In the course of 5 decades, tuberculosis stays at its most elevated peak in the event of mortal cases revealed. This manuscript is given with an aim to update the information on tuberculosis, its pathogenesis and antitubercular chemotherapies which have been being used to prevent and cure it currently. Rising rates of tuberculosis and its high resistance toward drugs has created a need to discover better diagnostic tools and effective vaccines. This article reviews the currently available relevant publications elaborating the approach of nanoparticles futuristically in reference to diagnosis, treatment and prevention of tuberculosis. This review covers the prospect of using nanotechnology-based drug delivery systems for effective eradication of mycobacterial infections. Drug loaded polylactide-co-glycolide (PLGA) nanoparticles shows long-term stability and target only infected cells without harming the normal cells. Drug delivery using nanoparticle was previously successfully used for cancer treatment but it may also be used for treatment of tuberculosis. Transferring drug by using biodegradable nanoparticles would turn out to be a beneficial approach to stop TB epidemic.

Keywords: Mycobacterium tuberculosis, alveolar macrophages, nanotechnology, plga nanoparticles, polylactide-co-glycolide

TB, tuberculosis; M. tuberculosis, Mycobacterium tuberculosis ; HIV, human immunodeficiency virus; NPs, nanoparticles; MDR, multidrug-resistant; XDR, extremely drug-resistant; PLGA, poly(lactide-co-glycolide); PLA, poly lactic acid; PGA, poly glycolic acid; INH, isoniazid; RIF, rifampicin; PZA, pyrazinamide; DC’s, dendritic cells

Around the world, tuberculosis (TB) remains the second most continuous irresistible malady causing dreariness and demise after the human immunodeficiency infection (HIV). 33% of the total populace is contaminated with Mycobacterium tuberculosis H₃₇Rv (M. tuberculosis), the etiologic specialist of TB. In an investigation, a gauge is given by WHO that around 8-10 million new TB cases are accounted for every year worldwide and the event of TB is at present is as yet expanding .¹ TB is accounted for to be the ninth essential source of death worldwide and the central reason from a solitary and specific irresistible operator, notwithstanding positioning over HIV/AIDS. Drug resistant TB is a proceeding with danger. In 2016, 6 lacs new cases were accounted for resistant from rifampicin (RIF), which is the best first-line treatment drug, besides of which 4, 90,000 had multidrug-resistant TB (i.e. MDR-TB). Half (47%) of these cases were in India, China and the Russian Federation. Universally, the TB death rate is falling at around 3% every year. TB rate is falling at around 2% every year; this needs to enhance to 4-5% every year by 2020 to accomplish the initial (2020) points of reference of the End TB Strategy² TB bacilli live and multiply inside lung macrophages, the plain cells that have advanced to inundate and wreck microorganisms that achieve the surface of the lungs alongside breathed in air.³ A few components have developed by M. tuberculosis to beat the foe condition of the essential host cell i.e. Macrophage.⁴ The normal qualities of the TB bacilli involve the developement: it develops with a moderate development rate; it indicates torpidity; it creates complex cell envelope; it maintains through intracellular pathogenesis; characteristic of hereditary homogeneity. In aggregation with thick peptidoglycan layer, novel biosynthesis pathways deliver an assortment of other cell wall components which incorporates mycolic acids, mycocerosic corrosive, lipoarabinomannan and arabinogalactan, which intensely mean mycobacterial life span, trigger provocative host responses and assume a vital job in its pathogenesis.⁵ TB mortality has diminished since 1990; yet considerably additionally difficult circumstance has occurred i.e. the expansion of multidrug-resistant (MDR) and extensively drug resistant (XDR) strains of M. tuberculosis, which is a severe wellbeing challenge. Medication delicate TB can be dealt with a half year of chemotherapy with the present four-drug cutting edge regimen. MDR-TB can be restored with no less than 18– two years of treatment utilizing 4-6 drugs, including a fluoroquinolone and one injectable specialist is required. XDR strains of M. tuberculosis moreover are impervious to fluoroquinolones and somewhere around one second line drug.⁶ Two types of TB exists i.e. latent TB and active TB. In inactive TB, microscopic organisms demonstrates lethargy in human body and this stage stays for longer time; it tends to be dealt by having one pharmaceutical for 9-10 months and in the event of active TB, microbes repeats and spreads in the body, in this way making harm the host cells.⁷ The treatment of tuberculosis and other mycobacterial infections with chemotherapy is an exceptionally difficult assignment. Nanoparticle-based frameworks have huge planned for determination, treatment and aversion of TB.⁸

