Nanocarrier-enhanced intracellular delivery of benznidazole for treatment of Trypanosoma cruzi infection
Xiaomo Li, … , Evan A. Scott, David M. Engman
Xiaomo Li, … , Evan A. Scott, David M. Engman
Published May 10, 2021
Citation Information: JCI Insight. 2021;6(9):e145523. https://doi.org/10.1172/jci.insight.145523.
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Research Article Microbiology

Nanocarrier-enhanced intracellular delivery of benznidazole for treatment of Trypanosoma cruzi infection

Abstract

Chagas disease is caused by infection with the protozoan parasite Trypanosoma cruzi (T. cruzi), an intracellular pathogen that causes significant morbidity and death among millions in the Americas from Canada to Argentina. Current therapy involves oral administration of the nitroimidazole benznidazole (BNZ), which has serious side effects that often necessitate cessation of treatment. To both avoid off-target side effects and reduce the necessary dosage of BNZ, we packaged the drug within poly(ethylene glycol)-block-poly(propylene sulfide) polymersomes (BNZ-PSs). We show that these vesicular nanocarriers enhanced intracellular delivery to phagocytic cells and tested this formulation in a mouse model of T. cruzi infection. BNZ-PS is not only nontoxic but also significantly more potent than free BNZ, effectively reducing parasitemia, intracellular infection, and tissue parasitosis at a 466-fold lower dose of BNZ. We conclude that BNZ-PS was superior to BNZ for treatment of T. cruzi infection in mice and that further modifications of this nanocarrier formulation could lead to a wide range of custom controlled delivery applications for improved treatment of Chagas disease in humans.

Authors

Xiaomo Li, Sijia Yi, Débora B. Scariot, Santiago J. Martinez, Ben A. Falk, Cheryl L. Olson, Patricia S. Romano, Evan A. Scott, David M. Engman

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Figure 4

BNZ-PSs are more potent than free BNZ against T. cruzi in vivo.

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BNZ-PSs are more potent than free BNZ against T. cruzi in vivo. (A) Mice...
(A) Mice (n = 5 per group) were infected with T. cruzi Y strain trypomastigotes on day 0 and treated with 2 i.v. doses of BNZ-PS and PS after parasitemia had reached approximately 2 × 105/mL on day 7. Standard oral treatment with BNZ was given daily for 14 days (7–21 d.p.i.). Parasitemia was monitored every few days through the end of the experiment on day 25, when mice were sacrificed and organs were collected for further analysis. (B) Effective suppression of parasitemia by BNZ and BNZ-PS. *P ≤ 0.05 for BNZ 100 mg/kg and BNZ-PS 1.5 and 0.15 mg/kg vs. untreated and PS. (C) Cardiac parasitosis was quantitated by quantitative PCR. *P ≤ 0.01 vs. untreated and PS. (D) Cardiac inflammation was quantitated in heart sections 2 ways — by total cellularity (top) and by the percentage of cellular area occupied by nuclei (bottom). *P ≤ 0.05 vs. untreated, PS, and BNZ. (E) Representative cardiac histology from the experiment in C. Scale bar: 100 μM. All error bars reflect mean ± SEM. One-way ANOVA with Tukey’s post hoc test was used for multiple comparisons.