Abstract
Diaminobutyric polypropylenimine (DAB) dendrimers have been shown to be highly efficient non-viral gene delivery systems for cancer therapy. However, their cytotoxicity currently limits their applications. To overcome this issue, PEGylation of DAB dendrimer, using various PEG molecular weights and dendrimer generations, has been attempted to decrease the cytotoxicity and enhance the DNA condensation, size and zeta potential, cellular uptake and transfection efficacy of these dendriplexes. Among all the PEGylated dendrimers synthesized, generation 3- and generation 4-DAB conjugated to low molecular weight PEG (2 kDa) at a dendrimer: DNA ratio of 20:1 and 10:1 resulted in an increase in gene expression on almost all tested cancer cells lines (by up to 3.2-fold compared to unmodified dendrimer in A431 cells). The highest level of β-galactosidase gene expression (10.07 × 10−3 ± 0.09 × 10−3 U/mL) was obtained following treatment of B16F10-Luc cells with G4-dendrimer PEGylated with PEG2K at a dendrimer: DNA ratio of 20:1. These delivery systems significantly decreased cytotoxicity on B16F10-Luc cells, by more than 3.4-fold compared to unmodified dendrimer. PEGylated generations 3- and 4-DAB dendrimers are therefore promising gene delivery systems for cancer therapy, combining low cytotoxicity and high transfection efficacy.
Highlights
Gene therapy has become one of the most intensively studied strategies for the treatment of various diseases, ranging from monogenic diseases such as cystic fibrosis to complex disorders such as cancer[1]
For representation we have shown the synthesis of G3-diaminobutyric polypropylenimine (DAB) dendrimer conjugated to M-PEG2K (Supplementary Fig. 1)
DNA condensation efficiency of G3- PEGylated dendrimers decreased when the molecular weight of conjugated polyethylene glycol (PEG) increased: G3-PEG2K was able to condense more than 70% of the DNA at the weight ratios of 5:1 and higher
Summary
Gene therapy has become one of the most intensively studied strategies for the treatment of various diseases, ranging from monogenic diseases such as cystic fibrosis to complex disorders such as cancer[1]. The use of therapeutic genes in cancer treatment is still limited by the lack of safe and efficacious gene delivery vectors[2] To overcome this problem, various non-viral vectors, such as cationic liposomes and cationic polymers, are currently under development, due to advantages such as their simplicity to use, ease of production and quality control, high DNA carrying capacity, low immunogenicity and their ability to achieve prolonged exogenous gene expression[3]. Various non-viral vectors, such as cationic liposomes and cationic polymers, are currently under development, due to advantages such as their simplicity to use, ease of production and quality control, high DNA carrying capacity, low immunogenicity and their ability to achieve prolonged exogenous gene expression[3] Among these non-viral delivery systems, dendrimers appear to be promising, owing to their well-defined size and structure, low polydispersity and high transfection efficiency[4,5,6]. The aim of this study is to investigate the influence of the conjugation of PEG with various molecular weights to DAB dendrimers with various generations, on the cytotoxicity, physicochemical properties, DNA condensation, cellular uptake and transfection efficacy of the dendriplexes
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