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Lipid Nanoparticles Loaded with an Antisense Oligonucleotide Gapmer Against Bcl-2 for Treatment of Lung Cancer

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Abstract

Purpose

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.

Methods

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.

Results

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.

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Abbreviations

2’OMe:

2’-O-methyl

ASOs:

Antisense oligonucleotides

Bcl-2:

B-cell lymphoma 2

DLS:

Dynamic lighting scattering

DOPE:

1,2-dioleoyl-sn-glycero-3-phosphoethanolamine

DOTAP:

1,2-dioleoyl-3-trimethylammonium-propane

Egg PC:

Egg L-α-phosphatidylcholine

GAP:

Gapmer

LNPs:

Lipid nanoparticles

PS:

Phosphorothioate

PTX:

Paclitaxel

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported in part by a contract from Nanjing Luye Sike Pharmaceutical Co. Ltd. (Nanjing, China).

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio, 43210, USA

    Xinwei Cheng & Robert J. Lee

  2. Department of Pharmacology, Hainan Medical University, Xueyuan Road, Haikou, 571199, Hainan, China

    Qibing Liu

  3. Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 West 12th Ave., Columbus, Ohio, 43210, USA

    Hong Li, Yang Liu, Tianqi Guo, Ke Shang & Robert J. Lee

  4. Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio, 43210, USA

    Chen Kang

  5. First Affiliated Hospital of Jiamusi University, Jiamusi University, Jiamusi, 154007, Heilongjiang, China

    Chengyun Yan

  6. State Key Laboratory of Long-Acting and Targeted Drug Delivery, Nanjing, 210061, Jiangsu, China

    Guang Cheng

  7. Nanjing Hightech Industrial Development Zone, 28 Gaoxin Road, Nanjing, 210061, Jiangsu, China

    Guang Cheng

Authors
  1. Xinwei Cheng
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  2. Qibing Liu
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  3. Hong Li
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  4. Chen Kang
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  5. Yang Liu
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  9. Guang Cheng
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  10. Robert J. Lee
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Correspondence to Guang Cheng or Robert J. Lee.

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Cheng, X., Liu, Q., Li, H. et al. Lipid Nanoparticles Loaded with an Antisense Oligonucleotide Gapmer Against Bcl-2 for Treatment of Lung Cancer. Pharm Res 34, 310–320 (2017). https://doi.org/10.1007/s11095-016-2063-5

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  • DOI: https://doi.org/10.1007/s11095-016-2063-5

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