Parallel Synthesis and Quantitative Structure-Activity Relationship (QSAR) Modeling of Aminoglycoside-Derived Lipopolymers for Transgene Expression

Bhavani Miryala, Zhuo Zhen, Thrimoorthy Potta, Curt M. Breneman, Kaushal Rege

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

We describe the parallel synthesis of lipopolymers generated by conjugating alkanoyl chlorides to polymers derived from aminoglycoside antibiotic monomers as novel vehicles for transgene delivery and expression in mammalian cells. Parallel screening of lipopolymers led to the identification of six leads that demonstrated higher transgene expression efficacies in several cancer cells, when compared to the parental polymers as well as 25 kDa poly(ethylene imine), a current standard for polymer-mediated transgene expression. Quantitiative structure-activity relationship (QSAR)-based cheminformatics modeling was employed in order to investigate the role of lipopolymer physicochemical properties (molecular descriptors) on transgene expression efficacy. The predictive ability of the QSAR model, investgated using lipopolymers not employed for training the model, demonstrated excellent agreement with experimentally observed transgene expression. Our findings indicate that lipid substitution on aminoglycoside-derived polymers results in high levels of transgene expression compared to unsubstituted polymers. Taken together, these materials show significant promise in nonviral transgene delivery with several applications in biotechnology and medicine.

Original languageEnglish (US)
Pages (from-to)656-668
Number of pages13
JournalACS Biomaterial Science and Engineering
Volume1
Issue number8
DOIs
StatePublished - Dec 14 2015

Keywords

  • aminoglycosides
  • cheminformatics
  • combinatorial chemistry
  • gene delivery
  • lipids
  • structure-property relationships

ASJC Scopus subject areas

  • Biomaterials
  • Biomedical Engineering

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