Innovative Therapeutic Approaches Based on Nanotechnology for the Treatment and Management of Tuberculosis

Figures & data

Figure 1 Cell wall structure of MTB and its interaction with the anti-TB drugs.

Notes: Adapted from Tuberculosis drugs and mechanisms of action. National Institute of Allergy and Infectious Diseases. https://www.niaid.nih.gov/diseases-conditions/tbdrugs. Accessed March 1, 2023.²¹

Figure 2 Pathogenesis of tuberculosis.

Table 1 Symptoms Difference Between Latent and Active TB

Features	Latent TB	Active TB	Ref.
Infectivity	Latent TB patients are unable to transmit the infection	People with active TB can spread the disease	[42]
Symptoms	No	Five major symptoms; cough lasting three or more weeks, coughing up blood, losing weight, night sweats, shortness of breath, and fever	[43]
Skin test	Positive	Positive	[44,45]
Interferon gamma release assay	Positive	Positive	[45]
Sputum acid-fast bacillus smear	Negative	Negative or positive	[47]
Chest radiography	Normal or stable calcified granulomas	Abnormal findings with active TB infections	[48]
Treatment	Conceder treatment to prevent progression to active TB	Isolation and drug regimen	[49]

Table 2 Classification of TB and Their Main Symptoms

Type of TB	Specific TB	Devastating Effect	Symptoms	Ref.
	Laryngeal	Bacterium attacks the throat’s vocal cords.	Frequently confused with other throat diseases like chronic laryngitis and laryngeal carcinoma	[50]
Pulmonary	Cavitary	Bacterium creates gradual destruction to the lung by developing cavities or expanded air spaces, in the lungs.	Coughing up blood, excessive sweating, fever, losing weight and fatigue. TB empyema occurs when the illness progresses into the pleural space (pleural pus).	[51]
	Miliary	Lymphatic and hematogenous spreading and it’s possible that happen soon after the primary infection.	Night sweating, fever and losing weight are all symptoms of this condition. Since the initial chest X-ray is often clear, it might be difficult to diagnose.	[52]
	Pleurisy	The pleural space, which is placed between the lungs and the chest wall is ruptured at the edge of the lung by a granuloma.	The mass of fluid in the lungs rises quickly, compressing the lungs and causing breathing problems (dyspnea) and severe chest discomfort that gets worse when patients take a big breath (pleurisy).	[53]
Extrapulmonary	Adrenal	The bacterium affects the adrenal gland and the production of adrenal hormone.	Inadequate adrenal gland production causes weakness or faintness.	[54]
	Lymph node	The bacterium impacts the lymph nodes and causes them to become enlarged.	Lymph nodes become so large, they rupture through the skin if not diagnosed in time	[55]
	Osteal	The bacterium infects the bones and spines.	Bone tissue weakening and even bone fractures depending on where the disease has spread in the body and back deformity.	[56]
	Peritonitis	The bacterium can attack the intestines’ outer linings as well as the linings of the abdominal wall.	Increased fluid production, similar to that of tuberculosis pleuritis. Abdominal distention and pain are caused by an increase in fluid. Patients are fatigued to moderate sick with a fever.	[57]
	Renal	Pyuria, or the white blood cell presence in the urine, is caused by the bacterium and can harm reproductive organs.	In men, renal TB can lead to swelling of the tube that connects the testicles with the vas deferens, a condition known as Renal tuberculosis in males can cause inflammation of the tube that links the testicles to the vas deferens, a disease named epididymitis.	[58]
	Meningitis	The bacterium causes stroke or a brain tumor.	This highly deadly type of extra pulmonary TB, attacks the brain.	[59]
	Pericarditis	Pericarditis happens by excessing builds fluid around the heart.	The heart’s ability to pump blood and function normally might be affected when TB damages this tissue.	[60]

Figure 3 TB infection risk factors.

