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

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.

Gentamicin loaded niosomes against intracellular uropathogenic Escherichia coli strains

“…S1, it is possible to observe that both media don't affect the integrity of empty and loaded vesicles, it is possible to observe only an increase of the dimension, especially in RPMI media. This result could suggest only a surface nanocarrier interaction with RPMI components and not its degradation 37 .…”

A Current Perspective on the Potential of Nanomedicine for Anti-Tuberculosis Therapy

“…Mukhtar M et al demonstrated the promising anti-TB activity of mannosylated-chitosan and hyaolorunic-acid nanoparticles containing isoniazid, which targeted the CD44 and mannose receptors of macrophages [ 55 ]. The novel MmpL3 (mycobacterial membrane protein large 3) inhibitors, BM625 and BM819, in nanoemulsion and niosomes, showed potent antimycobacterial activity against Mtb [ 56 ].…”

Advanced drug delivery and therapeutic strategies for tuberculosis treatment

“…For highly lipophilic drugs, such as BM859, which demonstrated significant antimycobacterial action against M. tuberculosis H37Rv, niosomes are a preferable method of drug delivery. Sadhu et al developed ethionamide niosomes with sufficient stability for intravenous injection [128,129]. Niosomes loaded with hydrophilic D-cycloserine and lipophilic ethionamide kill drug-resistant TB by releasing 96% of ethionamide and 97% of D-cycloserine [130].…”

“…Kaur et al developed a Brig 96 microemulsion to work in combination with lipophilic and hydrophilic drugs [203]. The drug penetration is thermos-dependent in nature [210] D-cycloserine and Ethionamide Niosome ↓ MIC; ↑ drug release and entrapment efficiency [130] Prednisolone PEGylated PPI dendrimers uniform biodistribution of drug in vital organs [174] Protein based vaccine Nanoemulsion ↑ Potency and thermostability due to addition of adjuvants [211] N′-Dodecanoylisonicotinohydrazide liposome-in-Hydrogel system Thermoresponsive and self-healing properties useful for intra-articular administration for bone TB therapy; rapid drug release into synovial fluid after localized injection, followed by a steady-state drug release [118] Photodynamic antimicrobial chemotherapy Zinc phthalocyanine-liposomes Inactivation of both sensible and resistant strains of M. tuberculosis [121] Epigallocatechin gallate with trehalose Microencapsulation Dose dependent killing and time dependent killing; ↓ bacterial loads; no granulomas, lesion or inflammation developed [191] Eugenol Diluted solution Antimycobacterial effect; synergistic effect when combined with other ATDs [212] Macozinone Capsule Inhibit the enzyme decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1) involved in the synthesis of the mycobacterial cell wall [213] β-sitosterol Capsule Counteract the side effects caused by long-term ATD therapy; Showed improvements in the levels of hemoglobin, neutrophil, creatinine, and urea, with eventual weight gain and higher lymphocyte and eosinophil counts, as compared to the placebo [214] Astaxanthin Microencapsulation Cost effective natural component with potent antimycobacterial activity [190] Calcium phosphate nanocontainers filled with 1,3-benzothiazin-4-one-043 Microemulsion Significant antibacterial activity [215] 1,5-diarylpyrrole and 1,5-diarylpyrazole Nanoemulsion and niosome Comparatively potent antimycobacterial activity exhibited by noisome of 1,5-diarylpyrazole than nanoemulsion of 1,5-diarylpyrrole [128] Microemulsions of INH, pyrazinamide, and RIF exhibited good antibacterial characteristics [237].…”