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. 2020 Dec 14;4(6):581–600. doi: 10.1042/ETLS20190154

Table 2. List of research studies published since 2015 that utilized metal NP or TB drug-loaded metal NP to cure TB.

# Aim TB drug Metal agent Dosage form Method Results
1 [84] Investigate the efficacy of gallium NPs against Human immunodeficiency and tuberculosis coinfection N/A Gallium NP NP were prepared using a high- pressure homogenizer. Characterization: Morphology, cytotoxicity on THP-1 cells, and growth inhibition against M. tuberculosis (H37Ra) or HIV-1. Rod-shaped NPs with no toxicity on cells and Ga was released within 15 days. Significant inhibition in growth of TB bacteria was observed with the Ga NP compared with the free metal.
2 [85] Investigate the efficacy of gallium NP on M. tuberculosis-infected macrophages N/A Gallium NP NP were prepared using a high- pressure homogenizer. Characterization: Morphology, cytotoxicity on THP-1 cells, and growth inhibition against M. tuberculosis (H37Ra) or HIV-1. Increased levels of IL-6, IL-8, IL-1β, IL-4, and TNF-α were observed when TB bacteria infected macrophages. Gallium NPs were able to regulate these levels. These NPs inhibited the growth of TB bacteria for 15 days.
3 [86] Targeting macrophages by gallium NPs RIF used as control Gallium NP NP were prepared using high- pressure homogenizer. Characterization: Morphology, cytotoxicity and drug uptake by THP-1 cells, growth inhibition against M. tuberculosis (H37Ra), and loading on monocyte-derived macrophages. The size and zeta potential of NP were dependent on polymer type. The morphology of gallium was approximately rectangular. Gallium NP prepared by dendrimers showed faster uptake by THP-1 macrophages. All formulations showed TB bacteria growth inhibition for 15 days.
4 [59] Design therapeutic nanoparticles for lung delivery INH Iron NP INH, D-Leucine NPs (LC NP) and INH PLGA NPs were prepared by spray drying. Characterization: Drug quantification, aerodynamic characterization, size, morphology, in vitro drug release, cytotoxicity, and uptake by RAW 246.9. Irregularly shaped particles with an average diameter of 11 µm with a near-uniform size distribution. Higher INH release was observed from the LC NPs compared with PLGA NPs within 10 h. No cytotoxicity effects were shown with the lowest concentration (10–25 µg/ml) and the highest concentration (500 µg/ml) decreased the cell viability by 52% compared with the control cells.
5 [87] Design theragnostic nanoparticles encapsulating INH INH Iron NP Fe-MIL-101-NH2 was synthesized by milling in an agate ball mill for 24 h and INH was incorporated by mixing. Characterization: Size, morphology, drug release, and in vitro cytotoxicity on fibroblasts L929. 12% of INH was loaded in the NPs with a diameter range of 3.37–6.45 μm based on the micronization method used and a sustained release profile of INH. NPs accumulated inside the L929 fibroblasts with no signs of toxicity.
6 [88] Explore the antitubercular effect of MgO and ZnO NPs N/A MgO, ZnO NP MgO and ZnO NPs were prepared. Characterization: Antitubercular activity against MDR and XDR, cytotoxicity on Vero and HepG2 cells. The NPs didn't show cytotoxicity. The inhibitory effects could be associated with the ZnO NPs. These NPs sacrificed MDR and had a synergetic effect to clear resistant strains.
7 [89] Characterize silver NPs synthesized by a Streptomyces sp. NH28 strain N/A Silver NP Silver NP were biosynthesized by an Actinobacterial strain. Characterization: Validation of biosynthesis, determination of functioning groups, Morphology, zeta potential, size, Minimal inhibitory concentration (MIC) of silver NPs against many bacterial strains. Spherical NPs with a mean size of 19.9 nm with a negative zeta potential of −13.8 mV. The antibacterial effect was observed against all strains and didn't show any toxic effects when exposed to L929 fibroblasts.
8 [90] Assess the efficacy of silver NPs on TB bacteria N/A Silver NP NPs were prepared using a single dispersion and stabilized by polyvinylpyrrolidone. Characterization: Size, in vitro antitubercular effects against H37Rv strain, and in vivo efficacy using mice. NP with size 43.6 ± 10.7 nm were prepared to enhance the suppression of TB bacteria by 2 fold and decrease the count of TB bacteria in the spleen and lungs by 2 x in mice.
9 [91] Design a green synthesis of silver NPs N/A Silver Nano composi te NPs were prepared by a one-step reaction using Chitosan. Characterization: Size, antitubercular effect, and cytotoxicity. Spherical nanocomposites with a size 11–17.5 nm and IC50 against normal lung cells was 357.2 μg/ml. M. tuberculosis was inhibited by an MIC of 1.95 μg/ml.
10 [92] Prepare silver NP loaded with antibacterial drugs Vancom ycin Silver NP NPs were prepared by a citrate reduction process. Characterization: Size, morphology, antibacterial effect against M. smegmatis. Spherical NP with a size 30 ± 3 nm were prepared successfully. The internalization of the drug inside the bacteria was enhanced through formulation with NPs.