Table 3 Comprehensive Overview of the Various Conventional Technologies Used in Tuberculosis Diagnosis

Method	Use	Detection	Duration and Sensitivity	Ref.
Culture	The gold standard (Agar-based and egg-based media incorporating green malachite and Middlebrook broths or solid media)	Sputum samples can be cultured in one of two ways: 1. Solid media (observed by visualizing the colonies), dug susceptibility testing and mycobacterial growth 2. Liquid media (detected by microscopic observation), drug susceptibility testing and tuberculosis detection	Results within 3 or 4 weeks with 79–82% sensitivity	[79,80]
Löwenstein–Jensen media (LJ)	Malachite green dye added to glycerated egg-potato medium	Prevent MTB from growing while also providing a contrast color that makes Mycobacterium colonies easier to observe. Susceptibility test for antibiotic.	Results within 2 to 3 weeks or several months. (92.7%) sensitivity	[81]
Microscopic Diagnosis (smear microscopy)	Ziehl Neelsen technique; bacteriological stain used to identify acid-fast organisms, mainly Mycobacteria.	The detection of acid-fast bacilli (AFB) in stained and acid-washed smears examined microscopically may provide the primary bacteriologic diagnosis of mycobacteria among a clinical specimen. This is a quick and effortless technique.	Results within 1–2 days, with (78–92.9%) sensitivity	[82]
Skin test	Mantoux test, performed by injection of 0.1 mL of fluid containing 5 TU (tuberculin units) PPD (purified protein derivative) into the forearm’s top layers of skin.	Transverse induration at the TB skin tests (TST) spot is measured in millimeters after 48–72 hours, and the optimum cut point ranges from 2 mm to 16 mm, depending on prevalence and testing purpose.	Results within 48–72 hours. Sensitivity in younger patients is 70%, in elderly patients is 27%	[83,84]
Interferon-gamma release assays (IGRA)	QuantiFERON – TB Gold and T-Spot TB assay. A blood test determines whether or not a person has been exposed to the (TB) bacterium.	The cytokine INF, which is produced by the T cells during the infection by MTB, is measured via a serological test. Unable differentiate between latent and active infections.	Results within 24 hours with 93% sensitivity	[85,86]
Chest radiography	CXR chest X-ray identification of lung abnormalities.	Cavitation caused by TB bacteria in lung tissue and acute TB pulmonary could be detected easily by using CXR imaging, however, in the extra-pulmonary TB area not able to be recognized using chest radiography.	Results within a few minutes, sensitivity is 93%	[87]
Molecular assays	Detect mycobacterial gene mutations associated with anti-TB drug resistance: 1. Line probe assay (LPA) 2. Nucleic acid amplification technology (NAAT)	1. LPA: Rapid technique based on polymerase chain reaction (PCR) that is used to detect MTB complex as well as drug sensitivity to rifampicin (RPM) and isoniazid (INH) 2. NAAT: Rapid molecular method for detecting tiny quantities of an organism’s genetic material in a particular specimen (genetic material nucleic acids). NAAT method entails amplification inhibition screening.	1. Results within 1–2 days sensitivity 81.3–100% 2. Results within 24 hours and sensitivity 98.2%	[88–91]
Volatile organic compounds test (VOCs)	VOCs in the head space of cultured MTBs were collected on sorbent traps and analyzed using gas chromatography/mass spectrometry (GC/MS).	VOCs in exhale breath serve as tuberculosis (TB) biomarkers since MTB produces VOC metabolites as being detected in the exhale of infected people.	Results within few minutes, an hour, 8 hours, or 24 hours, sensitivity 89.4%	[92, 93]

