Dataset Information

Enhanced synthesis de novo of phosphatidylinositol in lymphocytes treated with cationic amphiphilic drugs.

ABSTRACT: A variety of amphiphilic cations caused very large increases in the rates of incorporation of Pi and glycerol into phosphatidylinositol in pig mesenteric small lymphocytes. This synthesis de novo of phosphatidylinositol led to a doubling of the phosphatidylinositol concentration in the cells within 3.5 h. The increase in synthesis of phosphatidylinositol labelled with [3H]- or [14C]-glycerol was matched by an approximately equivalent decrease in incorporation of glycerol into phosphatidylcholine, phosphatidylethanolamine and triacylglycerol. Amphilic cations which produced these effects included, in order of decreasing effectiveness, trifluoperazine (half-maximal effect at about 70 mum) greater than chlorpromazine approximately promethazine approximately imipramine greater than cinchocaine greater than amethocaine approximately cetyltrimethylammonium greater than fenfluramine greater than amphetamine greater than 2-phenethylamine greater than cocaine approximately procaine; the most effective compounds were those with the largest and most hydrophobic non-polar substituents. The response to cations was not changed by varying the extracellular Ca2+ concentration in the range 10 nm-1mm. The active amphiphilic cations interacted with anionic phospholipids causing aggregation of aqueous dispersions and/or changes in chromatographic behaviour. These results indicate that amphiphilic cations redirect glycerolipid synthesis de novo, probably owing to inhibition of phosphatidate phosphohydrolase, so that phosphatidylinositol synthesis is increased at the expense of other glycerolipids.

SUBMITTER: Allan D

PROVIDER: S-EPMC1165565 | biostudies-other | 1975 Jun

REPOSITORIES: biostudies-other

ACCESS DATA

Similar Datasets

Project description:Since the recent clinical approval of siRNA-based drugs and COVID-19 mRNA vaccines, the potential of RNA therapeutics for patient healthcare has become widely accepted. Lipid nanoparticles (LNPs) are currently the most advanced nanocarriers for RNA packaging and delivery. Nevertheless, the intracellular delivery efficiency of state-of-the-art LNPs remains relatively low and safety and immunogenicity concerns with synthetic lipid components persist, altogether rationalizing the exploration of alternative LNP compositions. In addition, there is an interest in exploiting LNP technology for simultaneous encapsulation of small molecule drugs and RNA in a single nanocarrier. Here, we describe how well-known tricyclic cationic amphiphilic drugs (CADs) can be repurposed as both structural and functional components of lipid-based NPs for mRNA formulation, further referred to as CADosomes. We demonstrate that selected CADs, such as tricyclic antidepressants and antihistamines, self-assemble with the widely-used helper lipid DOPE to form cationic lipid vesicles for subsequent mRNA complexation and delivery, without the need for prior lipophilic derivatization. Selected CADosomes enabled efficient mRNA delivery in various in vitro cell models, including easy-to-transfect cancer cells (e.g. human cervical carcinoma HeLa cell line) as well as hard-to-transfect primary cells (e.g. primary bovine corneal epithelial cells), outperforming commercially available cationic liposomes and state-of-the-art LNPs. In addition, using the antidepressant nortriptyline as a model compound, we show that CADs can maintain their pharmacological activity upon CADosome incorporation. Furthermore, in vivo proof-of-concept was obtained, demonstrating CADosome-mediated mRNA delivery in the corneal epithelial cells of rabbit eyes, which could pave the way for future applications in ophthalmology. Based on our results, the co-formulation of CADs, helper lipids and mRNA into lipid-based nanocarriers is proposed as a versatile and straightforward approach for the rational development of drug combination therapies.

Dataset Information

Enhanced synthesis de novo of phosphatidylinositol in lymphocytes treated with cationic amphiphilic drugs.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets