Therapeutic inhibition of peritoneal carcinomatosis by nanoparticle/siRNA-mediated knockdown of specific integrins and selectins

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Peritoneal carcinomatosis (PC) is a common form of pancreatic and gastric carcinoma progression, which substantially contributes to the rather poor prognosis. New therapeutic strategies, including the selective inhibition of PC, are thus desperately needed. In this regard, tumor cells as well as endothelial/mesothelial/non-malignant stroma cells can be explored as therapeutic target. Integrins are heterodimeric cell adhesion molecules consisting of α- and β-subunits. Certain integrins are upregulated in tumors and putatively play a pivotal role in PC. Previous results from the Wicklein group indicate that the integrins α2, α3, α5, α6, αV, β1 and β4 are most promising for being explored. Likewise, in xenografts E- and P-selectin were demonstrated to increase hematogenous metastasis and PC formation. This project aims at the exploration of novel therapeutic intervention strategies in preclinical mouse models and the functional analyses of selected selectins/integrins in vitro and in vivo. For specific single or combined target gene inhibition, we will employ RNA interference (RNAi)-mediated gene knockdown based on the delivery of RNA molecules (small interfering RNAs, siRNAs). siRNAs will be formulated in nanoparticles and applied intraperitoneally. A major challenge is the development of nanoparticle formulations with high stability and activity in the peritoneum. From the Aigner group, polymeric nanoparticles comprising low molecular weight polyethylenimines (PEI) and chemical modifications thereof are available. In this project, these nanoparticles will be further developed and explored for the first time for PC inhibition. Beyond knockdown of integrins, this will also involve targeting upstream regulators (PCDHB9, FBXO50), and using the integrin-inhibiting miR-31 for miRNA replacement therapy. For prolonged treatment duration, hydrogels as sustained NP release systems will be established as well and optimized with regard to desired release kinetics. Objectives thus include (i) the identification and analysis of optimal target genes (integrins, selectins, integrin upstream genes and combinations thereof) for RNAi-based inhibition of PC, (ii) exploring tumor cells (integrins) as well as endothelial/mesothelial/non-malignant stroma cells (selectins, integrins) as targets, (iii) the development and in vitro / in vivo analysis of optimized, polymeric nanoparticles and sustained release systems for peritoneal delivery of therapeutic siRNAs/miRNAs, and (iv) preclinical therapy studies in mouse models, using optimal nanoparticle systems and siRNAs. This will cover pre-treatment (prior to tumor cell exposure, aiming at the abolishment of the onset of PC), post-treatment (after tumor cell exposure, for treating established intraperitoneal carcinomas) and prolonged treatment protocols, aiming at both.