Biodegradable Sucrose Ester-Based Cationic Lipids as Novel Vectors for Efficient and Safe Delivery of IGF-1R siRNA

Abstract

The key to the success of siRNA therapy depends on the use of siRNA delivery agents that effectively penetrate tumor cells and simultaneously protect siRNA from RNase attacks. Sucrose esters (SEs) are found to have tremendous potential applications in siRNA delivery because of their biocompatibility and low toxicity. However, the esterification of sucrose yields complex mixtures that greatly limit their progress in this field. We synthesized a series of novel sucrose monoester-based cationic lipids (SECLs) by using 1′,4,6′-trichlorogalactosucrose (TGS) to achieve monoesterification of sucrose. SECL-based liposomes formed from these lipids and colipids [dioleoylphosphatidylethanolamine (DOPE) or cholesterol (Chol)] could effectively condense genes into nanocomplexes, which exhibited significantly higher uptake rates and gene silencing efficiency than 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) liposome. Furthermore, SECL-based liposomes containing cholesterol-mediated IGF-1R siRNA delivery could inhibit tumor growth by the downregulation of Bcl-2 and the upregulation of Bax. Most importantly, these liposomes displayed low cytotoxicity in vitro and in vivo because they could be degraded under tumor acidic pH environments. Our study establishes a novel method for the synthesis of SEs from TGS and demonstrates the applicability of SECLs for gene delivery with the potential for clinical therapy.

Construction Strategy of Functionalized Liposomes and Multidimensional Application

“…Recently, micro RNA (miRNA), have been shown to be involved in the targeting of these molecules. [43] Based on their action on the target gene, nucleic acid medications can be grouped into small interfering RNA (siRNA), antisense oligonucleotides (ASO), and miRNA [44] They are equipped with robust Copyright 2020, John Wiley and Sons. b) Schematic representation of the L-SNA, wherein DNA (green) is embedded into the outer phospholipid membrane of a liposome core using a hydrophobic DNA anchor (depicted in red).…”

ROS-Responsive Bola-Lipid Nanoparticles as a Codelivery System for Gene/Photodynamic Combination Therapy

“…31,43,44 Cationic lipids are one of the most promising gene vectors, of which bola-type cationic lipids have shown promise as nanodrug delivery platforms in medicine. 45,46 Bolalipids are dumbbell-shaped molecules composed of one or two hydrophobic chains with two hydrophilic headgroups at both ends. 47 The hydrophilic head has one or more positive charges.…”

“…Chlorin e6 (Ce6), a second-generation PDT drug used in clinical practice, is a photosensitizer with near-infrared fluorescence emission and a high quantum yield of singlet oxygen. , Due to its low dark toxicity and strong tissue penetration, it has been widely used in the treatment of various malignant tumors . However, Ce6 is highly hydrophobic and prone to aggregate into larger particles in physiological environments, which limits its tumor accumulation. , Many researchers have proposed to encapsulate Ce6 into nanocarriers to improve its solubility and delivery efficiency to tumor cells, so as to enhance the therapeutic effect of PDT. ,, Cationic lipids are one of the most promising gene vectors, of which bola-type cationic lipids have shown promise as nanodrug delivery platforms in medicine. , Bola-lipids are dumbbell-shaped molecules composed of one or two hydrophobic chains with two hydrophilic headgroups at both ends . The hydrophilic head has one or more positive charges.…”