Influence of the Composition of Cationic Liposomes on the Performance of Cargo Immunostimulatory RNA

Abstract

In this study, the impact of different delivery systems on the cytokine-inducing, antiproliferative, and antitumor activities of short immunostimulatory double-stranded RNA (isRNA) was investigated. The delivery systems, consisting of the polycationic amphiphile 1,26-bis(cholest-5-en-3-yloxycarbonylamino)-7,11,16,20 tetraazahexacosan tetrahydrochloride (2X3), and the lipid-helper dioleoylphosphatidylethanolamine (DOPE), were equipped with polyethylene glycol lipoconjugates differing in molecular weight and structure. The main findings of this work are as follows: (i) significant activation of MCP-1 and INF-α, β, and γ production in CBA mice occurs under the action of isRNA complexes with liposomes containing lipoconjugates with long PEG chains, while activation of MCP-1 and INF-γ, but not INF-α or β, was observed under the action of isRNA lipoplexes containing lipoconjugates with short PEG chains; (ii) a pronounced antiproliferative effect on B16 melanoma cells in vitro, as well as an antitumor and hepatoprotective effect in vivo, was induced by isRNA pre-complexes with non-pegylated liposomes, while complexes containing lipoconjugates with long-chain liposomes were inactive; (iii) the antitumor activity of isRNA correlated with the efficiency of its accumulation in the cells and did not explicitly depend on the activation of cytokine and interferon production. Thus, the structure of the delivery system plays a vital role in determining the response to isRNA and allows for the choice of a delivery system depending on the desired effect.

Effect of Immunostimulatory RNA on the Fibrosis Development in Bleomycin- or LPS-Induced Mouse Models

“…Previously, we analyzed the cytokines released in mouse blood after i.v. administration of isRNA pre-complexed with cationic liposomes [13]. The main cytokines whose levels significantly increased in response to isRNA were found to be monocyte chemoattractant protein 1 (MCP-1) and interferons α and γ; the cytokines IL-6 and IL-10 were moderately activated, and a slight activation of IL-1α and TNF-α was also noted.…”

“…The impact of isRNA on cytokine levels, encompassing both pro-inflammatory and antiinflammatory mediators, has been substantiated [13]. Unraveling the mechanisms underlying the augmentation of cytokines assumes paramount significance.…”

“…Given the propensity for heightened cytokine levels during inflammation, augmentation may precipitate a cytokine storm, culminating in an allergic shock and posing a life-threatening risk. On the other side, augmentation of IFN-α-levels by isRNA treatment unveils promising avenues for its application in combating infections and malignancies [13]. These pathologies are closely related to inflammation and fibrosis, so the application of isRNA that affects the synthesis and secretion of inflammatory mediators, as well as anti-inflammatory and anti-proliferative cytokines and chemokines, can have both positive and negative effects on the development of fibrotic changes in tissues.…”

Liposome-Based Drug Delivery Systems in Cancer Research: An Analysis of Global Landscape Efforts and Achievements

“…Functional biopolymers have been recognized as a viable solution to these challenges, resulting in significant progress in the development of biopolymer–liposome hybrids’ promise [ 12 , 13 ]. The new methods include surface-modified liposomes, biopolymer-integrated liposomes, and specialty formulations including liposomes enclosed within hydrogels, films, nanofibers, and pH-sensitive liposomes [ 14 , 15 , 16 , 17 , 18 ].…”