Abstract
The construction of efficient and low toxic non-viral gene delivery vectors is of great significance for gene therapy. Herein, two novel polycations were constructed via Michael addition from low molecular weight polyethylenimine (PEI) 600 Da and amino acid-containing linkages. Lysine and histidine were introduced for the purpose of improved DNA binding and pH buffering capacity, respectively. The ester bonds afforded the polymer biodegradability, which was confirmed by the gel permeation chromatography (GPC) measurement. The polymers could well condense DNA into nanoparticles and protect DNA from degradation by nuclease. Compared with PEI 25 kDa, these polymers showed higher transfection efficiency, lower toxicity, and better serum tolerance. Study of this mechanism revealed that the polyplexes enter the cells mainly through caveolae-mediated endocytosis pathway; this, together with their biodegradability, facilitates the internalization of polyplexes and the release of DNA. The results reveal that the amino acid-linked low molecular weight PEI polymers could serve as promising candidates for non-viral gene delivery.
Highlights
Gene therapy is a promising therapeutic method for delivering nucleic acid agents or genome-editing tools into diseased cells [1]
We adopted a strategy of crosslinking PEI 600 Da via Michael addition polymerization to form degradable polymers containing nontoxic amino acid-containing bridges
For their special basicity and pH buffering capacity of lysine and histidine respectively, these two amino acids were introduced to the bridge to crosslink low molecular weight (LMW) PEI
Summary
Gene therapy is a promising therapeutic method for delivering nucleic acid agents or genome-editing tools into diseased cells [1]. One of the great challenges of gene delivery is to design novel non-viral vectors that fulfill the promise of high delivery efficiency and high safety [4]. Various non-viral systems, such as cationic liposomes [5], polymers [6], inorganic nanoparticles [7] and quantum dots [8], have been developed to improve the gene delivery properties. Among these types, cationic polymers have attracted great attention because of some remarkable advantages including facile manufacturing, high nucleic acid capacity, good stability and modification [7]
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