Pre-Clinical Study of Iron Nanoparticles Fortified Artesunate for Efficient Targeting of Malarial Parasite

Abstract

Background: Artesunate the most potent antimalarial is widely used for the treatment of multidrug-resistant malaria. The antimalarial cytotoxicity of Artesunate has been mainly attributed to its selective, irreversible and iron-catalyzed radical mediated damage of parasite biomolecules. In the present research, iron nanoparticle fortified artesunate was tested in P. falciparum and in an experimental malaria mouse model for enhancement in the selectivity and toxicity of Artesunate towards parasite. Artesunate was fortified with nontoxic biocompatible surface modified iron nanoparticle which is specially designed and synthesized for sustained pH-dependent release of Fe2+ within the parasitic food vacuole for enhanced ROS spurt. Methods: Antimalarial efficacy of Iron nanoparticle fortified Artesunate was evaluated in Plasmodium falciparum culture grown in O +ve human blood and in Plasmodium berghei ANKA infected swiss albino mice. Infected mice were daily administered intraperitoneally with Artesunate, nanoparticle fortified Artesunate and monitored for parasitemia. Internalization of iron nanoparticles, pH dependent release of Fe2+, production of reactive oxygen species and parasite biomolecule damage by iron nanoparticle fortified Artesunate was studied using various biochemical, biophysical, ultra-structural and fluorescence microscopy. Results: The nanoparticle fortified Artesunate was highly efficient in 1/8th concentration of Artesunate IC50 and led to retarded growth of P. falciparum with significant damage to macromolecules mediated via enhanced ROS production. Similarly, preclinical In vivo studies also signified a radical reduction in parasitemia with ~8-10-fold reduced dosage of Artesunate when fortified with iron nanoparticles. Interpretation: Surface coated iron-nanoparticle fortified Artesunate can be developed into a potent therapeutic agent towards multidrug-resistant malaria in humans. Funding Statement: This study is supported by Center for Study of Complex malaria in India funded by National Institute of Health, USA, and by Department of Science and Technology (DST-INDIA) and LRE JNU. DK and NY are supported by Shiv Nadar Foundation fellowships. SA is funded by ICMR, Government of India. Declaration of Interests: The authors declare that there are no conflicts of interest. Ethics Approval Statement: Animal studies were performed in accordance with guidelines of the Institutional Animal Ethics Committee (IEAC) of Jawaharlal Nehru University, Delhi and Committee for Control and Supervision of Experiments on Animals (CPCSEA).