Sweet Vector for Gene Delivery: the Sugar Decoration of Polyplexes Reduces Cytotoxicity with a Balanced Effect on Gene Expression

Abstract

The use of sugar-functionalized polyplexes as a nonviral gene delivery vector with lower cytotoxicity than the well-known polymeric carrier branched polyethyleneimine (BPEI) is investigated. The substitution of primary amine groups in the BPEI chains with lactose residues leads to larger polyplexes, presumably due to the higher amount of polymer required to complete DNA condensation. Nevertheless, the sugar functionalization substantially reduces the cytotoxicity of the assemblies. The nanocomplexes are taken up by the cells to a greater extent, whereas the levels of gene expression are maintained compared to those obtained using BPEI, which is known for its excellent transfection efficiency. Accordingly, the preparation of lower-cytotoxicity polyplexes while maintaining gene expression, which is highly relevant to the field, is demonstrated.

Current Designs of Polymeric Platforms Towards the Delivery of Nucleic Acids Inside the Cells with Focus on Polyethylenimine

“…The substitution of primary amine groups in bPEI chains with lactose residues was demonstrated by us to lead to a substantial reduction in cytotoxicity with a balanced effect in gene expression. [170] The simultaneous alkylcarboxylation and galactose conjugation to 25 kDa PEI is effective in the delivering of DNA to hepatocyte cells. The alkylcarboxylated chains presumably improve the hydrophilic-hydrophobic balance in the polycations which are uptaken in high yields due to the abundance of asialoglycoprotein receptors (ASGPRs) in liver parenchymal cells.…”

Polysaccharide‐Polyplex Nanofilm Coatings Enhance Nanoneedle‐Based Gene Delivery and Transfection Efficiency

“…[8][9][10] Synthetic vectors can be engineered to increase cargo loading, biodegrade, target specific cells and exhibit extended shelf-life. [5][6][7]11,12] The main limitation of these vectors is the balance between transfection efficiency and cytotoxicity. For example, polyplexes made of poly(ethylene imine) (PEI), a widely used polycation, are highly effective but simultaneously highly cytotoxic due to the quaternary amine in the structure and lack of degradation.…”

“…For example, polyplexes made of poly(ethylene imine) (PEI), a widely used polycation, are highly effective but simultaneously highly cytotoxic due to the quaternary amine in the structure and lack of degradation. [5,[12][13][14] Conversely, synthetic strategies aiming to reduce the cytotoxicity of polycations have resulted in decreased transfection levels. [5,[12][13][14] Therefore, attempts to develop a non-viral delivery system with high transfection efficiency and minimal cytotoxicity are currently under investigation.…”

Fluorination effect to intermediate molecular weight polyethylenimine for gene delivery systems

“…Unlike viral gene delivery carriers possessing their own innate cellular internalization and gene delivery mechanisms, polymeric gene delivery carriers do not have the sufficient capability to circumvent the series of barriers including interaction with serum proteins, internalization through cellular membranes, endosomal escape, release of cargo nucleic acids, and intracellular trafficking to target subcellular organelles (He et al, ; Hill, Chen, Chen, Pfeifer, & Jones, ; Li, Wei, & Gong, ). Therefore, to develop ideal gene delivery carriers, many strategies have been applied, such as crosslinking of low molecular weight compounds (Choi, Ryu, Lee, Kim, & Kim, ; Lee, Ryu, Kim, Choi, & Kim, ; Parmer et al, ; Shim, Bhang, Yoon, Choi, & Xia, ; Won, Akoné, Engbersen, Feijen, & Kim, ) and grafting of bio‐functional moieties including amino acids (An et al, ; Bai, Choi, Nam, An, & Park, ), peptides (Cerrato, Künnapuu, & Langel, ; Jaing, Lv, & Luo, ; Ryu, Lee, Park, & Kim, ), carbohydrates (Albuquerque et al, ), triazine (Wang et al, ), polyethylenglycol (Kono, ), or N‐isobutyramide (Kono, ).…”