Novel nanoparticles function as chemo- and adjunctive-therapy against experimental cerebral malaria

Neurological dysfunction is an important complication of blood stage Plasmodium falciparum (Pf) infection and the syndrome is called cerebral malaria (CM). We have developed human serum albumin (HSA) nanoparticles (NPs) that are nanoscale aggregates of albumin as a carrier for drug delivery and conjugated anti-bloodstage Plasmodium drugs, including artemether (A) and artemisinin to these NPs. Our preliminary data indicate that our novel artemether-conjugated NPs (A-NPs) provide complete protection against experimental CM (eCM). A-NPs exhibit anti-parasite activity and are preferentially targeted to infected red blood cells (iRBCs) over uRBCs. Our control NPs (C-NPs), which are NPs without drug, provide significant (p<0.05) protection against eCM without affecting parasitemia. These findings suggest that A-NPs may exhibit both anti-parasite- and adjunctive-therapy effects in a single, easy to administer compound.

There is currently no FDA-approved adjunctive therapy of CM to ameliorate the pathogenic host response during CM and to decrease mortality in the 15-30% of CM patients who die after adequate anti-parasite chemotherapy. In addition, this adjunctive therapy to ameliorate the pathogenic host response may also decrease the neurological impairment after Pf infection that results in life-long disability for African children who survive CM. We use the well-defined, reproducible P. berghei ANKA infection of mice as our model for CM (i.e., eCM). We hypothesize that our novel nanoparticles protect from development of eCM by decreasing pathogenic processes leading to eCM, i.e., vasogenic edema, oxidant stress, inflammation, sequestration, and coagulopathy. 

This proposal meets R21 exploratory grant guidelines because it is focused on assessing the efficacy of a new drug with undefined mechanisms for which there is little experimental support beyond our preliminary data. Follow-on studies will use the generated data for in-depth studies of mechanisms and to move the NPs to the clinic.

NIH project details

Drug-based Strategies

Dec 2020 — Nov 2023

$468,500

United States