Table 4 The First- and Second-Line Drugs for TB Treatment

First-Line Drugs	Main Characteristics	Adverse Reactions	Dose Amount	FDA-Approved Year
Isoniazid	Inhabits the synthesis of mycolic acid	Cell wall hepatitis, medication complications, peripheral neuropathy, lupus syndrome.	(5 mg/kg up to 300 mg)	1952
Pyrazinamide	Bactericidal slow metabolizing organism within the acidic area of gaseous granuloma or phagocyte interruption of electron transport across the membrane	Hyperuricemia, gouty arthritis, rarely nephritis	(15–30 mg/kg up to 2 g)	1952
Ethambutol	Cell wall synthesis inhibitor bacteriostatic prohibition transference of arabinosyl	Optic neuritis, exfoliate rash	(15–25 mg/kg)	1961
Rifampin	Block the synthesis of RNA, by blocking the DNA dependent the RNA polymerase	Drug interactions, body fluids becoming orange, GI, hepatitis, fever, severe renal failure, hemolytic anemia	(10 mg/kg upto 600 mg)	1966
Second-Line Drugs	Main Characteristics	Adverse Reactions	Dose Amount	FDA-Approved Year
Streptomycin	Prohibition of the synthesis of protein by an interruption in ribosomal function	Cochlear and vestibular toxicity nephrotoxicity	(15 mg/kg)	1944
PAS	Blocks the synthesis of folic acid	GI toxicity, rash, or fever	(15–20 mg/kg)	1946
Cycloserine	Blocks the synthesis of peptidoglycan synthesis	Dizziness, CNS, or depression	(15–20 mg/kg)	1952
Clofazimine	Mycobacterial DNA and mRNA binding	GI toxicity, ocular discoloration and cutaneous	(100–300 mg/day)	1954
Capreomycin	Blocks synthesis of the protein	Cochlear and vestibular toxicity, nephrotoxicity	(15–30 mg/kg)	1956
Ethionamide	Blocks the synthesis of mycolic acid (cell wall)	GI nausea, toxicity, or hepatitis	(15–20 mg/kg)	1956
Kanamycin	Blocks synthesis of the protein	Cochlear and vestibular toxicity, nephrotoxicity	(15–30 mg/kg)	1957
Amikacin	Blocks synthesis of the protein	Cochlear and vestibular toxicity, nephrotoxicity	(15–30 mg/kg)	1974
Ciprofloxacin	Blocks the DNA gyrase synthesis	Toxicity, CNS or tendon rupture	(750–1550 mg/d GI)	1987
Ofloxacin	Blocks the DNA gyrase synthesis	Toxicity, CNS or tendon rupture	(600–800 mg/day)	1995
Levofloxacin	Blocks the DNA gyrase synthesis	Toxicity, CNS or tendon rupture	(500 mg/day)	1996
Moxifloxacin	Blocks the DNA gyrase synthesis	Toxicity, CNS or tendon rupture	(400 mg/day)	1999
Gatifloxacin	Blocks the DNA gyrase synthesis	GI toxicity, hypoglycemia, CNS	(400 mg/day)	1999

Figure 4 Authorized nanomedicines available on the global markets: (a) Current status of development, (b) indications, and (c) formulation.

Figure 5 BCG vaccination induces an immune response, with MTB-specific effects. (A) BCG is absorbed by DCs or macrophages and could activate the anti-TB immune response when their cell walls perform as PRRs and are connected to a co-stimulatory receptor-ligand. (B) The formation of plasma cells, memory cells, and antigens with particular antibodies is triggered by B cell activation.Memory T and B cells remain in lymph nodes after activation.

Figure 6 BCG vaccination results in the formation of trained immunity.

Figure 7 Theranostic NPs and their functions.

