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

Subject Area Pharmacology
Pharmacy
Term from 2019 to 2022
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 411866030
 
Final Report Year 2023

Final Report Abstract

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 urgently needed. 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. This notion was also supported by previous results from the Wicklein group. This project aimed at the exploration of novel therapeutic intervention strategies in preclinical mouse models and the functional analysis of selected selectins/integrins in vitro and in vivo. For specific target gene inhibition, RNA interference (RNAi)-mediated gene knockdown was employed. This was based on the stable transfection of cells for expressing small interfering RNAs (siRNAs) or the delivery of siRNAs in nanoparticles by intraperitoneal injection. Based on polymeric nanoparticles already available from the Aigner group and comprising low molecular weight polyethylenimines (PEI), novel chemically modified polymers and nanoparticles were developed and extensively characterized. This also included their exploration for the transfection of hard-to-transfect cells and their use in PC cells. Optimal nanoparticles for PC cell transfection were identified and used for subsequent functional studies. In parallel, based on the stable transfection of tumor cells with expression vectors for intracellular siRNA expression and stable knockdown, optimal target genes (integrins) for RNAi-based inhibition of PC were identified and further studied. This also included the persistence of their knockdown and possible co-/counter-regulation of other members of the integrin family. Preclinical studies in mouse models, based on these stable cell lines, identified particularly relevant integrins (α2, α3 and β4), whose knockdown was associated with prolonged survival. Next-generation sequencing (NGS) revealed multiple genes being up- and downregulated upon integrin α3 and β4 knockdown, which are currently further studied. In contrast, the combination with E- or P-selectin deficiency in mice did not yield additive effects and subsequent studies thus focused exclusively on integrins. Nanoparticles identified as optimal for therapeutic intervention were tested in initial in vivo therapy studies in tumor-bearing (PC) mice. First data indicate the relevance and feasibility of therapeutic integrin α3 knockdown, using siRNAs formulated in the above nanoparticles. This provides the basis for further therapy studies in vivo and analyses of molecular effects of this therapeutic intervention.

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