Synergetic treatment of dihydroartemisinin and perillyl alcohol by liposomal nanoplatform for enhanced therapy of cerebral malaria and neurological injury alleviation in C57BL/6J mice

Abstract

To improve the efficacy of artemisinins against cerebral malaria (CM) in murine, dihydroartemisinin (DHA) and perillyl alcohol (POH) co-loaded liposomes (DP@Tyr-Lips) were designed and prepared, in which POH was expected to exert neuroprotective effects and synergistic therapeutic effects with DHA against CM. Furtherly, tyrosine (Tyr)acted as a substrate of LAT1 transporter could target the brain tissue, was used to modify Lips for improving the accumulation of drugs in the brain via BBB amino acid transporters. DP@Tyr-Lips were prepared with uniform particle size of 91.99 ± 2.67 nm, excellent physical and serum stability, and property of anti-phagocyte phagocytosis. The cumulative release percentages of DHA and POH from DP@Tyr-Lips at 24 h were 66.91 % ± 1.56 % and 58.77 % ± 0.31%, respectively, showing a certain sustained release behavior. Importantly, the inhibition rate of plasmodium of DP@Tyr-Lips was higher than that of DHA-sol. Furthermore, DP@Tyr-Lips could obviously accumulate in the brain and effectively inhibit the occurrence and development of CM, and prolong the survival time of CM mice due to its better biological safety. These findings illustrated that the combination DHA with POH in Tyr modified Lips could achieve the synergistic therapeutic effect and exhibit a significantly enhanced inhibitory effect on the growth of plasmodium, and also improve the neurological injury in a mouse model of CM.