Table 5 The Benefits and Drawbacks of Various Contrast Agents for Nanotheranostic Applications

Nano Theranostic Agents	Application	Advantages	Disadvantages	Ref.
Metal oxide	To construct a theranostic NP, Super paramagnetic iron oxide NPs (SPIONs) must be used and the ability to deliver therapeutic agents at the same time must be incorporated into the NP.	FDA approval for clinical use, ie, Combidex, Ferridex, Gadodiamide, Lumenhance. SPIONs exhibit magnetic properties. The flexible surface is modified with different coatings, therapeutic molecules and dyes.	Not biocompatible Toxic (release of metal ions) Indicated inflammatory symptoms in respiratory systems	[164, 165]
Gold NP	Gold NP formulated as NPs, nano-shells, nanorods, and nanocages with the capability of use in theranostic applications like lung and chronic respiratory disease diagnosis	The size of the NPs determines by the magnitude of the light that is scattered and absorbed. Flexible surface modification with different ligands, dyes, coatings and therapeutic molecules.	Toxic. (Peroxidation of lipid, antioxidants upregulation, expressions of protein and gene of stress response in respiratory systems)	[166,167]
Quantum dots	QD is co-encapsulated in polymeric micellar, or liposomal NPs for theranostic applications.	Narrow wavelength emissions that are size-dependent. Ultra-high photostability with high fluorescent efficiency.	Low biocompatibility. Toxic due to heavy metals (lung injury and inflammation. Lessen cell viability, genetically damages, immune cell disordered)	[168–170]
Carbon nanotubes	Carbon allotrope and fullerenes-like carbon nanotubes (CNTs), graphene, nano-diamonds, and carbon dots are used to diagnose and treat lung and chronic respiratory disorders.	Intrinsic features, providing imaging modalities like NIR and Raman High surface area and inside space for loading drug and bioconjugation.	Low biocompatibility. Toxic; Produce free radicals and caused oxidative stress. Produce reactive oxygen species (ROS) caused chronic granulomatous disease.	[96,171]
Radioisotopes and fluorescents molecules	Positron emission tomography (PET) scans have long used radioisotopes like 11C, 13N, 5O, 18F, and 64Cu) attached to specific biomolecules in order to track their distribution and metabolism throughout the body.	Flexible incorporation with different nanodrug delivery systems. Early diagnosing. Monitoring non-invasive real-time treatment.	Targeting deficiency Short half-life Low biocompatibility. Toxic; Due to radiation exposure had side effect on the function of granulocyte and lymphocyte.	[172]

Table 6 Nanocarriers That Have Been Used for the Treatment of TB

Nanoparticles	Therapeutic Agents	Cell Line (MTT Assay)	Cell Lines (Antimycobacterial Assays)	Ref.
AgZnO	Rifampicin	(THP-1): Human monocytic cell line (MCF-7): Breast cancer cell line.	Escherichia coli	[190,191]
ZnO	Ciprofloxacin and ceftazidime	MRC-5: Lung normal cell line THP-1: Human monocytic cell line.	E. coli bacteria, Staphylococcus aureus	[192, 193]
Graphene oxide (GO)	Ethambutol	(3T3): Eukaryotic cells	Mycobacterium smegmatis cells	[194]
Chitosan nanoparticles (CSNP)and lipid	Bedaquiline (BDQ). Rifampicin	(J774): Macrophage cell lines	Staphylococcus aureus	[195,196]
Poly(lactic-co-glycolic acid) (PLGA)	Clarithromycin	N/A	Staphylococcus aureus, Listeria monocytogenes, Klebsiella pneumonia	[197]
Solid lipid nanoparticle (SLN)	Ethambutol hydrochloride	A549: Adenocarcinomic human alveolar basal epithelial cells	N/A	[198]
Gold nanorods (AuNRs)	Rifampicin	(RAW 264.7): Macrophage cells	N/A	[199]
Polymeric nanoparticle	Pyrazinamide	Animal study on Charles Foster strain rats	N/A	[200]
liposomes	Rifampicin	(A549): Adenocarcinomic human alveolar basal epithelial cells	N/A	[201]
Microspheres poly(lactic-co-glycolic acid)	Moxifloxacin Hydrochloride	Animal study on Male Swiss albino mice	Microplate Alamar Blue Assay on M. tuberculosis	[202]
Silica nanoparticles (SiNPs)	Pretomanid (pa-824) and Moxifloxacin	(Raw 264.7): Monocyte/macrophage-like cells	Monocyte cells infected with M. tuberculosis strain no: H37Rv-GFP	[203]
Carbon nanotube	Isoniazid	N/A	Monocyte cells infected with M. tuberculosis strain no: H37Rv	[204]
Niosomes	Ethambutol	Animal study on Swiss Albino mice lungs Livers and spleens of guinea pigs	Löwenstein–Jensen medium used for culture of Mycobacterium species	[205]
Dendrimer	Rifampicin	(RAW 264.7): Monocyte/macrophage-like cells.	N/A	[206]
Dry powder	Nitroimidazo-oxazine PA-824	Animal study on guinea pigs lung	TB-infected animals	[207]
Cyclodextrins	Rifampicin and Levofloxacin	(RAW 264.7): Monocyte/macrophage-like cells (L929) mouse fibroblast cells	Mycobacterium smegmatis cells	[208]
Nanoemulsions	Rifampicin	N/A	Mycobacterium tuberculosis (strain ATCC 25,618 / H37Rv)	[209]
Nanosuspensions	Clofazimine	Animal study on C57BL/6 mice	Monocyte cells infected with M. tuberculosis strain no: H37Rv	[210]

