期刊
ACS APPLIED MATERIALS & INTERFACES
卷 9, 期 3, 页码 2181-2195出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsami.6b15064
关键词
siRNA; polyplex nanoparticles; intravenous administration; aliphatic polycarbonate; polyethylene glycol; protein corona
资金
- Belgium National Fund for Scientific Research
- TELEVIE
- Centre Anti-Cancereux and Fonds Leon Fredericq pres de l'Universite de Liege
- Belgian Federal Government Office Policy of Science (SSTC) [PAI-7/05]
- National Fund for Scientific Research (FNRS)
Guanidine and morpholine functionalized aliphatic polycarbonate polymers are able to deliver efficiently histone deacetylase 5 (HDAC5) siRNA into the cytoplasm of cancer cells in vitro leading to a decrease of cell proliferation were previously developed. To allow these biodegradable and biocompatible polyplex nanoparticles to overcome the extracellular barriers and be effective in vivo after an intravenous injection, polyethylene glycol chains (PEG(750) or PEG(2000)) were grafted on the polymer structure. These nanoparticles showed an average size of about 150 nm and a slightly positive zeta-potential with complete siRNA complexation. Behavior of PEGylated and non-PEGylated polyplexes were investigated in the presence of serum, in terms of siRNA complexation (fluorescence correlation spectroscopy), size (dynamic light scattering and single-particle tracking), interaction with proteins (isothermal titration calorimetry) and cellular uptake. Surprisingly, both PEGylated and non-PEGylated formulations presented relatively good behavior in the presence of fetal bovine serum (FBS). Hemocompatibility tests showed no effect of these polyplexes on hemolysis and coagulation. In vivo biodistribution in mice was performed and showed a better siRNA accumulation at the tumor site for PEGylated polyplexes. However, cellular uptake in protein-rich conditions showed that PEGylated polyplex lost their ability to interact with biological membranes and enter into cells, showing the importance to perform in vitro investigations in physiological conditions closed to in vivo situation. In vitro, the efficiency of PEGylated nanoparticles decreases compared to non-PEGylated particles, leading to the loss of the antiproliferative effect on cancer cells.
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