome Pharma A/S” was established based on this phenomenon to develop anticancer liposomal formulations. The major limitation of this approach is that the amount of sPLA2over-expressed in cancer tissues is insufficient for quick and efficient release of anticancer drugs that are cytotoxic in micromolar concentrations. siRNAs on the other hand are active at nanomolar concentrations. Therefore, this approach holds promise for selective delivery of potent drugs like siRNA in tumors that are known to over-express sPLA2as in e.g. prostate, pancreas, breast and colon cancer (Murata et al. (1993) Br. J. Cancer 68, 103-111; Tribler et al. (2007) 27, 3179-3185). As an extension of our previous work, we propose here new strategies for exploiting the sPLA2delivery approach as well as for formulating the siRNA nano-particles and testing them in vitroand in vivo.