Tuberculosis drugs and mechanisms of action. National Institute of Allergy and Infectious Diseases. https://www.niaid.nih.gov/diseases-conditions/tbdrugs. Accessed March 1, 2023.

 Google Scholar

Wen Z, Li T, Zhu W, Chen W, Zhang H, Wang W. Effect of different interventions for latent tuberculosis infections in China: a model-based study. BMC Infect Dis. 2021;22:488.

 Web of Science ®Google Scholar

Lee SH. Tuberculosis infection and latent tuberculosis. Tuberc Respir Dis. 2016;79(4):201–206.

 PubMedGoogle Scholar

Esmail H, Barry III CE, Wilkinson RJ. Understanding latent tuberculosis: the key to improved diagnostic and novel treatment strategies. Drug Discov Today. 2012;17(9–10):514–521.

 PubMed Web of Science ®Google Scholar

Vonasek B, Ness T, Takwoingi Y, et al. Screening tests for active pulmonary tuberculosis in children. Cochrane Database Syst Rev. 2020;7. doi:10.1002/14651858.CD013693.pub2

 Google Scholar

Lee SH. Diagnosis and treatment of latent tuberculosis infection. Tuberc Respir Dis. 2015;78(2):56–63.

 PubMedGoogle Scholar

Piccazzo R, Paparo F, Garlaschi G. Diagnostic accuracy of chest radiography for the diagnosis of tuberculosis (TB) and its role in the detection of latent TB infection: a systematic review. J Rheumatol Suppl. 2014;91:32–40.

 PubMedGoogle Scholar

Kiazyk S, Ball T. Tuberculosis (TB): latent tuberculosis infection: an overview. Can Commun Dis Rep. 2017;43(3–4):62.

 PubMedGoogle Scholar

Özüdogru E, Cakli H, Altuntas E, Gürbüz M. Effects of laryngeal tuberculosis on vocal fold functions: case report. Acta otorhinolaryngologica italica. 2005;25(6):374.

 PubMedGoogle Scholar

Lee KM, Choe KH, Kim SJ. Clinical investigation of cavitary tuberculosis and tuberculous pneumonia. Korean J Intern Med. 2006;21(4):230.

 PubMedGoogle Scholar

Ray S, Talukdar A, Kundu S, Khanra D, Sonthalia N. Diagnosis and management of miliary tuberculosis: current state and future perspectives. Ther Clin Risk Manag. 2013;9:9.

 PubMed Web of Science ®Google Scholar

Jeon D. Tuberculous pleurisy: an update. Tuberc Respir Dis. 2014;76(4):153–159.

 PubMedGoogle Scholar

Kelestimur F. The endocrinology of adrenal tuberculosis: the effects of tuberculosis on the hypothalamo-pituitary-adrenal axis and adrenocortical function. J Endocrinol Invest. 2004;27(4):380–386.

