tris1,10-phenantroline iron (II) loaded into a nanostructured lipid system: characterization and anti-tuberculosis activity

Author(s)

Rachel Temperani Amaral Machado

• Document type: Master's Dissertation
• Press: Araraquara. 0000-00-00.
• Institution: Universidade Estadual Paulista (Unesp). Faculdade de Ciências Farmacêuticas. Araraquara
• Defense date: 2021-10-25
• Advisor: Fernando Rogério Pavan; Patricia Bento da Silva

Abstract

Tuberculosis (TB) presents about 10 million cases per year worldwide. In addition, the high rates of resistance to the main classes of antimicrobials contribute to TB being among the biggest killers of an infectious agent. Thus, the need to control and combat this disease, which represents a serious threat to global public health, is evident. Therefore, it is necessary to face the challenge of developing new agents active against TB. In this work, the metallic complex tris-(1,10-phenanthroline)iron(II) ([Fe(phen)3]2+) was selected for the study, as previous works by our group demonstrated that this complex is a good candidate against TB. Furthermore, when loaded into a nanostructured lipid system (NLS) it demonstrated good oral bioavailability. Given these facts, the objective of this work was to characterize the complex incorporated into NLS and verify its anti-Mycobacterium tuberculosis activity. The frequency of resistance of Mycobacterium tuberculosis to [Fe(phen)3]2+ is lower than that of other first-line drugs for the treatment of tuberculosis, such as rifampicin. It has been shown to be specific in inhibiting mycobacteria. It was possible to obtain NLS consisting of cholesterol as the oil phase, soy phosphatidylcholine, sodium oleate and Eumulgin® HRE 40 [polyoxyl 40 hydrogenated castor oil]; in a ratio of 3: 6: 8, as surfactant and phosphate-buffer pH 7.4 as aqueous phase, and successfully load the complex [Fe(phen)3]2+ to it (NLS+[Fe(phen)3]2+). The NLS+[Fe(phen)3]2+ formulation proved to be stable for up to 90 days at 5°C and are also stable after 24 hours in solutions with pHs that match those found in the stomach and blood, and in contact with means of culture used in other in vitro methodologies, proving the integrity of the particles during these assays. NLS showed a entrapment efficiency rate close to 60% of [Fe(phen)3]2+. NLS+[Fe(phen)3]2+ particles were homogeneous (PdI = 0.17), with a negative surface charge of -34.7mV and average size of 163nm, defined by the dynamic light scattering (DLS) technique and confirmed by transmission electron microscopy (TEM), which also revealed its spherical morphology. [Fe(phen)3]2+ had a MIC90 value of 4.17 µM in its free form and 23.39 µM when incorporated into NLS. Future studies must analyze the in vitro release profile, and the in vivo activity and safety of NLS+[Fe(phen)3]2+ in order to fully understand whether this combination of the [Fe(phen)3]2+ and the NLS has the potential to proceed as a drug candidate against TB. (AU)

• FAPESP's process: 19/10326-7 - In search of the mechanism of action of the tris-(1,10-phenanthroline)iron (II) complex and its possible effects against Mycobacterium tuberculosis
• Grantee: Rachel Temperani Amaral Machado
• Support Opportunities: Scholarships in Brazil - Master