Abstract
Small interfering RNAs (siRNAs) are promising as therapeutics for intractable diseases such as cancer. However, efficient and safe delivery of siRNAs in vivo remains a challenge. Polymer-lipid hybrid nanoparticles (P/LNPs) have been evaluated for therapeutic delivery of siRNA. In this study, a microfluidic hydrodynamic focusing (MF) system was used to prepare P/LNPs loaded with VEGF siRNA. P/LNPs made by MF were smaller in particle size and had narrower size distribution compared to P/LNPs formed by bulk mixing (BM). MF-synthesized P/LNPs demonstrated low vehicle cytotoxicity and potent tumor cell inhibition in vitro. In addition, P/LNPs produced by the microfluidic chip exhibited prolonged blood circulation and increased AUC after i.v. injection compared to free siRNA. Furthermore, P/LNPs synthesized by MF induced greater down-regulation of VEGF mRNA and protein levels as well as greater tumor inhibition in a xenograft tumor model. Taken together, P/LNPs prepared by MF have been shown to be an effective and safe therapeutic siRNA delivery system for cancer treatment both in vitro and in vivo.
Highlights
VEGF overexpression has been shown to increase angiogenesis, which promotes proliferation and metastasis of cancer cells [1, 2]
Polydispersity index (PDI) and zeta potential of the various Polymer-lipid hybrid nanoparticles (P/LNPs) were determined by dynamic light scattering (DLS) and zeta potential measurement
LNPs-siRNABM had a size of 177.5 nm and P/ LNPs-siRNA-bulk mixing (BM) had a size of 194 nm. It appears that incorporation of PEI with molecular weight of 800Da (PEI-800) into LNPs slightly increased the particle size as well as the polydispersity index (PDI)
Summary
VEGF overexpression has been shown to increase angiogenesis, which promotes proliferation and metastasis of cancer cells [1, 2]. [3] Because of their relative safety, many non-viral delivery systems have been evaluated for siRNA delivery [4,5,6,7,8,9]. Both polycation polyethylenimine (PEI) and cationic lipids have been used for siRNA delivery. They form electrostatic nanocomplexes with siRNA [10, 11]. Polyethylene glycol (PEG) coating has been shown to reduce the particle size and improve the stability of these nanocomplexes [13, 14]. Further improvements in siRNA delivery efficiency may be possible if the process of nanocomplex synthesis can be optimized
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