 PubMed Web of Science ®Google Scholar

Benjelloun A, Darouassi Y, Zakaria Y, Bouchentouf R, Errami N. Lymph nodes tuberculosis: a retrospective study on clinical and therapeutic features. Pan Afr Med J. 2015;20:65.

 PubMedGoogle Scholar

Johnson JL, Ellner JJ. Tuberculosis and atypical mycobacterial infections. In: Tropical Infectious Diseases. Elsevier Inc; 2006:394–427.

 Google Scholar

Srivastava U, Almusa O, Tung KW, Heller MT. Tuberculous peritonitis. Radiol Case Report. 2014;9(3):971.

 PubMedGoogle Scholar

Daher EDF, da Silva Junior GB, Barros EJG. Renal tuberculosis in the modern era. Am J Trop Med Hyg. 2013;88(1):54.

 PubMed Web of Science ®Google Scholar

Chin JH. Tuberculous meningitis: diagnostic and therapeutic challenges. Neurol Clin Pract. 2014;4(3):199–205.

 PubMedGoogle Scholar

Mayosi BM, Burgess LJ, Doubell AF. Tuberculous pericarditis. Circulation. 2005;112(23):3608–3616.

 PubMed Web of Science ®Google Scholar

Drancourt M, Carrieri P, Gévaudan M-J, Raoult D. Blood agar and Mycobacterium tuberculosis: the end of a dogma. J Clin Microbiol. 2003;41(4):1710–1711.

 PubMed Web of Science ®Google Scholar

Parker RA. Implications of tuberculosis sputum culture test sensitivity on accuracy of other diagnostic modalities. Am J Respir Crit Care Med. 2019;199(5):664–664.

 PubMed Web of Science ®Google Scholar

Pestariati P, Rachmawati M. Solid Media (Lowenstein Jensen) and Liquid Media (Mycobacteria Growth Indicator Tube) Usage Against Mycobacterium tuberculosis Culture in Sputum Suspect Tuberculosis. Health Notions. 2021;5(6):220–224.

 Google Scholar

Abdelaziz MM, Bakr WM, Hussien SM, Amine AE. Diagnosis of pulmonary tuberculosis using Ziehl–Neelsen stain or cold staining techniques? J Egypt Public Health Assoc. 2016;91(1):39–43.

 PubMedGoogle Scholar

Lee JE, Kim H-J, Lee SW. The clinical utility of tuberculin skin test and interferon-γ release assay in the diagnosis of active tuberculosis among young adults: a prospective observational study. BMC Infect Dis. 2011;11(1):1–7.

 PubMedGoogle Scholar

Rose DN, Schechter CB, Adler JJ. Interpretation of the tuberculin skin test. J Gen Intern Med. 1995;10(11):635–642.

 PubMed Web of Science ®Google Scholar

Trajman A, Steffen R, Menzies D. Interferon-gamma release assays versus tuberculin skin testing for the diagnosis of latent tuberculosis infection: an overview of the evidence. Pulm Med. 2013;2013. doi:10.1155/2013/601737

 Google Scholar

Walsh MC, Camerlin AJ, Miles R, et al. The sensitivity of interferon-gamma release assays is not compromised in tuberculosis patients with diabetes. Int J Tuberc Lung Dis. 2011;15(2):179–184.

 PubMed Web of Science ®Google Scholar

Nalunjogi J, Mugabe F, Najjingo I, et al. Accuracy and incremental yield of the chest X-Ray in screening for tuberculosis in Uganda: a cross-sectional study. Tuberc Res Treat. 2021;2021. doi:10.1155/2021/6622809

 PubMedGoogle Scholar

Phillips M, Cataneo RN, Condos R, et al. Volatile biomarkers of pulmonary tuberculosis in the breath. Tuberculosis. 2007;87(1):44–52.

