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Enhanced antitumor efficacies of multifunctional nanocomplexes through knocking down the barriers for siRNA delivery.

Biomaterials (2015-01-27)
Lu Han, Cui Tang, Chunhua Yin
ABSTRACT

Multifunctional nanocomplexes (NCs) consisting of urocanic acid-modified galactosylated trimethyl chitosan (UA-GT) conjugates as polymeric vectors, poly(allylamine hydrochloride)-citraconic anhydride (PAH-Cit) as charge-reversible crosslinkers, and vascular endothelial growth factor (VEGF) siRNA as therapeutic genes, were rationally designed to simultaneously overcome the extracellular, cellular, and intracellular barriers for siRNA delivery. The strong physical stability of UA-GT/PAH-Cit/siRNA NCs (UA-GT NCs) at pH 7.4 and 6.5 endowed protection from massive dilution, competitive ions, and ubiquitous nucleases in the blood and tumorous microenvironment. Their internalization into hepato-carcinoma cells was facilitated through the recognition of galactose receptors, followed by effective escape from endosomes/lysosomes owing to the strong buffering capacity of imidazole residues. At the meantime, the endosomal/lysosomal acidity triggered the charge reversal of PAH-Cit in UA-GT NCs, thus evoking their structural disassembly and subsequently accelerated release of siRNA in the cytosol. As a result, robust in vivo performance in terms of both gene silencing and tumor inhibition was achieved by UA-GT NCs at a low siRNA dose. Moreover, neither histological nor hematological toxicity was detected following repeated intravenous administration. Therefore, UA-GT NCs potentially served as an efficient and safe candidate in the treatment of hepatocellular carcinoma through knocking down the overall barriers for siRNA delivery.

MATERIALS
Product Number
Brand
Product Description

Galactose, European Pharmacopoeia (EP) Reference Standard
Supelco
Galactose, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
2-Propen-1-amine hydrochloride, AldrichCPR
Sigma-Aldrich
D-(+)-Galactose, meets analytical specification of Ph. Eur., BP
Millipore
D-(+)-Galactose, suitable for microbiology, ≥99.0%
Sigma-Aldrich
D-(+)-Galactose, ≥99%
Sigma-Aldrich
D-(+)-Galactose, powder, anhydrous, BioReagent, suitable for cell culture, suitable for insect cell culture
Sigma-Aldrich
D-(+)-Galactose, ≥98%
Sigma-Aldrich
D-(+)-Galactose, BioXtra, pH 5.0-7.0 (20 °C, 1 M in H2O), ≥99%
USP
Galactose, United States Pharmacopeia (USP) Reference Standard
SAFC
Galactose, plant-derived
Sigma-Aldrich
Lactobionic acid, 97%
Sigma-Aldrich
4-Imidazoleacrylic acid, 99%
Sigma-Aldrich
Lactobionic acid, cell impermeant agent
Sigma-Aldrich
N-Hydroxysuccinimide, 98%
Sigma-Aldrich
Citraconic anhydride, 98%
Sigma-Aldrich
N-Hydroxysuccinimide, purum, ≥97.0% (T)
Sigma-Aldrich
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide, ≥97.0% (T)
Sigma-Aldrich
Allylamine hydrochloride, 98%
Lactobionic acid, European Pharmacopoeia (EP) Reference Standard