The design of efficient vehicles for nucleic acid transfection is a key roadblock in gene therapy and transient protein expression processes. Molecular design of such vehicles has traditionally relied on ad hoc approaches, with few studies focusing on quantitative structure-property relationships. Here, we describe the combinatorial synthesis and cheminformatics modeling of novel aminoglycoside-derived lipopolymers for transgene delivery and expression in cancer cells. The lipopolymers were synthesized by N-acylation reaction between free amines of aminoglycoside based polymers and three different alkanoyl chlorides. The synthesized lipopolymers were characterized using <sup>1</sup>H NMR and FTIR spectroscopy. Parallel screening of lipopoplymers led to the identification of several lead candidates that demonstrated higher levels of transgene expression than 25 kDa polyethyleneimine (used as a standard for non-viral gene delivery) in several cancer cells. Importantly, several leads were found to maintain transgene expression efficacy even in the presence of serum. Quantitative Structure-Activity Relationship (QSAR) cheminformatics modeling was employed in order to elucidate the role of lipopolymer physicochemical properties (molecular descriptors) on transgene expression efficacy. Molecular visualization methods were employed to further study the role of individual molecular descriptors selected in the QSAR model. The predictive ability of the QSAR model was investigated using lipopolymers not employed for training the model; model predictions demonstrated excellent agreement with experimental observations. Taken together, aminoglycoside lipopolymers show significant promise in non-viral transgene delivery with several applications in biotechnology and medicine.

Combinatorial synthesis and cheminformatics modeling of aminoglycoside lipopolymers for transgene expression

249th National Meeting (2015)

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