title: Parasite impairment by targeting Plasmodium-infected RBCs using glyceryl-dilaurate nanostructured lipid carriers.
abstract: Antimalarial therapy is a major contributor to declining malaria morbidity and mortality. However, the high toxicity and low bioavailability of current antimalarials and emerging drug resistance necessitates drug-delivery research. We have previously developed glyceryl-dilaurate nanolipid carriers (GDL-NLCs) for antimalarial drug delivery. Here, we show evidence that GDL-NLCs themselves selectively target Plasmodium-infected red blood cells (iRBCs), and cause severe parasite impairment. The glyceryl-dilaurate lipid-moiety was important in the targeting. GDL-NLCs localized to the parasite mitochondrion and uptake led to mitochondrial-membrane polarization and Ca(2+) ion accumulation, ROS release, and stage-specific iRBC lysis. GDL-NLC treatment also resulted in externalization of iRBC-membrane phosphatidylserine and enhanced iRBC clearance by macrophages. GDL-NLC uptake disrupted the parasite-induced tubulovesicular network, which is vital for nutrient import by the parasite. Laser optical trap studies revealed that GDL-NLCs also restored iRBC flexibility. Such restoration of iRBC flexibility may help mitigate the vasculature clogging that can lead to cerebral malaria. We demonstrate the suitability of GDL-NLCs for intravenous delivery of antimalarial combinations artemether-clindamycin and artemether-lumefantrine in the murine model. Complete parasite clearance was achieved at 5-20% of the therapeutic dose of these combinations. Thus, this nanostructured lipid formulation can solubilize lipophilic drugs, selectively target and impair the parasite-infected red cell, and therefore constitutes a potent delivery vehicle for antimalarials.
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India.
authors.forename: Soniya A
authors.initials: SA
authors.lastname: Jain
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
authors.forename: Himanish
authors.initials: H
authors.lastname: Basu
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India.
authors.forename: Priyanka S
authors.initials: PS
authors.lastname: Prabhu
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India.
authors.forename: Umangi
authors.initials: U
authors.lastname: Soni
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India.
authors.forename: Medha D
authors.initials: MD
authors.lastname: Joshi
authors.affiliation: Atomic and Molecular Sciences Laboratory, Tata Institute of Fundamental Research, Mumbai, India.
authors.forename: Deepak
authors.initials: D
authors.lastname: Mathur
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India.
authors.forename: Vandana B
authors.initials: VB
authors.lastname: Patravale
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India. Electronic address: pathaksue@gmail.com.
authors.forename: Sulabha
authors.initials: S
authors.lastname: Pathak
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
authors.forename: Shobhona
authors.initials: S
authors.lastname: Sharma
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002460:Cell Line; D004075:Diglycerides / Q000494:pharmacology*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004705:Endocytosis; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology*; D005453:Fluorescence; D005990:Glycerol / Q000494:pharmacology*; D007700:Kinetics; D008055:Lipids / Q000737:chemistry*; D008288:Malaria; D008297:Male; D051379:Mice; D049329:Nanostructures / Q000737:chemistry* / Q000648:ultrastructure; D010271:Parasites / Q000187:drug effects*; D010316:Particle Size; D010961:Plasmodium / Q000187:drug effects*; D055672:Static Electricity
chemical_list: D000962:Antimalarials; D004075:Diglycerides; D004337:Drug Carriers; D008055:Lipids; C025405:1,2-didodecanoylglycerol; D005990:Glycerol
keywords: Drug-delivery; Glyceryl-dilaurate nanostructured lipid carriers; Infected-RBCs; Mitochondrion; NLCs; Plasmodium