One of the problems in the treatment of neglected tropical diseases, including Chagas disease, is that available treatments have limited therapeutic efficacy and severe side effects, and their poor penetration into patient tissues and cells results in low bioavailability. Despite the low efficacy rate in the chronic phase of the disease, BZN is the drug of choice for treatment, but factors such as the strain of the parasite, the generation of drug resistance by the parasite, the age of the patient, prolonged periods of treatment, among others, influence the outcome and effectiveness of treatment. This highlights the need to search for new therapies with good trypanocidal activity and without the severe toxicity shown by BNZ treatment. Some reports suggest that these limitations can be overcome by the use of nanosystems [14–16]. In this work, the trypanocidal activity of Zn-MOF doped with BNZ (BNZ@Zn-MOF) has been evaluated against the experimental acute infection in the mouse model. The characterization of the BNZ@Zn-MOF allowed to confirm its correct synthesis, the main characteristics of the Zn(II) polymer are its formation through two organic linkers, 4,4'-bipyridyl and acetate, which in their crystallization present a linear structure in the form of a nanotube, a triclinic system and a P-1 space group, describes a crystalline structure characterized by no particular symmetry in its axes and angles, with no particular symmetry constraint on the arrangement of atoms in the crystal lattice [9]. The doping of MOF with BNZ using the mechanochemical method was satisfactory and similar to that observed in previous work [10, 12], and by reported theoretical calculations [17], it is shown that the electron density in the excited state of BZN is shifted towards the imidazole and mainly towards the nitro group, since BZN, being an organic structure with a nitro group attached at position 2 of the imidazole, shifts the electron density towards itself. In this sense, the formation of monolayer and multilayer crystals is directly related to the coordination of the metal with the ligands and is generated in a natural way by the MOF synthesis process; multilayer crystals allow the incorporation of a greater amount of drug into the structure, in addition to providing protection to avoid its fluctuation in concentration when it is in the bloodstream and tissues [18, 19]. Zinc, as an endogenous transition metal with low toxicity, has been considered as an ideal candidate in the preparation of MOFs for applications in biological systems [20, 21]. Some data in the literature are discrepant, where some Zn-based formulations show some degree of cytotoxicity [22–24], however, the concentrations used in this work did not show toxicity at the concentrations used. Controlled drug release not only delivers the right amount of active ingredient at the right time and in the right place, but it also efficiently achieves uniform drug concentrations, the use of smaller doses, and the absence of side effects. According to the results, it was found that BNZ@Zn-MOF preserves the release pharmacokinetics of BNZ similar to that observed in other nanosystems [25, 15].
Oral drug delivery is a safe and minimally invasive route that allows a degree of patient autonomy, and the cost of manufacturing drugs for this route is low. Drug-loaded nanoparticles have been developed and evaluated as oral drug delivery systems [26]. Some nanopreparations have been designed for evaluation during acute infection with T. cruzi, where most of these preparations have shown good efficiency in parasite elimination and an increase in drug solubility. The results obtained in this work are consistent with other studies using nanocarriers to deliver BZN in models of experimental infection with T. cruzi [16, 27, 28]. It was observed that the trypanocidal activity of the drug was unaffected, reducing the peak parasitemia and the number of parasites in the circulating blood, using extremely low doses of the drug compared to the doses used in the standard treatment and without apparent tissue damage, allowing the survival of the mice. However, doses as low as 20 ng of BNZ@Zn-MOF do not eliminate parasite persistence in tissues. On the other hand, BZN treatment has generally been associated with elevations in serum levels of some enzymes in at least 10% of patients, and the severity of treatment-related liver injury has been mild and self-limited with transient and asymptomatic elevations in serum enzymes, occasionally accompanied by hypersensitivity reactions [29], our results show that the doses used in this work do not cause elevations in the values of the enzymes analyzed and are consistent with the values reported for these markers [30; and with those obtained in other related works [31], suggesting that the Zn-MOF structure administered to mice does not induce liver damage.
The pharmacological therapy currently used in the treatment of Chagas disease is inadequate in terms of efficacy and safety, because BNZ has low solubility and limited absorption, so it is necessary to administer considerable doses in the treatments, generating a certain toxicity and increased side effects [12]. The use and applications of MOFs have increased rapidly in recent years, but there is still a lack of understanding of their structure, properties and stability under different conditions [32, 33]. The results of this work show that BNZ administered orally to mice at low concentrations through the system of organometallic structures (Zn-MOFs) (1 µg BNZ@Zn-MOF vs. 250 µg BZN); shows an antiparasitic inhibitory effect similar to that induced by the high concentrations of free BNZ used in current therapies (8–10 mg/kg/d), in addition, the variable size observed in MOFs can simultaneously prolong the time of blood circulation and therefore its bioavailability, as has been observed with the use of MOFs in cancer therapies [34]. On the other hand, the presence of Zn in the molecule could mediate a stimulation of the immune system in favor of host defense against T. cruzi, as has been suggested in the field of metalloimmunology [35]. In conclusion, the results of this work show that the administration of BZN by means of organo-metallic nanotransporters represents a useful tool to reduce the infection, offering strategies to improve the solubility and efficacy of BZN, using low doses and favoring the absence of side effects, proposing a pharmacological alternative in the therapy of Chagas disease. However, further studies are needed to better understand its mechanism of action and its safe use.