title: Lipid Nanoparticles Loaded with an Antisense Oligonucleotide Gapmer Against Bcl-2 for Treatment of Lung Cancer.
abstract: Bcl-2 is an anti-apoptotic gene that is frequently overexpressed in human cancers. G3139 is an antisense oligonucleotide against bcl-2 that has shown limited efficacy in clinical trials. Here, we report the synthesis of a new antisense oligonucleotide containing additional chemical modifications and its delivery using nanoparticles.
  
  
  
  An oligonucleotide G3139-GAP was synthesized, which has 2'-O-methyl nucleotides at the 5' and 3' ends based on a "gapmer" design. Furthermore, G3139-GAP was incorporated into lipid nanoparticles (LNPs) composed of DOTAP/egg PC/cholesterol/Tween 80. The LNP-loaded G3139-GAP was evaluated in A549 lung cancer cells both in vitro and in a murine xenograft model for biological activity and therapeutic efficacy.
  
  
  
  The LNPs showed excellent colloidal and serum stability, and high encapsulation efficiency for G3139-GAP. They have a mean particle diameter and zeta potential of 134 nm and 9.59 mV, respectively. G3139-GAP-LNPs efficiently downregulated bcl-2 expression in A549 cells, as shown by 40% and 83% reduction in mRNA and protein levels, respectively. Furthermore, G3139-GAP-LNPs were shown to inhibit tumor growth, prolong survival, and downregulate tumor bcl-2 expression in an A549 murine xenograft tumor model. These data indicate that G3139-GAP-LNPs have excellent anti-tumor efficacy and warrant further evaluation.
authors.affiliation: Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio, 43210, USA.
authors.forename: Xinwei
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Pharmacology, Hainan Medical University, Xueyuan Road, Haikou, 571199, Hainan, China.
authors.forename: Qibing
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 West 12th Ave., Columbus, Ohio, 43210, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio, 43210, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Kang
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 West 12th Ave., Columbus, Ohio, 43210, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 West 12th Ave., Columbus, Ohio, 43210, USA.
authors.forename: Tianqi
authors.initials: T
authors.lastname: Guo
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 West 12th Ave., Columbus, Ohio, 43210, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Shang
authors.affiliation: First Affiliated Hospital of Jiamusi University, Jiamusi University, Jiamusi, 154007, Heilongjiang, China.
authors.forename: Chengyun
authors.initials: C
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Long-Acting and Targeted Drug Delivery, Nanjing, 210061, Jiangsu, China. cheng@luye.cn.|Nanjing Hightech Industrial Development Zone, 28 Gaoxin Road, Nanjing, 210061, Jiangsu, China. cheng@luye.cn.
authors.forename: Guang
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio, 43210, USA. lee.1339@osu.edu.|Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 West 12th Ave., Columbus, Ohio, 43210, USA. lee.1339@osu.edu.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
mesh_terms: D000072283:A549 Cells; D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000737:chemistry*; D010316:Particle Size; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013873:Thionucleotides / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D008055:Lipids; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D013873:Thionucleotides; C408162:oblimersen
keywords: antisense oligonucleotide; bcl-2; cancer; drug delivery; lipid nanoparticles