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Hydrophobicity Tuning of Cationic Polyaspartamide Derivatives for Enhanced Antisense Oligonucleotide Delivery.
Yum, Jongmin; Aulia, Fadlina; Kamiya, Keisuke; Hori, Mao; Qiao, Nan; Kim, Beob Soo; Naito, Mitsuru; Ogura, Satomi; Nagata, Tetsuya; Yokota, Takanori; Uchida, Satoshi; Obika, Satoshi; Kim, Hyun Jin; Miyata, Kanjiro.
Affiliation
  • Yum J; Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
  • Aulia F; Nucleotide and Peptide Drug Discovery Center (TIDE Center), Institute of Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-0034, Japan.
  • Kamiya K; Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
  • Hori M; Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
  • Qiao N; Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
  • Kim BS; Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
  • Naito M; Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
  • Ogura S; Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
  • Nagata T; Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
  • Yokota T; Nucleotide and Peptide Drug Discovery Center (TIDE Center), Institute of Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-0034, Japan.
  • Uchida S; Nucleotide and Peptide Drug Discovery Center (TIDE Center), Institute of Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-0034, Japan.
  • Obika S; Department of Advanced Nanomedical Engineering, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
  • Kim HJ; Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
  • Miyata K; Department of Biological Engineering, College of Engineering, Inha University, 100 Inha-ro, Michuhol-gu, Incheon 22212, Republic of Korea.
Bioconjug Chem ; 35(2): 125-131, 2024 02 21.
Article in En | MEDLINE | ID: mdl-38290165
ABSTRACT
Various cationic polymers are used to deliver polyplex-mediated antisense oligonucleotides (ASOs). However, few studies have investigated the structural determinants of polyplex functionalities in polymers. This study focused on the polymer hydrophobicity. A series of amphiphilic polyaspartamide derivatives possessing various hydrophobic (R) moieties together with cationic diethylenetriamine (DET) moieties in the side chain (PAsp(DET/R)s) were synthesized to optimize the R moieties (or hydrophobicity) for locked nucleic acid (LNA) gapmer ASO delivery. The gene knockdown efficiencies of PAsp(DET/R) polyplexes were plotted against a hydrophobicity parameter, logD7.3, of PAsp(DET/R), revealing that the gene knockdown efficiency was substantially improved by PAsp(DET/R) with logD7.3 higher than -2.4. This was explained by the increased polyplex stability and improved cellular uptake of ASO payloads. After intratracheal administration, the polyplex samples with a higher logD7.3 than -2.4 induced a significantly higher gene knockdown in the lung tissue compared with counterparts with lower hydrophobicity and naked ASO. These results demonstrate that the hydrophobicity of PAsp(DET/R) is crucial for efficient ASO delivery in vitro and in vivo.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Polymers / Oligonucleotides, Antisense Language: En Journal: Bioconjug Chem Journal subject: BIOQUIMICA Year: 2024 Type: Article Affiliation country: Japan
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Polymers / Oligonucleotides, Antisense Language: En Journal: Bioconjug Chem Journal subject: BIOQUIMICA Year: 2024 Type: Article Affiliation country: Japan