TY - JOUR
T1 - Development of Cationic Lipid LAH4-L1 siRNA Complexes for Focused Ultrasound Enhanced Tumor Uptake
AU - Abuhelal, Shahd
AU - Centelles, Miguel
AU - Wright, Michael
AU - Mason, James
AU - Thanou, Maya
N1 - Funding Information:
This work has been funded by the Schlumberger foundation─Faculty for the future─fellowship scheme. The authors thank Janis Romanopulos for help in preparing . This work is dedicated to Dr. Michael Wright co-author of this paper who lost the fight against leukemia on September 15, 2022.
Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.
PY - 2023/3/29
Y1 - 2023/3/29
N2 - RNAi has considerable potential as a cancer therapeutic approach, but effective and efficient delivery of short interfering RNA (siRNA) to tumors remains a major hurdle. It remains a challenge to prepare a functional siRNA complex, target enough dose to the tumor, and stimulate its internalization into tumor cells and its release to the cytoplasm. Here, we show how these key barriers to siRNA delivery can be overcome with a complex comprising siRNA, cationic lipids, and pH-responsive peptides that is suited to tumor uptake enhancement via focused ultrasound (FUS). The complex provides effective nucleic acid encapsulation, nuclease protection, and endosomal escape such that gene silencing in cells is substantially more effective than that obtained with either equivalent lipoplexes or commercial reagents. In mice bearing MDA-MB-231 breast cancer xenografts, both lipid and ternary, lipid:peptide:siRNA complexes, prepared with near-infrared fluorescently labeled siRNA, accumulate in tumors following FUS treatments. Therefore, combining a well-designed lipid:peptide:siRNA complex with FUS tumor treatments is a promising route to achieve robust in vivo gene delivery.
AB - RNAi has considerable potential as a cancer therapeutic approach, but effective and efficient delivery of short interfering RNA (siRNA) to tumors remains a major hurdle. It remains a challenge to prepare a functional siRNA complex, target enough dose to the tumor, and stimulate its internalization into tumor cells and its release to the cytoplasm. Here, we show how these key barriers to siRNA delivery can be overcome with a complex comprising siRNA, cationic lipids, and pH-responsive peptides that is suited to tumor uptake enhancement via focused ultrasound (FUS). The complex provides effective nucleic acid encapsulation, nuclease protection, and endosomal escape such that gene silencing in cells is substantially more effective than that obtained with either equivalent lipoplexes or commercial reagents. In mice bearing MDA-MB-231 breast cancer xenografts, both lipid and ternary, lipid:peptide:siRNA complexes, prepared with near-infrared fluorescently labeled siRNA, accumulate in tumors following FUS treatments. Therefore, combining a well-designed lipid:peptide:siRNA complex with FUS tumor treatments is a promising route to achieve robust in vivo gene delivery.
UR - http://www.scopus.com/inward/record.url?scp=85151373500&partnerID=8YFLogxK
U2 - 10.1021/acs.molpharmaceut.2c00909
DO - 10.1021/acs.molpharmaceut.2c00909
M3 - Article
SN - 1543-8384
VL - 20
SP - 2341
EP - 2351
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 5
ER -
