Nano-Based Drug Delivery Systems of Potent MmpL3 Inhibitors for Tuberculosis Treatment.

Patrizia Nadia Hanieh,Gianluigi Cabiddu,Alessandro De Logu,Federica Rinaldi,Giovanna Poce,Jacopo Forte,Sara Consalvi,Carlotta Marianecci,Maria Carafa,Mariangela Biava

doi:10.3390/pharmaceutics14030610

Patrizia Nadia Hanieh, Gianluigi Cabiddu + Show 8 more

Open Access

https://doi.org/10.3390/pharmaceutics14030610

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Abstract

Tuberculosis remains one of the world’s deadliest infectious diseases, accounting for nearly 1.3 million deaths every year. Tuberculosis treatment is challenging because of the toxicity, decreased bioavailability at the target site of the conventional drugs and, most importantly, low adherence of patients; this leads to drug resistance. Here, we describe the development of suitable nanocarriers with specific physicochemical properties to efficiently deliver two potent antimycobacterial compounds. We prepared nanoemulsions and niosomes formulations and loaded them with two different MmpL3 inhibitors previously identified (NEs + BM635 and NIs + BM859). NEs + BM635 and NIs + BM859 were deeply characterized for their physicochemical properties and anti-mycobacterial activity. NEs + BM635 and NIs + BM859 showed good hydrodynamic diameter, ζ-Potential, PDI, drug-entrapment efficiency, polarity, and microviscosity and stability. Even though both formulations proved to perform well, only NIs + BM859 showed potent antimycobacterial activity against M. tuberculosis (MIC = 0.6 µM) compared to that of the free compound. This is most probably caused by the fact that BM635, being highly hydrophobic, encounters maximum hindrance in diffusion, whereas BM859, characterized by high solubility in aqueous medium (152 µM), diffuses more easily. The niosomal formulation described in this work may be a useful therapeutic tool for tuberculosis treatment, and further studies will follow to characterize the in vivo behavior of the formulation.

Highlights

Infectious diseases remain one of the most life-threatening challenges in the modern world, regardless of advanced technology and innovation
We have developed a potent class of antimycobacterial compounds acting as inhibitors of the essential mycobacterial membrane protein large 3 (MmpL3)
The sonication performed on the samples in the non-homogenous zone led to formation of monophasic dispersion represented by the yellow zone [19–21]

Summary

Introduction

Infectious diseases remain one of the most life-threatening challenges in the modern world, regardless of advanced technology and innovation. Prior to the COVID-19 pandemic, tuberculosis (TB) was the leading cause of deaths worldwide from a single infectious agent, accounting for 1.3 million deaths in 2020 [1]. Even though the combination of timely diagnosis and treatment with first-line drugs for six months can cure people who develop drug-susceptible TB and prevent the transmission of infection, cure success rates are very low. TB (MDR-TB) is caused by M. tuberculosis (Mtb) strains resistant to isoniazid (INH) and rifampicin (RIF), whereas extensively drug-resistant TB (XDR-TB) is caused by Mtb strains resistant to INH and RIF, in addition to any fluoroquinolone and at least bedaquiline or linezolid, if not both. The World Health Organization (WHO) estimates that the success rate of treatment of MDR/XDR TB patients was 59% in 2018 [1].

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