am9b22781_si_001.pdf (431.27 kB)
Microfluidic-Based Holonomic Constraints of siRNA in the Kernel of Lipid/Polymer Hybrid Nanoassemblies for Improving Stable and Safe In Vivo Delivery
journal contribution
posted on 2020-03-20, 10:13 authored by Wei Wei, Jing Sun, Xi-Ying Guo, Xin Chen, Ru Wang, Chong Qiu, Hai-Tao Zhang, Wen-Hao Pang, Jian-Cheng Wang, Qiang ZhangA safe and efficient delivery system
is critical for clinical application
of siRNA. However, the conventional electrostatic interaction-based
siRNA nanoplexes with bulk mixing preparation were always unsatisfactory
for its stability and safety. In this study, the new core–shell
lipid/PCL-PEI/siRNA nanoparticles (LPS NPs) endowing holonomic constraint
of siRNA in the inner core were prepared by microfluidic technology.
On the microfluidic chip, siRNAs were completely compressed into the
inner hydrophilic core of reverse PCL-PEI micelles at a low N/P ratio
of 5, followed by coating a neutral lipid membrane to form core–shell
nanoparticles, which had a uniform size (120.2 ± 1.4 nm) and
a negative charge (−8.8 ± 1.6 mV). Compared to bulk mixing-based
LMS NPs, the lower usage of cationic PCL-PEI materials and stronger
protection of siRNA in serum were found in the microfluidic-based
LPS NPs. Furthermore, it was demonstrated that the LPS NPs exhibited
significant downregulation of EGFR mRNA and protein expression level
both in vitro and in vivo, and showed significant inhibition of tumor
growth following systemic administration along with no obvious systemic
toxicity. These findings demonstrated that the microfluidic-based
lipid/polymer hybrid nanoassemblies would offer a promising siRNA
delivery system for clinical application.