Improved Liver Delivery of Primaquine by Phospholipid-Free Small Unilamellar Vesicles with Reduced Hemolytic Toxicity

Hemolytic toxicity caused by primaquine (PQ) is ahigh-risk condition that hampers the wide use of PQ to treat liver-stage malaria. This study demonstrated that phospholipid-freesmall unilamellar vesicles (PFSUVs) composed of Tween80 andcholesterol could encapsulate and deliver PQ to the hepatocyteswith reduced exposure to the red blood cells (RBCs). Nonionicsurfactant (Tween80) and cholesterol-forming SUVs with a meandiameter of 50 nm were fabricated for delivering PQ. Drug release/retention, drug uptake by RBCs, pharmacokinetics, and liveruptake of PFSUVs-PQ were evaluated inin vitroandin vivomodelsin comparison to free drugs. Additionally, the stress effect on RBCsinduced by free PQ and PFSUVs-PQ was evaluated by examiningRBC morphology. PFSUVs provided >95% encapsulationefficiency for PQ at a drug-to-lipid ratio of 1:20 (w/w) and stably retained the drug in the presence of serum. When incubatedwith RBCs, PQ uptake in the PFSUVs group was reduced by 4- to 8-folds compared to free PQ. As a result, free PQ inducedsignificant RBC morphology changes, while PFSUVs-PQ showed no such adverse effect. Intravenously (i.v.) delivered PFSUVs-PQproduced a comparable plasma profile as free PQ, given i.v. and orally, while the liver uptake was increased by 4.8 and 1.6-folds,respectively, in mice. Within the liver, PFSUVs selectively targeted the hepatocytes, with no significant blood or liver toxicity in mice.PFSUVs effectively targeted PQ to the liver and reduced RBC uptake compared to free PQ, leading to reduced RBC toxicity.PFSUVs exhibited potential in improving the efficacy of PQ for treating liver-stage malaria.

Automated summary

The study demonstrated that phospholipid-free small unilamellar vesicles composed of Tween80 and cholesterol could effectively encapsulate and deliver primaquine (PQ) to hepatocytes, reducing exposure to red blood cells and hemolytic toxicity. This approach showed potential in improving the efficacy of PQ for treating liver-stage malaria.