Journal
ACS APPLIED MATERIALS & INTERFACES
Volume 6, Issue 13, Pages 10393-10407Publisher
AMER CHEMICAL SOC
DOI: 10.1021/am501928p
Keywords
gene therapy; RNA interference; MSCs; disulfide bond; histidine(Bzl)
Funding
- 973 program [2013CB967500]
- National Natural Science Foundation of China [51173136, 21104059, 81371949, 30970726]
- Shanghai Rising-Star Program [12QA1403400]
- Chen Guang project
- Div Of Chem, Bioeng, Env, & Transp Sys
- Directorate For Engineering [1346387] Funding Source: National Science Foundation
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Polylysine with cleavable PEGylation and hydrophobic histidylation (mPEG-SS-Lys(n)-r-His(m)) was designed and developed for efficient siRNA delivery and tumor therapy. mPEG-SS-Lys(n)-r-His(m) was used to carry and deliver small interfering RNA (siRNA) for silencing endogenous vascular endothelial growth factor (VEGF) expression and inhibiting tumor growth in HepG2 tumor-bearing mice. In this gene vector, histidine(Bzl) was selected for hydrophobic histidylation for the proton sponge ability of the imidazole ring and hydrophobic benzyl group. Cleavable PEGylation was introduced for in vivo circulation as well as selective PEG detachment in response to intracellular reduction condition in order to release the genetic payload. PEG detachment induced gene release was supported by agarose gel electrophoresis retardation assay, undertaken in the intracellular relevant reduction condition. In vitro transfection evaluation of histidylated copolymers, using pEGFP as genetic model, indicated significantly higher GFP expression than unmodified counterparts, comparable to the gold standard PEI. The efficacy of hydrophobic histidylation was found to be pronounced in mesenchymal stem cells (MSCs). In vivo application of the VEGF-siRNA package by tailored mPEG-SS-Lys(n)-r-His(m) showed distinct tumor suppression in terms of macroscopic tumor volume and molecular analysis.
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