title: Multicomponent mannose-containing liposomes efficiently deliver RNA in murine immature dendritic cells and provide productive anti-tumour response in murine melanoma model.
abstract: Here we demonstrate the ability of mannosylated liposomes (ML) targeted to mannose receptors (MR) to perform the targeted delivery of model plasmid DNA encoding EGFP and total tumour RNA into murine bone-marrow-derived dendritic cells (DCs) and enhance the efficiency of anti-tumour response triggered by these DCs in murine melanoma model. ML consist of cationic lipid 2X3 (1,26-Bis(cholest-5-en-3β-yloxycarbonylamino)-7,11,16,20-tetraazahexacosan tetrahydrochloride), helper lipid DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), and 2.5, 5 or 10% mol. of novel mannosylated lipoconjugates. In the structure of lipoconjugates D-mannose was attached to ditetradecylglycerol residue via succinyl (lipoconjugate 1) or diethylsquarate (lipoconjugate 2) linker groups. ML spontaneously form complexes with plasmid DNA and RNA due to electrostatic interaction between positively charged lipid amino group and negatively charged phosphate of nucleic acids. ML demonstrated the benefit in transfection efficiency (TE) of pDNA into DC progenitors and immature DCs in comparison with the control liposomes at low N/P (nitrogen to phosphate) ratios (1/1 and 2/1) but not at high N/P ratios where the TE was comparable with control liposomes. Moreover, ML at low N/P were more effective in RNA delivery into immature DCs in comparison with DC progenitors. At high N/P ratios liposomal formulations containing 5 and 10% mol. of mannosylated lipoconjugate 2 with diethylsquarate linker were the most effective (up to 50% of transfected cells). DCs transfected ex vivo with ML/melanoma B16 RNA complexes after i.v. injection into mice caused five- to six-fold inhibition of melanoma lung metastasis number. Moreover, the i.v. injection of ML/melanoma B16 RNA complexes into mice induced generation of the melanoma B16-specific cytotoxic T-lymphocytes, which were two-fold more efficient in B16 cell killing than those from control liposome group.
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentieva Ave. 8, Novosibirsk 630090, Russia.
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Markov
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentieva Ave. 8, Novosibirsk 630090, Russia.
authors.forename: Nadezhda L
authors.initials: NL
authors.lastname: Mironova
authors.affiliation: Lomonosov Moscow State University of Fine Chemical Technologies, Vernadskogo Ave. 86, Moscow 119571, Russia.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Shmendel
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentieva Ave. 8, Novosibirsk 630090, Russia.
authors.forename: Roman N
authors.initials: RN
authors.lastname: Serikov
authors.affiliation: Lomonosov Moscow State University of Fine Chemical Technologies, Vernadskogo Ave. 86, Moscow 119571, Russia.
authors.forename: Nina G
authors.initials: NG
authors.lastname: Morozova
authors.affiliation: Lomonosov Moscow State University of Fine Chemical Technologies, Vernadskogo Ave. 86, Moscow 119571, Russia.
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Maslov
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentieva Ave. 8, Novosibirsk 630090, Russia.
authors.forename: Valentin V
authors.initials: VV
authors.lastname: Vlassov
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentieva Ave. 8, Novosibirsk 630090, Russia. Electronic address: marzen@niboch.nsc.ru.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Zenkova
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004247:DNA / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D003713:Dendritic Cells / Q000378:metabolism / Q000637:transplantation*; D015316:Genetic Therapy; D049452:Green Fluorescent Proteins / Q000235:genetics; D037181:Lectins, C-Type / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry* / Q000378:metabolism; D008297:Male; D008358:Mannose / Q000737:chemistry* / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D012334:RNA, Neoplasm / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D011956:Receptors, Cell Surface / Q000378:metabolism; D014162:Transfection
chemical_list: D037181:Lectins, C-Type; D008081:Liposomes; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D012334:RNA, Neoplasm; D011956:Receptors, Cell Surface; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D004247:DNA; D008358:Mannose
keywords: Dendritic cells; Mannose receptor; Mannosylated liposomes; Targeting