Hepatocellular targeted α-tocopherol based pH sensitive galactosylated lipids: design, synthesis and transfection studies

Abstract

Receptor mediated gene delivery to the liver offers advantages in treating genetic disorders such as hemophilia and hereditary tyrosinemia type I (HTI). Prior findings demonstrated that tethering the d-galactose head group to cationic lipids directs genes to the liver asialoglycoprotein receptors (ASGPRs). In our continued efforts to develop safer and efficient lipofectins, we demonstrated that cationic lipids bearing α-tocopherol, an antioxidant, as a hydrophobic domain could deliver genes efficiently with high safety profiles in multiple cell lines. Towards developing ASGPR targeted pH sensitive cationic lipids, we have designed a galactosylated cationic lipid (Toc-Gal) with α-tocopherol as the hydrophobic core covalently connected with a pH responsive triazole moiety and a non-targeting control lipid (Toc-OH) without the galactose head group. In this study, we present the design and synthesis of a pH sensitive galactosylated cationic lipid (Toc-Gal), its comparative transfection biology, cellular uptake studies, serum stability and cytotoxicity profiles in both ASGPR positive and negative liver cells, HepG2 and SK-Hep-1, respectively.

Quantification of Surface GalNAc Ligands Decorating Nanostructured Lipid Carriers by UPLC-ELSD

“…Using this strategy, SiRNA/lipid nanoparticles decorated by PEGylated-GalNAc surfactants were designed to deliver genes in hepatocytes [44,45]. Gal targeting moieties were also introduced at the surface of different liposomes or lipid nanoparticles using Gal derivatives of cholesterol [38], alpha-tocopherol [46], or DSPE (distearoyl phosphatidylethanolamine) [35,36,47]. However, the number of Gal or GalNAc moieties introduced at the surface of the nanoparticles was not experimentally quantified, and when calculated, total incorporation of surfactants in the formulation was assumed [35].…”

“…Several GalNAc- or Gal-functionalized lipid nanoparticles described in the literature have already demonstrated their interest in delivering therapeutic compounds to the liver, and their ASGPR recognition efficiency was assumed to be correlated with the surface density of Gal or GalNAc residues [29]. However, no quantification protocol was developed, and only in a few cases, the number of Gal or GalNAc residues were roughly estimated based on the hypothesis of full incorporation of saccharide-surfactants at the nanoparticle surface [35,36,38,44,45,46,47]. Among these studies, the Gal ligand density decorating the surface of lipid nanocapsules investigated by Morille et al for gene therapy can be calculated from reported data, assuming total incorporation of the saccharide moieties (Supplementary Information, Table S4, Figure S6) [35].…”

Novel synthesis of platinum complexes and their intracellular delivery to tumor cells by means of magnetic nanoparticles

“…cation lipids and modified antibody structures). 67,68 The triazole group in the Pt complex may facilitate the entrance of protons, anions and water, favouring the high osmotic pressure inside the endosome. The consequent swelling of the endosomal vesicles and the acidic hydrolysis of the platinum(II) complex enable the metal release and therefore the endosomal escape, as shown in Fig.…”

Review of Zinc(II) Scaffolds: Efficient Role in Gene Delivery

“…Hence it is necessary to deliver the genetic material into the targeted cell to cure such diseases. As of now, different types of nano-vectors [2][3][4][5] are being in use to deliver the desired gene into the cytosol [3][4][5][6] effectively. From the recent past, cationic lipids are also emerged as a new choice and extensively have been using as vectors (vehicles) in order to replace the novel gene in place of such a defective gene.…”

“…Generally, there exists a strong electrostatic interaction between the anionic phosphate backbone of deoxyribonucleic acid (DNA) and cationic part of lipid that affects the higher cellular uptake of the gene. [4][5][6][7] However, there is a problem with cationic lipids that, the highly positive surface charges can induce non-specific binding to the components of blood and may lead to less-transport efficacy and high toxicity. In this regard, to overcome the above anomalies, Zn(II)-coordinated cationic lipids are widely investigated and are expected to become ideal carriers for the gene delivery system (GDS) owing to their favourable bio-compatibilities and their sole structures.…”