title: Polyethylenimine-functionalized carbon nanotubes tagged with AS1411 aptamer for combination gene and drug delivery into human gastric cancer cells.
abstract: In this project, synergistic cancer cell death was achieved by a targeted delivery system comprising Bcl-xL-specific shRNA and a very low DOX content, which simultaneously activated an intrinsic apoptotic pathway. A modified branched polyethylenimine (PEI 10kDa) was grafted through polyethylene glycol (PEG) linker to carboxylated single-walled carbon nanotubes (SWCNT) to serve as a vehicle for shRNA delivery. The SWNT-PEG-PEI conjugate was covalently attached to AS1411 aptamer as the nucleolin ligand to target the co-delivery system to the tumor cells overexpressing nucleolin receptors on their surface. The final vehicle was eventually obtained after intercalation of DOX with pBcl-xL shRNA-SWCNT-PEG-10-10%PEI-Apt. Cell viability assay, GFP expression and transfection experiment against L929 (-nucleolin) and AGS (+nucleolin) cells illustrated that the tested targeted delivery system inhibited the growth of nucleolin-abundant gastric cancer cells with strong cell selectivity. Subsequently, we illustrated that the combination treatment of the selected shRNAs and DOX had excellent tumoricidal efficacy as verified by MTT assay. Furthermore, very low concentration of DOX, approximately 58-fold lower than its IC50 concentration, was used which could mitigate toxic side effects of DOX. Overall, our work revealed that combination of shRNA-mediated gene-silencing strategy with chemotherapeutic agents constitutes a valuable and safe approach for antitumor activity.
authors.affiliation: Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Sahar
authors.initials: S
authors.lastname: Taghavi
authors.affiliation: Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Azadeh Hashem
authors.initials: AH
authors.lastname: Nia
authors.affiliation: Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address: abnouskh@mums.ac.ir.
authors.forename: Khalil
authors.initials: K
authors.lastname: Abnous
authors.affiliation: Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address: ramezanim@mums.ac.ir.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ramezani
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D052157:Aptamers, Nucleotide; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology; D016503:Drug Delivery Systems; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D006801:Humans; D020128:Inhibitory Concentration 50; D037742:Nanotubes, Carbon; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D011094:Polyethyleneimine / Q000031:analogs & derivatives / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage; D016601:RNA-Binding Proteins / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014162:Transfection; D000097796:Nucleolin
chemical_list: D000970:Antineoplastic Agents; D052157:Aptamers, Nucleotide; D004317:Doxorubicin; D037742:Nanotubes, Carbon; D009838:Oligodeoxyribonucleotides; D010750:Phosphoproteins; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D000097796:Nucleolin; C513936:AGRO 100; C544016:poly(ethylene glycol)-co-poly(ethyleneimine)
keywords: AS1411 aptamer; Doxorubicin; Nucleolin; SWCNT; pBcl-xL shRNA