title: Systemic delivery of sticky siRNAs targeting the cell cycle for lung tumor metastasis inhibition.
abstract: RNA interference allows the design of new inhibitors that target deregulated pathways in cancer. However systemic delivery of siRNA for the treatment of solid tumors still remains an issue. In our study, in order to suppress the progression of lung cancer metastasis in mice, we developed sticky siRNA (ssiRNA) to inhibit survivin and cyclin B1, two candidates involved in cell survival and proliferation. We exploited the linear polyethylenimine (PEI) as potent non-viral carrier to efficiently deliver our inhibitors. As a proof of concept, we have chosen a very aggressive mammary adenocarcinoma model (TSA-Luc cells), which forms lung metastases upon systemic cell injection. We confirmed in vitro, that the ssiRNAs delivered with PEI are not only able to inhibit our target genes at the mRNA and protein levels, but are also able to block the cell cycle and cell proliferation through a mechanism of RNA interference. More importantly, we showed in vivo by luciferase dosage, bioimaging and tissue section, an inhibition of lung tumor metastases after systemic delivery of cyclin B1 and survivin ssiRNA complexed with PEI. Alternating treatment with cisplatin and ssiRNA/PEI showed an additive effect between the two anticancer drugs on lung tumor inhibition leading to a significant increase in animal survival. Moreover a promising window between activity (IC₅₀) and toxicity (LD₅₀), essential for therapeutic application, was observed. Our data show that systemic delivery of ssiRNA/PEI complexes targeting the cell cycle is a valuable strategy for the treatment of lung tumor metastasis and that it can be combined with chemotherapy.
authors.affiliation: Polyplus-transfection SA, Bioparc, BP 90018, Boulevard Sébastien Brant, 67401 Illkirch, France.
authors.forename: Marie-Elise
authors.initials: ME
authors.lastname: Bonnet
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Gossart
authors.forename: Elodie
authors.initials: E
authors.lastname: Benoit
authors.forename: Mélanie
authors.initials: M
authors.lastname: Messmer
authors.forename: Omar
authors.initials: O
authors.lastname: Zounib
authors.forename: Valérie
authors.initials: V
authors.lastname: Moreau
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Behr
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lenne-Samuel
authors.forename: Valérie
authors.initials: V
authors.lastname: Kedinger
authors.forename: Aline
authors.initials: A
authors.lastname: Meulle
authors.forename: Patrick
authors.initials: P
authors.lastname: Erbacher
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Bolcato-Bellemin
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology / Q000628:therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000627:therapeutic use; D056744:Cyclin B1 / Q000235:genetics*; D005260:Female; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D007928:Lethal Dose 50; D008175:Lung Neoplasms / Q000556:secondary / Q000628:therapy*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D011094:Polyethyleneimine / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; C117749:Birc5 protein, mouse; C534700:Ccnb1 protein, mouse; D056744:Cyclin B1; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000077022:Survivin; D011094:Polyethyleneimine; D002945:Cisplatin
keywords: Cancer; Cell cycle; Delivery; Metastasis; Sticky siRNA