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Biomaterials. 2014 Aug;35(24):6636-45. doi: 10.1016/j.biomaterials.2014.04.058. Epub 2014 May 10.

Parasite impairment by targeting Plasmodium-infected RBCs using glyceryl-dilaurate nanostructured lipid carriers.

Author information

1
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India.
2
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
3
Atomic and Molecular Sciences Laboratory, Tata Institute of Fundamental Research, Mumbai, India.
4
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India. Electronic address: pathaksue@gmail.com.

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.

KEYWORDS:

Drug-delivery; Glyceryl-dilaurate nanostructured lipid carriers; Infected-RBCs; Mitochondrion; NLCs; Plasmodium

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