Journal
ACS APPLIED MATERIALS & INTERFACES
Volume 8, Issue 10, Pages 6400-6410Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsami.6b00825
Keywords
sheddable; tumor acidity; PEGylation; polyethylenimine-poly(trimethylene carbonate); gene delivery
Funding
- National Natural Science Foundation of China [81272453, 81472850]
- Key Research Program of the Chinese Academy of Sciences [KGZD-EW-T06]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDA09030301]
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Amphiphilic PEI derivatives/DNA complexes are widely used for DNA delivery, but they are unstable in vivo and have cytotoxicity due to the excess cationic charge. PEGylation of cationic complexes can improve sterical stability and biocompatibility. However, PEGylation significantly inhibits cellular uptake and endosomal escape. In this work, sheddable ternary complexes were developed by coating a tumor acidity-sensitive beta-carboxylic amide functionalized PEG layer on the binary complexes of amphiphilic cationic polyethylenimine-poly(trimethylene carbonate) nanoparticles/DNA (PEI-PTMC/DNA). Such sheddable ternary complexes markedly reduced their nonspecific interactions with serum protein in the bloodstream and obtained minimal cytotoxicity due to the protection of the PEG shell. At the tumor site, the PEG layer was deshielded by responding to the tumor acidic microenvironment and the positively charged complexes re-exposed that had higher affinity with negatively charged cell membranes. Meanwhile the positively charged complexes facilitated endosomal escape. Accordingly, this delivery system improved the biocompatibility of gene-loaded complexes and enhanced the gene transfection efficiency. Such PEGylated complexes with the ability to deshield the PEG layer at the target tissues hold great promise for efficient and safe gene delivery in vivo.
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