Cleavable
PEGylation and Hydrophobic Histidylation of Polylysine for siRNA Delivery
and Tumor Gene Therapy
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Abstract
Polylysine with cleavable PEGylation
and hydrophobic histidylation (mPEG-SS-Lys<sub><i>n</i></sub>-r-His<sub><i>m</i></sub>) was designed and developed for
efficient siRNA delivery and tumor therapy. mPEG-SS-Lys<sub><i>n</i></sub>-r-His<sub><i>m</i></sub> 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<sub><i>n</i></sub>-r-His<sub><i>m</i></sub> showed
distinct tumor suppression in terms of macroscopic tumor volume and
molecular analysis