Multifunctional pH-Sensitive Amino Lipids for siRNA Delivery

Abstract

RNA interference (RNAi) represents a powerful modality for human disease therapy that can regulate gene expression signature using small interfering RNA (siRNA). Successful delivery of siRNA into the cytoplasm of target cells is imperative for efficient RNAi and also constitutes the primary stumbling block in the clinical applicability of RNAi. Significant progress has been made in the development of lipid-based siRNA delivery systems, which have practical advantages like simple chemistry and easy formulation of nanoparticles with siRNA. This review discusses the recent development of pH-sensitive amino lipids, with particular focus on multifunctional pH-sensitive amino lipids for siRNA delivery. The key components of these multifunctional lipids include a protonatable amino head group, distal lipid tails, and two cross-linkable thiol groups, which together facilitate the facile formation of stable siRNA-nanoparticles, easy surface modification for target-specific delivery, endosomal escape in response to the pH decrease during subcellular trafficking, and reductive dissociation of the siRNA-nanoparticles for cytoplasmic release of free siRNA. By virtue of these properties, multifunctional pH-sensitive lipids can mediate efficient cytosolic siRNA delivery and gene silencing. Targeted siRNA nanoparticles can be readily formulated with these lipids, without the need for other helper lipids, to promote systemic delivery of therapeutic siRNAs. Such targeted siRNA nanoparticles have been shown to effectively regulate the expression of cancer-related genes, resulting in significant efficacy in the treatment of aggressive tumors, including metastatic triple negative breast cancer. These multifunctional pH-sensitive lipids constitute a promising platform for the systemic and targeted delivery of therapeutic siRNA for the treatment of human diseases. This review summarizes the structure-property relationship of the multifunctional pH-sensitive lipids and their efficacy in in vitro and in vivo siRNA delivery and gene silencing.

The delivery of therapeutic oligonucleotides

“…Another interesting strategy is the design of multifunctional lipids that include a pH responsive head group and well as SH moieties. The multifunctional LNPs provide increased stability in the blood but then promote endosome escape in the low pH and reducing environment of the cell interior (176). Another approach that may avoid some of the toxicities of cationic LNPs involves using siRNA entrapped in neutral liposomes (165,177).…”

Targeting fibronectin for cancer imaging and therapy

“…RNAi therapy requires safe and efficient delivery of siRNA to tumor sites with high onfFN expression. Advances in developing siRNA delivery systems made this a possibility 143, 144 . Studies have been done using APT EDB as targeting moiety, with EDB siRNA encapsulated in liposome for treatment of a high-risk breast cancer model derived from breast cancer stem cells (BCSC), as illustrated in Figure 7.…”

MicroRNA-Based Drugs for Brain Tumors

“…Endosomal escape and release from nanocarrier are two major factors that impact the efficiency of synthetic nanocarriers. The polymeric delivery systems can destabilize the late endosomal (LE) compartment by proton-sponge effect during its acidification (pH 5 -6) [105]. Therefore, endosomal escape of polymer-nucleic acid complex should accompany the escape of oligonucleotides from the polymers for a functional activity.…”

“…Therefore, endosomal escape of polymer-nucleic acid complex should accompany the escape of oligonucleotides from the polymers for a functional activity. Similarly, the fate of ~70 % of siRNA delivered by lipid nanoparticles reach late endosomes (LE), packed into exosomes for exocytosis [106] and the remaining would be degraded after fusion with lysosome [105,107].…”