11 [93] Investigate the antimycobacterial activity of silver N/A Silver NP Silver NP were prepared by a chemical reduction method. Characterization: Size, morphology, MIC against M. tuberculosis H37Rv. Spherical and tetrahedral silver NP with an average size of 59 nm were prepared. The system showed an antibacterial effect on this TB strain with an MIC of 1 µg/ml.
12 [63] Fabricate a nanoscale multi-drug delivery system RIF, PZA Silver NP The biodegradable polymer chitosan–grafted- (cetyl alcohol- maleic anhydride-pyrazinamide) was made by multiple reactions. Silver NP and RIF were incorporated. Characterization: Size, morphology, drug release, in vitro cytotoxicity on Vero and THP-1 cells, and antitubercular activity. FTIR confirmed the successful synthesis of silver, RIF, and polymer containing PZA. PZA and RIF were in an amorphous phase with a size of 140 nm and their full release was performed within 12 h. The combination therapy showed better antitubercular effect than their single administration.
13 [94] Design and characterize biodegradable silver NPs N/A Silver acetate, silver carbene complexes (SCCs) NP A solution of silver was added to the Diblock Copolymer, Poly (butynyl phosphotriester)210-block- Poly(L-lactide)50 (PPE210-b- PLLA50). Characterization: Stability, release kinetics, and antibacterial activity Staphylococcus aureus and Escherichia coli. 50% of silver was released within 2.5–5.5 h. Encapsulating silver within NPs increased the minimum inhibition order by 70%.
14 [95] Green synthesis of silver NPs by yeast N/A Silver chloride NP NPs were prepared using yeast. Characterization: Crystalline nature of NP, size, morphology, antitubercular activity against M. tuberculosis H37Rv. Spherical NPs with a diameter of 17 nm sacrificed the bacteria by inducing oxidative stress. These NPs showed a 95% reduction in TB bacteria with an administrated dose of 37 µg/ml.
15 [96] Investigate the changes in immune response to TB when silver NP is administered N/A Silver, carbon black NP Different concentrations of silver NP with different stabilizers were used in the preparation method. Characterization: Size, morphology, cell viability on human monocyte-derived macrophages (MDM) and in vitro release. Different formulations showed different sizes and zeta potentials. Importantly, silver NPs reduced cellular viability, increased IL8, and decreased IL10 mRNA expression when exposed to MDM. For the TB- infected MDM, silver NP suppressed. M. tb-induced expression of IL1β, IL10, and TNFα mRNA, and TB bacteria was inhibited by silver NPs.
16 [97] Evaluate the biological risks associated with exposure to NP N/A Silver, black carbon NP Silver NPs were prepared by bath reduction using sodium citrate. Characterization: Cell viability on human monocyte-derived macrophages (MDM). After 4 h of silver NP exposure to MDM, no toxicity was observed. But after 24 h, the cell viability was reduced by 60–70%. Silver NPs up-regulated Hsp72 leading to suppress NF-kB induced by M.tb, thus hosting immune responses.
17 [98]g Evaluate the antitubercular activity of metal NPs N/A Silver, Gold NP NPs were synthesized from plants, such as Barleria prionitis, Plumbago zeylanica, and Syzygium cumini. Characterization: In vitro and ex vivo minimum inhibitory concentration, internalization by macrophage, and cytotoxicity. A combination of gold and silver NP had the most striking antitubercular effect with a MIC of less than 2.56 µg/ml. No antibacterial effect was observed for gold NPs with concentrations of < 100 µg/ml. Metal NPs entered macrophage cells.
18 [99] Compare the efficacy of silver and gold NPs N/A Silver, Gold NP Biological synthesis of silver and gold NPs was done using environmental bacterium. Chemical synthesis was performed using reduction reactions. Characterization: Size, Morphology, antitubercular effects in vitro and ex vivo using infected THP-1 cells and cytotoxicity assays. Ag and AuNPs were spherical and Polyhedral in morphology, respectively. AgNPs showed better antitubercular efficacy than the gold NPs.
19 [98] To investigate the efficacy of phytogenic metal nanoparticles N/A Silver, gold NP NPs were prepared using medicinal plants, such as Barleria prionitis, Plumbago zeylanica, and Syzygium cumini. Characterization: Size, morphology, MIC against H37Rv, toxicity, and uptake by THP-1 macrophages. The size and morphology were dependent on the phytogenic source. Mixed Ag and Au spherical NPs prepared by Syzygium cumini with a diameter of 10–20 nm showed the most powerful formulation against TB bacteria. 45% cell viability was observed at a dose of 30 µg/ml of the mixture of Au-Ag NPs. Silver NPs showed more potent antibacterial effects than gold NPs.
20 [100] Synthesized NPs using environmental bacteria N/A Silver, zinc NP Silver and zinc oxide NP were prepared using a bacterial culture of Pseudomonas hibiscicola. Characterization: Size, morphology, cytotoxicity on a Vero cell line, and testing of the antimicrobial efficacy against many strains including Mycobacterium tuberculosis H37Rv. Polydisperse spherical silver and zinc NPs with a mean size of 39 and 62 nm were prepared. IC50 values for silver and zinc NPs were 5.54 and 6.24 mg/ml. Authors concluded that metal NPs could enhance the antibacterial efficacy of many drugs like gentamicin.
