ZIF-8 as a promising drug delivery system for benznidazole: development, characterization, in vitro dialysis release and cytotoxicity

Abstract

Chagas disease (CD), caused by the flagellate protozoan Trypanosoma cruzi, is one of the major public health problems in developing countries. Benznidazole (BNZ) is the only drug available for CD treatment in most countries, however, it presents high toxicity and low bioavailability. To address these problems this study used Zeolitic Imidazolate Framework-8 (ZIF-8), which has garnered considerable attention due to its potential applications, enabling the controlled delivery of drugs. The present work developed and characterized a BNZ@ZIF-8 system, and the modulation of BNZ release from the ZIF-8 framework was evaluated through the in vitro dialysis release method under sink conditions at different pH values. Moreover, the in vitro evaluation of cell viability and cytotoxicity by MTT assay were also performed. The dissolution studies corroborated that a pH sensitive Drug Delivery System capable of vectorizing the release of BNZ was developed, may leading to the improvement in the bioavailability of BNZ. The MTT assay showed that no statistically significant toxic effects occurred in the developed system, nor significant effects on cell viability.

Figure 1

UV–Vis spectra of BNZ and ZIF-8.

Figure 2

TG curves of BNZ, ZIF-8, physical mixture (PM) and BNZ@ZIF-8 (β = 10 °C min⁻¹).

Figure 3

DSC curves of BNZ, ZIF-8, physical mixture (PM) and BNZ@ZIF-8 (β = 10 °C min⁻¹).

Figure 4

DTA curve of ZIF-8 (β = 10 °C min⁻¹).

Figure 5

XRD of the BNZ, ZIF-8, PM and the BNZ@ZIF-8 with their respective main peaks.

Figure 6

Infrared spectra of BNZ, ZIF-8, physical mixture (PM) and BNZ@ZIF-8.

Figure 7

In vitro cumulative drug release (%) of BNZ and BNZ@ZIF-8 system through dialysis membrane (10,000 Da) under sink conditions at pH 4.5.

Figure 8

In vitro cumulative drug release (%) of BNZ and BNZ@ZIF-8 system through dialysis membrane (10,000 Da) under sink conditions at pH 7.6.

Figure 9

Comparative profile of the BNZ@ZIF-8 system through dialysis membrane (10,000 Da) under sink conditions at pH 4.5 and 7.6.

Figure 10

Effects of BNZ, ZIF-8 and BNZ@ZIF-8 at different concentrations on human cell viability (PBMC) according to the MTT assay at exposure time: (A) 24 h and (B) 48 h (**p < 0.05, ***p < 0.001 are related to significant differences between the tested and control groups; #p < 0.05 to the comparison between activity of ZIF-8 alone and when combined in the systems and δp < 0.05 the difference between the system and the drug alone, both at 10 μg/mL).