 PubMed Web of Science ®Google Scholar

Vishinkin R, Busool R, Mansour E, et al. Profiles of volatile biomarkers detect tuberculosis from skin. Adv Sci. 2021;8:2100235.

 Web of Science ®Google Scholar

Lee C-N, Wang Y-M, Lai W-F, et al. Super-paramagnetic iron oxide nanoparticles for use in extrapulmonary tuberculosis diagnosis. Clin Microbiol Infect. 2012;18(6):E149–E157.

 PubMed Web of Science ®Google Scholar

Chen Y, Chen H, Zhang S, et al. Structure-property relationships in manganese oxide-mesoporous silica nanoparticles used for T1-weighted MRI and simultaneous anti-cancer drug delivery. Biomaterials. 2012;33(7):2388–2398.

 PubMed Web of Science ®Google Scholar

Zhou Y, Kong Y, Kundu S, Cirillo JD, Liang H. Antibacterial activities of gold and silver nanoparticles against Escherichia coli and bacillus Calmette-Guérin. J Nanobiotechnology. 2012;10(1):1–9.

 PubMedGoogle Scholar

Sani A, Cao C, Cui D. Toxicity of gold nanoparticles (AuNPs): a review. Biochem Biophys Rep. 2021;26:100991.

 PubMedGoogle Scholar

Howell M, Wang C, Mahmoud A, Hellermann G, Mohapatra S, Mohapatra S. Dual-function theranostic nanoparticles for drug delivery and medical imaging contrast: perspectives and challenges for use in lung diseases. Drug Deliv Transl Res. 2013;3(4):352–363.

 PubMed Web of Science ®Google Scholar

Mohanta D, Patnaik S, Sood S, Das N. Carbon nanotubes: evaluation of toxicity at biointerfaces. J Pharm Anal. 2019;9(5):293–300.

 PubMed Web of Science ®Google Scholar

Indoria S, Singh V, Hsieh M-F. Recent advances in theranostic polymeric nanoparticles for cancer treatment: a review. Int J Pharm. 2020;582:119314.

 PubMed Web of Science ®Google Scholar

Jafari A, Mosavari N, Movahedzadeh F, et al. Bactericidal impact of Ag, ZnO and mixed AgZnO colloidal nanoparticles on H37Rv Mycobacterium tuberculosis phagocytized by THP-1 cell lines. Microb Pathog. 2017;110:335–344.

 PubMed Web of Science ®Google Scholar

Ivask A, ElBadawy A, Kaweeteerawat C, et al. Toxicity mechanisms in Escherichia coli vary for silver nanoparticles and differ from ionic silver. ACS Nano. 2014;8(1):374–386.

 PubMed Web of Science ®Google Scholar

Jafari A, Kharazi S, Mosavari N, et al. Synthesis of mixed metal oxides nano-colloidal particles and investigation of the cytotoxicity effects on the human pulmonary cell lines: a prospective approach in anti-tuberculosis inhaled nanoparticles. Orient J Chem. 2017;33(3):1529.

 Google Scholar

Martínez-Carmona M, Gun’Ko Y, Vallet-Regí M. ZnO nanostructures for drug delivery and theranostic applications. Nanomaterials. 2018;8(4):268.

 Web of Science ®Google Scholar

Saifullah B, Chrzastek A, Maitra A, et al. Novel anti-tuberculosis nanodelivery formulation of ethambutol with graphene oxide. Molecules. 2017;22(10):1560.

 PubMed Web of Science ®Google Scholar

Rawal T, Patel S, Butani S. Chitosan nanoparticles as a promising approach for pulmonary delivery of bedaquiline. Eur J Pharm Sci. 2018;124:273–287.

 PubMed Web of Science ®Google Scholar

Prabhu P, Fernandes T, Chaubey P, et al. Mannose-conjugated chitosan nanoparticles for delivery of rifampicin to osteoarticular tuberculosis. Drug Deliv Transl Res. 2021;11(4):1509–1519.