21 [101] Evaluate the antitubercular effects of mixed metal oxides N/A Silver, ZnO NP NPs were prepared by chemical reduction. Characterization: Size, morphology, toxicity on THP-1 cells, and antitubercular effects against M. tb. Spherical NPs with a diameter of 30–80 nm. MIC ratio of 8ZnO:2Ag NPs against M. tb was detected at ratio of ∼1/32 of the initial concentration of Ag NPs and ZnO NPs were estimated at ∼20 ppm and ∼60 ppm. Silver did not show antitubercular effects at any of the applied doses, while ZnO NPs showed a potent antibacterial activity at ∼1/128 and toxic effects on the cells.
22 [102] Determine the effective ratio of mixed metal NPs N/A Silver, ZnO NP NP were prepared by bath reduction in sodium citrate. Characterization: size, shape, cytotoxicity on THP-1 cells and antibacterial efficacy using Mycobacterium tuberculosis (H37RvMTB). Spherical particles with a size of 13 nm for Ag NPs and 4 nm for ZnO NPs. 0.663 ppm of 5Ag:5ZnO showed effective antibacterial results with no toxicity to THP-1 cells. The combination of both metals together showed better results.
23 [103] To design biodegradable microparticles containing mixed metal NPs to be delivered to the lungs RIF Silver, ZnO MP Capped silver NP were prepared by a bath reduction method and capped ZnO NP were prepared using an organometallic route. The MPs were prepared using a solvent evaporation method. Characterization: Size, morphology, elemental composition, antitubercular effect against H37Ra M. tb, and cytotoxicity on THP-1 cells. ZnO and silver NPs were formulated within PLGA microparticles with a diameter of 4 µm. Selective uptake of the MPs by M.tb infected macrophages and zinc and silver ions were released which disrupted the M.tb cell wall. This formulation increased the potency of RIF by 75%.
24 [60] Investigate the antibacterial effect of zinc and silver N/A Silver, ZnO NP Ag and ZnO NPs were prepared by a chemical reduction method. Characterization: size, morphology, MIC against M. tuberculosis H37Rv, MDR, and XDR. Spherical silver and ZnO NPs with a size of 5.4 ± 2.6 nm and 9.3 ± 3.9 nm were produced. The MIC of all of the formulations was 1 µg/ml. Silver and zinc NP showed a bacteriostatic effect against MDR and XDR strains of M.tb.
25 [104] Explore the antibacterial effect of TiO2 NPs N/A TiO2 NP NP were prepared by a sol-gel method using TiOSO4. Characterization: Size, morphology, antitubercular effect on TB bacteria, and cytotoxicity using lung bronchus cells. Spherical NP with diameter of 16 nm showed size and concentration-dependent antitubercular effects with a 3–4 times decrease in TB metabolic activity with very minimal toxicity when the maximum dose was applied.
26 [105] Green synthesis of NPs N/A ZnO NP NP were prepared using the extracted Limonia acidissima L. and a zinc nitrate solution. Characterization: Particle size and distribution, anti-TB activity against H37 RV strain, and morphology. Monodisperse spherical NPs with a diameter of 12–53 nm were prepared. The NPs inhibited the growth of TB at a concentration of 12.5 µg/ml.
27 [106] Green synthesis of ZnO N/A ZnO NP A hydrothermal combustion method was used for Phyto- synthesis ZnO-nanoparticles from Canthium dicoccum. Characterization: Size, zeta, potential, crystallinity structure, antibacterial activity and MIC Rod-shaped ZnO particles with an average size of 33 nm. B. subtilis inhibited bacteria with a MIC value of 78.12 µg/ml. TB growth was inhibited by 25–100 µg/ml of ZnO nanorods.
against positive and negative-gram bacteria and antitubercular efficacy against Mycobacterium tuberculosis (ATCC No- 27294).
28 [107] Green synthesis of ZnO as antitubercular agent N/A ZnO NP ZnO NPs were prepared by Capparis zeylanica. Characterization: Size, Morphology, Antitubercular effect on TB bacteria. Spherical NPs with a diameter of 34 nm. The maximum diameter of inhibition zone was observed in at (100 μg/ml) against M. tuberculosis (35 ± 1.86).
29 [108] Explore the synergistic effect of ZnO and RIF NPs. RIF ZnO NP ZnO NP were prepared by precipitation in liquid. Characterization: Size, morphology, antitubercular activity against Wild-type (WT) Mycobacterium smegmatis mc2155, zeta potential, and MIC. Uniformly distributed ZnO NPs with a diameter of 11 nm and zeta potential of +19.1 mV. The MIC for the ZnO NP was 256 µg/ml but 32 µg/ml of ZnO NPs were able to reduce the MIC of RIF from 64 µg/ml to 16 µg/ml which confirms a synergistic effects between both antitubercular agents.