Synthesis and biological evaluation of β-lapachone and nor-β-lapachone complexes with 2-hydroxypropyl-β-cyclodextrin as trypanocidal agents

Nicoletti, Caroline Deckmann; Faria, Ana Flávia Martins; Queiroz, Marcella de Sá Haddad; Galvão, Raíssa Maria dos Santos; Souza, André Luis Almeida; Futuro, Débora Omena; Ferreira, Vı́tor F.

doi:10.1007/s10863-020-09826-8

Cited by 9 publications

(5 citation statements)

References 70 publications

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“…Complexes of BNZ and cyclodextrin have been reported as a strategy to increase the hydrophilicity of BNZ, which improves the absorption, permeability, and bioavailability of BNZ oral formulations. Modifying these pharmacokinetic properties reduces the toxicity of BNZ, possibly by reducing lipophilicity of the drug ( 23 ) without inhibiting trypanocidal activity ( 24 ). Nevertheless, the BNZ-cyclodextrin complex was not superior to free BNZ in trypanocidal activity during murine T .…”

Section: Introductionmentioning

confidence: 99%

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

Li¹,

Yi²,

Scariot³

et al. 2021

JCI Insight

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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.

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Section: Introductionmentioning

confidence: 99%

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

Li¹,

Yi²,

Scariot³

et al. 2021

JCI Insight

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“…Recently, our group described for the first time the inclusion of β-Lap in cyclodextrin and its activity against T. cruzi, observing that complexation enhanced the SI compared to the free form of this drug [37]. In the present work, aiming to deepen the study of β-Lap complexes, free and encapsulated forms of the quinone were investigated on the three evolutionary forms of the parasite with emphasis on the forms relevant to mammalian infection (amastigotes and trypomastigotes) [2].…”

Section: Discussionmentioning

confidence: 99%

“…This class of guest molecules can improve drug solubility, stability, and bioavailability [31][32][33]. Complexation strategies have been successfully explored in studies with Bz to increase its plasma concentration and reduce its in vitro cytotoxicity without impairing biological activity [30,[34][35][36][37].…”

Section: Introductionmentioning

confidence: 99%

Characterization and trypanocidal activity of a β-lapachone-containing drug carrier

et al. 2021

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The treatment of Chagas disease (CD), a neglected parasitic condition caused by Trypanosoma cruzi, is still based on only two drugs, nifurtimox (Nif) and benznidazole (Bz), both of which have limited efficacy in the late chronic phase and induce severe side effects. This scenario justifies the continuous search for alternative drugs, and in this context, the natural naphthoquinone β-lapachone (β-Lap) and its derivatives have demonstrated important trypanocidal activities. Unfortunately, the decrease in trypanocidal activity in the blood, high toxicity to mammalian cells and low water solubility of β-Lap limit its systemic administration and, consequently, clinical applications. For this reason, carriers as drug delivery systems can strategically maximize the therapeutic effects of this drug, overcoming the above mentioned restrictions. Accordingly, the aim of this study is to investigate the in vitro anti-T. cruzi effects of β-Lap encapsulated in2-hydroxypropyl-β-cyclodextrin (2HP-β-CD) and its potential toxicity to mammalian cells.

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“…To counter this drawback, cyclodextrin derivatives have been used for inclusion in many studies [ 14 ]. For example, DM-β-CD formed a stable inclusion complex with dihydromyricetin [ 15 ], and HP-β-CD could improve the solubility and bioavailability of β-Lapachone (βLAP) and its derivative nor-β-Lapachone (NβL) [ 16 ]. The structural formulae of β-CD, HP-β-CD and DM-β-CD are shown in Figure 1 c–e.…”

Section: Introductionmentioning

confidence: 99%

Preparation, Characterization and Molecular Dynamics Simulation of Rutin–Cyclodextrin Inclusion Complexes

Chang

Song²,

Ma³

et al. 2023

Molecules

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Rutin is a natural flavonoid that carries out a variety of biological activities, but its application in medicine and food is limited by its water solubility. One of the classical methods used to enhance drug solubility is encapsulation with cyclodextrins. In this paper, the encapsulation of different cyclodextrins with rutin was investigated using a combination of experimental and simulation methods. Three inclusions of rutin/beta-cyclodextrin (β-CD), rutin/2-hydroxypropyl beta-cyclodextrin (HP-β-CD) and rutin/2,6-dimethyl beta-cyclodextrin (DM-β-CD) were prepared by the freeze-drying method, and the inclusions were analyzed using Fourier infrared spectroscopy (FTIR), X-ray diffraction analysis (XRD), differential scanning calorimetry (DSC) and ultraviolet–visible spectroscopy (UV) to characterize and demonstrate the formation of the inclusion complexes. Phase solubility studies showed that rutin formed a 1:1 stoichiometric inclusion complex and significantly increased its solubility. β-CD, HP-β-CD, DM-β-CD, rutin and the three inclusion complexes were modeled by using MS2018 and AutoDock 4.0, and molecular dynamics simulations were performed to calculate the solubility parameters, binding energies, mean square displacement (MSD), hydrogen bonding and radial distribution functions (RDF) after the equilibration of the systems. The results of simulation and experiment showed that rutin/DM-β-CD had the best encapsulation effect among the three cyclodextrin inclusion complexes.

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Synthesis and biological evaluation of β-lapachone and nor-β-lapachone complexes with 2-hydroxypropyl-β-cyclodextrin as trypanocidal agents

Cited by 9 publications

References 70 publications

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

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

Characterization and trypanocidal activity of a β-lapachone-containing drug carrier

Preparation, Characterization and Molecular Dynamics Simulation of Rutin–Cyclodextrin Inclusion Complexes

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