Nanotechnology in treatment of tuberculosis

Regardless of the overall accessibility of tuberculosis (TB) drugs, long length of the treatment, genuine unfavorable impacts, poor patient consistence and the rise of multidrug safe strains, demonstrates that the recognizable proof of novel antituberculars, the adjustment of existing medications and the improvement of new medication conveyance frameworks to abbreviate TB chemotherapy are direly required.⁹ Nanotechnology gives the best stage to pharmacology which gives a conclusion to end answer for the outlining of medication conveyance framework which is fit to target phagocytic cells defiled by intracellular pathogens, e.g. mycobacteria. Nanocarrier based enemy of TB treatment incorporates a controlled and managed drug delivery framework, expanding bioavailability of the counter TB tranquilize, lessening symptoms, and upgrading blood circulation time.¹⁰ Nanoparticles as drug transporters encourage higher soundness and higher bearer limit related to monstrous advancement of drug bioavailability that further coordinates to reduction in dosage amounts.¹¹ The fundamental plan to build up these novel medication conveyance frameworks is to enhance the patient consistence and diminish treatment time. The fruitful utilization of nanoparticle in various medication conveyance frameworks relies upon their diverse physicochemical properties and their capacity to cross through few anatomical hindrances inside body.¹² Directed conveyance of solution to the lungs is exceedingly attractive, particularly in the patients with particular aspiratory infections, for example, cystic fibrosis, asthma and tuberculosis; the standard favorable circumstances of utilizing nanoparticles for tranquilize conveyance is to diminish orderly symptoms and utilization of higher concentration of the drug at the focused on the targeted site.¹³ NP's can be intended to fortify as well as smother the invulnerable reactions. An association between NP's and insusceptible framework can be advantageous for different medicinal applications, for example, immunizations and therapeutics for some provocative sicknesses.¹⁴

Immunology of TB

In people, TB is transcendently an ailment of the lungs. M. tuberculosis contamination begins with the inward breath of irresistible microorganisms and their residence in the alveolar space of the lungs. The microorganisms are taken up by phagocytes in the lung, specifically by alveolar macrophages and dwell inside intracellular phagosomes.¹⁵ In the wake of spreading its disease in the alveolar macrophages; these macrophages begin to show numerous biomarkers on their surface which initiates the inborn resistant framework. These distinctive particular biomarkers help the drug stacked nanoparticles to focus on the infected macrophages or to join with particular macrophages.¹⁶ These receptors are for the most part conceivably fascinating for focusing on nanoparticles to TB-pertaining macrophages. Under perfect conditions, pathogen-encasing phagosomes combine successively with ahead of schedule and afterward late endocytic organelles to wind up bactericidal phagolysosomes. Be that as it may, M. tuberculosis can deflect phagosome development and phagosome– lysosome combination, therefore maintaining a strategic distance from presentation to the lower pH and hydrolytic condition of the phagolysosomes. Changed resistant framework will invigorate lymphocytes to deliver a multitude of lymphocytes despite the fact that they will most likely be unable to obliterate M. tuberculosis, they stay wary to counteract dynamic contamination.¹⁷ A few components have been embroiled in the capacity of M. tuberculosis to capture phagosome development; however our comprehension of this procedure is a long way from finish. Macrophages are entering into effector cells in mycobacterial executing yet can likewise give a specialty to M. tuberculosis augmentation. DCs inundating M. tuberculosis relocate to the depleting lymph nodes and take effector T cells that in way to come back to the lungs to control the contamination. These occasions prompt the arrangement of the granuloma at the site of disease. The exemplary TB granuloma is comprised of a focal center of tainted macrophages encompassed by epithelioid, frothy macrophages and a fringe edge of lymphocytes (B cells and T cells) in relationship with a tough covering of extracellular network laid by fibroblasts  (Figure 1 & Figure 2).¹⁸

Figure 1 Survival methodology of tuberculosis in host macrophages and development of granuloma during tb progression.

TB is transmitted in droplet aerosols and has waxy coat that protects it from drying out. Inhaled viable M. tuberculosis bacilli are internalized by alveolar macrophages and instead of forming phagolysosomes, the bacilli are protected in alveolar macrophages & undergo rapid replication. Active bacilli trigger a pro-inflammatory response which leads to the recruitment of neighboring lymphocytes & neutrophils, thus forming a cellular matrix of Granuloma. A lymphocytic cuff that is largely comprised of B and T cells characterizes the periphery of the granuloma, including neutrophils, foamy macrophages, dendritic cells & natural killer (NK) cells. Reactivation of infection occurs in the case where the core enclosing the bacilli breaks & releases infectious active M. tuberculosis into lungs airways

Figure 2 Advancement of nanoparticle in case of drug delivery.

Macrophages are particularly effective in internalizing foreign particles & delivering the particles to the acidified endosomes. Drug loaded PLGA nanoparticles are internalized by M. tuberculosis infected macrophages and drug by is then to be released intracellulary into the macrophages to kill bacterium more effectively than an equivalent amount of free drug. Nanoparticle-mediated targeted delivery of therapeutic agents induces selective apoptosis of targeted cells without harming the normal cells. This would reduce treatment related side effects & enhance the quality of life in infected person.