 PubMed Web of Science ®Google Scholar

Öztürk AA, Yenilmez E, Özarda MG. Clarithromycin-loaded poly (lactic-co-glycolic acid)(PLGA) nanoparticles for oral administration: effect of polymer molecular weight and surface modification with chitosan on formulation, nanoparticle characterization and antibacterial effects. Polymers. 2019;11(10):1632.

 PubMed Web of Science ®Google Scholar

Nemati E, Mokhtarzadeh A, Panahi-Azar V, et al. Ethambutol-loaded solid lipid nanoparticles as dry powder inhalable formulation for tuberculosis therapy. AAPS PharmSciTech. 2019;20(3):1–9.

 Web of Science ®Google Scholar

Ali HR, Ali MR, Wu Y, et al. Gold nanorods as drug delivery vehicles for rifampicin greatly improve the efficacy of combating Mycobacterium tuberculosis with good biocompatibility with the host cells. Bioconjug Chem. 2016;27(10):2486–2492.

 PubMed Web of Science ®Google Scholar

Varma JR, Kumar TS, Prasanthi B, Ratna JV. Formulation and characterization of pyrazinamide polymeric nanoparticles for pulmonary tuberculosis: efficiency for alveolar macrophage targeting. Indian J Pharm Sci. 2015;77(3):258.

 PubMed Web of Science ®Google Scholar

Zaru M, Mourtas S, Klepetsanis P, Fadda AM, Antimisiaris SG. Liposomes for drug delivery to the lungs by nebulization. Eur J Pharm Biopharm. 2007;67(3):655–666.

 PubMed Web of Science ®Google Scholar

Vishwa B, Moin A, Gowda D, et al. Pulmonary Targeting of inhalable moxifloxacin microspheres for effective management of tuberculosis. Pharmaceutics. 2021;13(1):79.

 PubMed Web of Science ®Google Scholar

Xia X, Pethe K, Kim R, et al. Encapsulation of anti-tuberculosis drugs within mesoporous silica and intracellular antibacterial activities. Nanomaterials. 2014;4(3):813–826.

 Web of Science ®Google Scholar

Zomorodbakhsh S, Abbasian Y, Naghinejad M, Sheikhpour M. The effects study of isoniazid conjugated multi-wall carbon nanotubes nanofluid on Mycobacterium tuberculosis. Int J Nanomedicine. 2020;15:5901.

 PubMed Web of Science ®Google Scholar

El-Ridy MS, Yehia SA, Kassem MA, Mostafa DM, Nasr EA, Asfour MH. Niosomal encapsulation of ethambutol hydrochloride for increasing its efficacy and safety. Drug Deliv. 2015;22(1):21–36.

 PubMed Web of Science ®Google Scholar

Ahmed RM. Development of Rifampicin Loaded in Surface-Modified 4.0 G PAMAM Dendrimer as a Novel Antituberculosis Pulmonary Drug Delivery System. Elsevier; 2020.

 Google Scholar

Garcia-Contreras L, Sung JC, Muttil P, et al. Dry powder PA-824 aerosols for treatment of tuberculosis in guinea pigs. Antimicrob Agents Chemother. 2010;54(4):1436–1442.

 PubMed Web of Science ®Google Scholar

Basha RY, Doble M. Dual delivery of tuberculosis drugs via cyclodextrin conjugated curdlan nanoparticles to infected macrophages. Carbohydr Polym. 2019;218:53–62.

 PubMed Web of Science ®Google Scholar

Henostroza MAB, Melo KJC, Yukuyama MN, Löbenberg R, Bou-Chacra NA. Cationic rifampicin nanoemulsion for the treatment of ocular tuberculosis. Colloids Surfaces A. 2020;597:124755.

 Google Scholar

Peters K, Leitzke S, Diederichs J, et al. Preparation of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic efficacy in murine Mycobacterium avium infection. J Antimicrob Chemother. 2000;45(1):77–83.

 PubMed Web of Science ®Google Scholar