Liposomal Systems as Nanocarriers for the Antiviral Agent Ivermectin

Abstract

RNA virus infections can lead to the onset of severe diseases such as fever with haemorrhage, multiorgan failure, and mortality. The emergence and reemergence of RNA viruses continue to pose a significant public health threat worldwide with particular attention to the increasing incidence of flaviviruses, among others Dengue, West Nile Virus, and Yellow Fever viruses. Development of new and potent antivirals is thus urgently needed. Ivermectin, an already known antihelminthic drug, has shown potent effects in vitro on Flavivirus helicase, with EC50 values in the subnanomolar range for Yellow Fever and submicromolar EC50 for Dengue Fever, Japanese encephalitis, and tick-borne encephalitis viruses. However ivermectin is hampered in its application by pharmacokinetic problems (little solubility and high cytotoxicity). To overcome such problems we engineered different compositions of liposomes as ivermectin carriers characterizing and testing them on several cell lines for cytotoxicity. The engineered liposomes were less cytotoxic than ivermectin alone and they showed a significant increase of the antiviral activity in all the Dengue stains tested (1, 2, and S221). In the current study ivermectin is confirmed to be an effective potential antiviral and liposomes, as drug carriers, are shown to modulate the drug activity. All together the results represent a promising starting point for future improvement of ivermectin as antiviral and its delivery.

Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen

“…Finally, the researchers showed a high and direct tendency of NS5 to IMPα /β [26]. In another study on human Huh-7 cells infected with DENV 1, DENV2, or DENV2 virus mouseadapted S221 strain, a fivefold reduction was seen in halfmaximal effective concentration (EC 50 ) of ivermectin while using liposomal systems as its nanocarriers, while the antiviral activity of the drug was significantly preserved [27].…”

Antivirus effectiveness of ivermectin on dengue virus type 2 in Aedes albopictus

“…Genetically modified Aedes aegypti mosquitoes that activate the conserved antiviral JAK/STAT pathway in the fat body tissue have been developed, and the modified population inhibits infection with several dengue virus (DENV) serotypes [26], but its use encounters regulatory barriers and public opposition in some countries. Few drugs have been tested to inhibit the virus transmission inside mosquito, although some drugs against dengue virus effectively in vitro have been reported, such as quercetin [27], ivermectin [28–30], dasatinib [31], pyran naphthoquinones [32], mycophenolic acid [33, 34], castanospermine [34], deoxynojirimycin [35, 36]. From these drugs, we choose ivermectin as an available compound for the investigation by considering following three facts: (i) ivermectin has been used for about 30 years for treatment of parasitic infections in human since 1988 [37], and ivermectin mass drug administration (MDA) to humans has been suggested as a possible vector control method to reduce Plasmodium transmission [38–40]; (ii) ivermectin has the ability to target exophagic and exophilic vectors [40, 41] with a different mode of action [42, 43] from the currently used insecticides [44], and then avoid known mosquito behavioral and physiological resistance mechanisms [45]; (iii) ivermectin is an inhibitor for the development of dengue virus in cells [28–30].…”

Ivermectin: an award-winning drug with expected antiviral activity against COVID-19

“…In light of these attributes, some studies have formulated ivermectin in micro- and nanoparticles, either using lipid nanocapsules [ 31 ], chitosan-alginate nanoparticles [ 32 ] or poly (lactic- co -glycolic acid) (PLGA) micro- and nanoparticles [ 33 , 34 ]. For antiviral purposes, ivermectin has been formulated in liposomes [ 35 ] and PLGA nanoparticles [ 29 ]. The latter ivermectin nanoformulation was shown to cross the intestinal epithelial barrier when administered via oral route, with considerable concentrations detected in the blood, enabling its potential application in ZIKV therapy.…”