Abstract
When studying polyethylenimine derivatives as nonviral vectors for gene delivery, among the important issues to be addressed are high toxicity, low transfection efficiency, and nucleic acid polyplex condensation. The molecular weight of polyethylenimine, PEGylation, biocompatibility and, also, supramolecular structure of potential carrier can all influence the nucleic acid condensation behavior, polyplex size, and transfection efficiency. The main challenge in building an efficient carrier is to find a correlation between the constituent components, as well as the synergy between them, to transport and to release, in a specific manner, different molecules of interest. In the present study, we investigated the synergy between components in dynamic combinatorial frameworks formed by connecting PEGylated squalene, poly-(ethyleneglycol)-bis(3-aminopropyl) and low molecular weight polyethylenimine components to 1,3,5-benzenetrialdehyde, via reversible imine bond, applying a dynamic combinatorial chemistry approach. We report comparative structural and morphological data, DNA binding affinity, toxicity and transfection efficiency concerning the ratio of polyethylenimine and presence or absence of poly-(ethyleneglycol)-bis(3-aminopropyl) in composition of dynamic combinatorial frameworks. In vitro biological assessments have revealed the fact that nonviral vectors containing poly-(ethyleneglycol)-bis(3-aminopropyl) and the lowest amount of polyethylenimine have significant transfection efficiency at N/P 50 ratio and display insignificant cytotoxicity on the HeLa cell line.
Highlights
Gene delivery holds great promise for correcting genetic defects and treating myriad of genetic and acquired diseases [1,2,3,4]
All other approaches are based on nonviral gene delivery systems, which try to mimic the efficiency of viral vectors by artificial means [7,8,9,10]
We have addressed and investigated the above mentioned issues by applying a dynamic combinatorial chemistry approach developed by our group [34,35,36] to produce a series of new systems (dynamic combinatorial frameworks (DCFs)) containing PEGylated squalene (SQ-PEG-NH2 ) [34,37], poly-(ethyleneglycol)-bis(3-aminopropyl) (Mn~1500 g/mol) (NH2 -PEG-HN2 ), and branched polyethylenimine of 2000 Da (PEI2000) components, reversibly connected in a hyperbranched structure
Summary
Gene delivery holds great promise for correcting genetic defects and treating myriad of genetic and acquired diseases [1,2,3,4]. Major problems in gene therapy are related to the development of efficient and targeted DNA carrier able to deliver large quantities of genetic material. Based on their design and properties, viral vectors currents show the best results in effective gene delivery [1,2,3,4,5,6]. Cationic polymers, represented commonly by polyethylenimine (PEI), including branched (B-PEI) and linear polyethylenimine (L-PEI), have become a safer alternative to viral vectors and have shown good transfection efficiency (TE) in different types of cells and their “proton sponge”
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