title: Antitumor activity of G3139 lipid nanoparticles (LNPs).
abstract: G3139, an antisense oligodeoxyribonucleotide (ODN) against Bcl-2, contains two CpG dinucleotides and has shown immunostimulatory activities in preclinical studies. It has been suggested that immunoactivation, rather than antisense activity, is primarily responsible for the therapeutic efficacy of G3139. Nanoparticle formulations naturally target phagocytic antigen presenting cells and therefore might enhance the immunological effects of G3139. In this study, a novel formulation of lipid nanoparticles (LNPs) encapsulating G3139 was synthesized and evaluated in mice bearing L1210 subcutaneous tumors. Intravenous injection of G3139-LNPs into mice led to increased serum levels of IL-6 and IFN-gamma, promoted proliferation of natural killer (NK) cells and dendritic cells (DCs), and triggered a strong antitumor immune response in mice. The observed effects were much greater than those induced by free G3139. Correspondingly, the G3139-LNPs more effectively inhibited tumor growth and induced complete tumor regression in some mice. In contrast, free G3139 was ineffective in tumor growth inhibition and did not prolong survival of the tumor-bearing mice. These results suggest that G3139-LNPs are a potential immunomodulatory agent and may have applications in cancer therapy.
authors.affiliation: Division of Pharmaceutics, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Pan
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Shujun
authors.initials: S
authors.lastname: Liu
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Yang
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Gao
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
mesh_terms: D000220:Adaptation, Biological / Q000187:drug effects / Q000276:immunology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology; D008055:Lipids / Q000737:chemistry*; D051379:Mice; D008811:Mice, Inbred DBA; D053758:Nanoparticles / Q000737:chemistry*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D013873:Thionucleotides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D008055:Lipids; D019253:Proto-Oncogene Proteins c-bcl-2; D013873:Thionucleotides; C408162:oblimersen