Establishment and evaluation of glucose-modified nanocomposite liposomes for the treatment of cerebral malaria

Abstract

Cerebral malaria (CM) is a life-threatening neurological complication caused by Plasmodium falciparum. About 627,000 patients died of malaria in 2020. Currently, artemisinin and its derivatives are the front-line drugs used for the treatment of cerebral malaria. However, they cannot target the brain, which decreases their effectiveness. Therefore, increasing their ability to target the brain by the nano-delivery system with brain-targeted materials is of great significance for enhancing the effects of antimalarials and reducing CM mortality. This study used glucose transporter 1 (GLUT1) on the blood–brain barrier as a target for a synthesized cholesterol-undecanoic acid–glucose conjugate. The molecular dynamics simulation found that the structural fragment of glucose in the conjugate faced the outside the phospholipid bilayers, which was conducive to the recognition of brain-targeted liposomes by GLUT1. The fluorescence intensity of the brain-targeted liposomes (na-ATS/TMP@lipoBX) in the mouse brain was significantly higher than that of the non-targeted liposomes (na-ATS/TMP@lipo) in vivo (P < 0.001) after intranasal administration. The infection and recurrence rate of the mice receiving na-ATS/TMP@lipoBX treatment were significantly decreased, which had more advantages than those of other administration groups. The analysis of pharmacokinetic data showed that na-ATS/TMP@lipoBX could enter the brain in both systemic circulation and nasal-brain pathway to treat malaria. Taken together, these results in this study provide a new approach to the treatment of cerebral malaria. Graphical Abstract

Recent Advances in Intranasal Liposomes for Drug, Gene, and Vaccine Delivery

“…The accumulation of brain-targeted liposomes should increase in the brain and decrease in other untargeted organs. Fluorescence imaging [ 37 ], isotope labeling [ 91 , 92 ], and green fluorescent protein (GFP) [ 68 ] have been used to visualize and confirm liposome delivery to the olfactory bulb and different parts of the brain (such as the striatum, cortex, and cerebellum) after IN administration. For example, successful brain delivery of cationic liposomes containing GFP mRNA and luciferase mRNA was confirmed by GFP fluorescence [ 68 ].…”

“…Tian et al prepared liposomes loaded with artesunate and ligustrazine hydrochloride to treat cerebral malaria [ 37 ]. They used cholesterol–undecanoate–glucose conjugate to target glucose transporter 1 at the BBB ( Figure 3 ) and found that the brain-targeted liposomes had a longer residence time (up to 48 h) in the mouse brain than the nontargeted liposomes.…”

“…In some cases, most drugs (>80%) enter the brain via this indirect route [ 70 ]. Liposomes can be modified with cholesterol–undecanoate–glucose conjugates to target glucose transporter 1 at the BBB, which allows them to cross the BBB efficiently from the systemic circulation and enter the brain [ 37 ]. However, in some cases, most drugs (>90%) enter the brain via direct nose-to-brain transport [ 90 ].…”

“… Representative structure of liposomes loaded with artesunate and ligustrazine with cholesterol–undecanoate–glucose conjugate to target glucose transporter 1 at the BBB for treatment of cerebral malaria [ 37 ]. …”

“…Many nanosized drug delivery systems developed recently, such as micelles [ 30 ], nanoemulsions [ 31 , 32 ], solid lipid nanoparticles [ 33 ], nanostructured lipid carriers [ 34 , 35 ], polymeric nanoparticles [ 36 ], and liposomes [ 37 ], have been administered intranasally due to the long residence times in the nasal cavity, improved stability, and increased uptake. Liposomes are a promising platform for drug, gene, and antigen delivery.…”