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Hydrophobicity Tuning of Cationic Polyaspartamide Derivatives for Enhanced Antisense Oligonucleotide Delivery.

Jongmin YumFadlina AuliaKeisuke KamiyaMao HoriNan QiaoBeob Soo KimMitsuru NaitoSatomi OguraTetsuya NagataTakanori YokotaSatoshi UchidaSatoshi ObikaHyun Jin KimKanjiro Miyata
Published in: Bioconjugate chemistry (2024)
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, log D 7.3 , of PAsp(DET/R), revealing that the gene knockdown efficiency was substantially improved by PAsp(DET/R) with log D 7.3 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 log D 7.3 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 .
Keyphrases
  • nucleic acid
  • copy number
  • genome wide
  • genome wide identification
  • high glucose
  • gene expression
  • dna methylation
  • endothelial cells