Novel Nanocarrier Platform for Effective Treatment of Visceral Leishmaniasis

Abstract

Leishmaniasis is among the five parasitic diseases that still require the development of new drugs. Ultrasmall cerium (Ce 3/4+ ) cation-doped maghemite (γ-Fe 2 O 3 ) nanoparticles (NPs) were tested as a potential drug to treat visceral leishmaniasis, a disease affecting millions of people worldwide. The NPs were engineered for binding a polycationic branched polyethylenimine (PEI) polymer, thereby rupturing the single lysosome of these parasites and enabling entry of the anti-Leishmania drug, pentamidine. Exploiting the known lanthanide cation/complexbased coordinative chemical reactivity enabled the binding of both active agents onto the surface of the NPs. To optimize the fabrication of the cytotoxic NPs, optimization via a DoE (Design of Experiments) process was used to identify the optimal NP with toxicity against the two stages of the parasite, promastigotes, which propagate in the insect, and amastigotes, which infect the mammalian host. The screen identified a single optimized NP (DoE Opt) that was further examined in a mouse model of visceral leishmaniasis. Intravenous injection of the NPs had no adverse effects on the cellular composition or biochemical parameters of the blood, demonstrating no signs of systemic toxicity. The optimized NP was able to eradicate visceral disease caused by Leishmania donovani infection. The study demonstrates the versatile ability of the ceriumdoped NPs to bind at least two cytotoxic ligands. This approach could be used for optimizing the binding of different drugs for the treatment of other diseases, including cancer. Since resistance to treatment with nanocarriers was not reported to date, such an approach could potentially overcome drug resistance that emerges when using soluble small molecule drugs.

A Systematic Study on the Physicochemical Interactions Between Polymeric Micelles and Mucin: Toward the Development of Optimal Drug Delivery Nanocarriers

“…The discrepancy in the size value between DLS and cryo‐TEM measurements is due to the fact that DLS is a scattering technique, which determines the hydrodynamic diameter, which encompasses the electric dipole layer and solvent effects. [ 42 ] The hydrophilic PEG corona thereby is not something that is directly visible and accounted for in cryo‐TEM. This is further confirmed by the close similarity between the cryo‐TEM data and the number distribution obtained from DLS, indicating that the sample comprises a significant population of smaller particles (Figure S2B, Supporting Information).…”

Doenças infecciosas: inovações e aprendizados para área médica

“…Outra inovação tecnológica em pauta são as NPs de maghemita ( γ-Fe 2 O 3) dopada com cátion de cério (Ce 3/4+) como uma possível estratégia terapêutica no enfrentamento da LV. Essas NPs atuariam ligando em um polímero de polietilenimina ramificada policatiônica (PEI) com atuação por meio da agressão do lisossomo único dos parasitas, fato que permite a entrada do fármaco pentamidina, o qual combate esse patógeno (KANNAN et al, 2021).…”

“…Por meio da análise em um modelo de camundongo que estava infectado por LV, ao se aplicar por via intravenosa os NPs, não se obteve efeitos adversos na constituição celular ou nas características bioquímicas sanguíneas, o qual corrobora para não toxicidade sistêmica dessa terapêutica e essa estratégia foi capaz de erradicar a doença. Esse modelo se torna importante porque até o presente momento não há relatos de resistência ao tratamento com nanocarreadores, uma solução para o problema de resistência às drogas de moléculas pequenas solúveis (KANNAN et al, 2021).…”

Innovating Leishmaniasis Treatment: A Critical Chemist’s Review of Inorganic Nanomaterials

“…Thus, the primary goal of this approach is to minimize side effects and improve treatment adherence. DDS are particularly promising for the treatment of Leishmaniasis, as they enable targeted and selective treatment by being engulfed by liver and spleen macrophages, where the Leishmania parasites reside. − Unlikely cancer cells, which rely on passive diffusion and endocytosis mechanisms for uptake, , macrophages can phagocytize larger foreign bodies as defensive response. , The Leishmania protozoan exists in two forms: the flagellate promastigote and the nonflagellate amastigote. Transmission to a mammal occurs through a mosquito bite, with mosquito’s contaminated saliva containing the promastigote form of the parasite.…”