Amino Acid-Linked Low Molecular Weight Polyethylenimine for Improved Gene Delivery and Biocompatibility

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.

Polyethylenimine-Modified Bombyx mori Silk Fibroin as a Delivery Carrier of the ING4-IL-24 Coexpression Plasmid

“…However, its high charge density would cause severe cytotoxicity [ 39 ]. In contrast, PEI with a low-molecular-weight showed low cytotoxicity, but its transfection efficiency was limited [ 40 ]. To overcome the contradiction between transfection and toxicity, in this study, we attempted to graft low-molecular-weight PEI with Bombyx mori silk fibroin protein, in order to improve the transfection efficiency of low-molecular-weight PEI while giving it lower cytotoxicity.…”

Histidine‐enhanced gene delivery systems: The state of the art

“…In this section, the use of histidine to modify gene therapy nanovectors such as PEI and chitosan for elevated transfection with improved biocompatibility are discussed. For example, LMW PEI chains could be connected together by degradable bonds such as a disulfide, ester or B‐aminoester to improve transfection efficiency and lower toxicity 108 . Also, the use of polyethylene glycol (PEG) and other hydrophilic chains to reduce aggregation and prolong the circulation time are very common.…”

“…In 2020, Wu et al 108 . constructed two novel polycations based on the low molecular weight polyethylenimine backbone (600 Da) with amino acid‐containing bridges through a Michael addition reaction.…”

Lipoic Acid-Modified Oligoethyleneimine-Mediated miR-34a Delivery to Achieve the Anti-Tumor Efficacy

“…However, the relatively high toxicity of PEI25K limited its clinical application in tumor gene therapy. In comparison to PEI25K, oligoethyleneimine (OEI) exhibited favorable biocompatibility but its transfection efficiency was relatively lower [ 25 , 26 , 27 ]. Thus, extensive efforts have been devoted to improve its transfection efficiency through the modification with other molecules such as β-cyclodextrin [ 26 ], acetal [ 28 ], alkyl acrylates [ 29 ], poly(β-amino ester) [ 30 ] and polypropylenimine dendrimers [ 31 ].…”