title: Tissue slice model of human lung cancer to investigate telomerase inhibition by nanoparticle delivery of antisense 2'-O-methyl-RNA.
abstract: Nanoparticles delivery of oligonucleotides represents a potential approach for cancer treatment. However, most of the experiments were based on established cancer cell lines and may not reflect the original solid tumor in vivo. Both, tumor microenvironment and tumor cell biological properties in the tumor can influence the delivery efficiency of oligonucleotides. Therefore, it is important to understand the effect of nanoparticles delivery of oligonucleotides on tumor response in intact tissue architecture of individual tumors. We used freshly isolated human tumor tissue slices and primary lung cancer cells from non-small cell lung cancer patients to evaluate this nanocarrier system. Chitosan-coated poly(lactide-co-glycolide) (PLGA) nanoparticles were used to form oligonucleotide-nanoparticle-complexes (nanoplexes) with antisense 2'-O-methyl-RNA (OMR) that can inhibit telomerase activity by binding to the RNA component of telomerase. OMR cellular uptake was strongly enhanced by nanoplexes mediated delivery in both, primary cells and tissue slices. More than 80% of primary cancer cells and 50% of cells in tissue slices showed OMR uptake. Telomerase activity was inhibited by approximately 45% in primary cancer cells and about 40% in tissue slices. Nanoplexes could penetrate into tumor tissue without influencing tissue architecture and the delivered OMR was able to inhibit telomerase activity with relatively low cytotoxicity.
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
authors.forename: Meng
authors.initials: M
authors.lastname: Dong
authors.forename: Claudia
authors.initials: C
authors.lastname: Philippi
authors.forename: Brigitta
authors.initials: B
authors.lastname: Loretz
authors.forename: Noha
authors.initials: N
authors.lastname: Nafee
authors.forename: Ulrich F
authors.initials: UF
authors.lastname: Schaefer
authors.forename: Godehard
authors.initials: G
authors.lastname: Friedel
authors.forename: Susanne
authors.initials: S
authors.lastname: Ammon-Treiber
authors.forename: Ernst-Ulrich
authors.initials: EU
authors.lastname: Griese
authors.forename: Claus-Michael
authors.initials: CM
authors.lastname: Lehr
authors.forename: Ulrich
authors.initials: U
authors.lastname: Klotz
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Mürdter
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D048271:Chitosan / Q000737:chemistry; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D053758:Nanoparticles; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D016372:RNA, Antisense / Q000008:administration & dosage*; D019098:Telomerase / Q000037:antagonists & inhibitors*; D046509:Tissue Culture Techniques
chemical_list: D016372:RNA, Antisense; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D048271:Chitosan; D019098:Telomerase