Mycobacterial growth in macrophages is restricted by PLGA nanoparticles

Biodegradable poly (lactide-co-glycolide) (PLGA) polymers have been considered broadly for the controlled arrival of peptide and protein drugs. It is the most alluring competitor used to manufacture gadgets for controlled drug conveyance applications.¹⁹ PLGA is the most ordinarily utilized FDA endorsed polymer for biodegradable and biocompatible controlled discharge molecules.²⁰ Polyester PLGA is a copolymer of poly lactic acid (PLA) and poly glycolic acid (PGA). It is the best characterized biomaterial accessible for drug transfer as for plan and execution.²¹ PLGA copolymer experiences corruption through cleavage of its spine ester linkages into oligomers, lactic and glycolic acid monomers. This has been appeared in both in vivo and in vitro for different drug composes and proteins with different polymer extents.²² The drug conveyance particular vehicle, i.e., PLGA, can pass on its payload with fitting length, biodistribution and center for the proposed supportive effect.²³ PLGA NPs are successfully phagocytosed by human alveolar macrophages²⁴ and we have seen ground-breaking microbicidal impacts when they convey a payload of hostile to TB drugs.²⁵ In spite of the fact that the macrophage is the effector cell in the host reaction to M. tuberculosis, it is likewise the specialty cell for the bacillus; where the bacterium can reproduce before causing cell mortality and proceeding onward to taint different cells.²⁶ Along these lines, Phagocytosis of NPs by macrophage allows the executed focused killing of intracellular bacilli. Such a breathed in approach can improve the feasibility of TB treatments by diminishing the repeatation of dosing and growing neighborhood testimony of the counter tubercular specialist.²⁷ PLGA is most outstanding among the different accessible biodegradable polymers by virtue of its long clinical experience, ideal corruption attributes and potential outcomes for maintained medication conveyance.²⁸ The other essential central purposes of PLGA based nano plan are their long-time span of usability, their ability of all courses of organization and adaptable debasement energy of the polymer; this polymer go about as archive and discharges the medication gradually after some time interval.²⁹ Nanoparticles (NPs) on entering the living structure instantly associate with proteins which serve various employments of nanoparticles including bio-signaling, therapeutics and drug delivery system.³⁰ In one of the examinations, wheat germ agglutinin-functionalized PLGA nanoparticles were used for in vivo conveyance of INH, RIF, and PZA for deferred entry of drug, allowing less continuous dosing to accomplish a remedial impact in cells.¹⁶ Nanoparticles of PLGA are having estimation lower than 10 microns in measurement and therefore accordingly could be accessible for coordinate phogocytosis into monocytes, leukocytes macrophages and different cells of endothelium framework.³¹ Drugs can be combined into PLGA nanoparticles by three techniques. Drugs can be joined inside the PLGA nanoparticles over the span of arrangement, medications might be consumed on performed PLGA nanoparticles or medication might be synthetically bound to PLGA Nanoparticles.^32,33 This component of conveyance of medications by utilizing nanoparticles made up of biodegradable material decidedly helps in showing signs of improvement treatment against tuberculosis by encouraging the delivery system using nanoparticles decreases toxicity and other cell harm.

Nanoparticle drug delivery system can possibly overhaul the momentum of TB ailment treatments, these particles having various special attributes which make them most encouraging stages for conveyance of medication. Nanoparticles can be thought to be the most favorable material as a medication conveyance vehicle; one nanoparticle can be used by various bioactive atoms, these particles can be connected on to the surface of particular biomolecules to deliver focused on cells and to discharge sedate. PLGA nanoparticle as a medication conveyance vehicle for the counter tuberculosis drugs thought to be more practical to slaughter M. tuberculosis more adequately than a comparable measure of customary medication.

The authors acknowledge financial support from the Department of Science and Technology-SERB, Council of Scientific and Industrial Research-Institute of Genomics and Integrative Biology under the research project GAP0145.

There is no conflict of interest.

1. Tomioka H, Namba K. Development of antituberculous drugs: current status and future prospects. Kekkaku. 2006;81(12):753–774.
2. World health organization. Global tuberculosis report. 2017.
3. Muttil P, Sharma R, Misra A, et al. Inhalable microparticles containing large payload of anti-tuberculosis drugs. Eur J Pharm Sci. 2007;32(2):140–150.
4. Meena LS, Rajni. Survival mechanism of pathogenic Mycobacterium tuberculosis FEBS J. 2010;277(11):2416–2427.
5. Cole ST, Brosch R, Parkhill J, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature. 1998;393(6685):537–544.
6. Anguru MR, Taduri AK, Bhoomireddy RD, et al. Novel drug targets for Mycobacterium tuberculosis: 2-heterostyrylbenzimidazoles as inhibitors of cell wall protein synthesis. Chemistry Cent J. 2017;11(68).
7. Bhowmik D, Chiranjib RM, Jayakar B, et al. Recent trends of drug used treatment of tuberculosis. Journal of Chemical and Pharmaceutical Research. 2009;1(1):113–133.
8. Mathuria JP. Nanoparticles in tuberculosis diagnosis, treatment and prevention: A hope for future. Digest Journal of Nanomaterials and Biostructures. 2009;4(2):309–312.
9. Horváti K, Bacsa B, Kiss É, et al. Nanoparticle encapsulated lipopeptide conjugate of antitubercular drug isoniazid: in vitro intracellular activity and in vivo efficacy in a guinea pig model of tuberculosis. Bioconjug Chem. 2014;25(12):2260–2268.
10. Kumarasingam K, Vincent M, Mane SR, et al. Enhancing antimycobacterial activity of isoniazid and rifampicin incorporated norbornene nanopaticles. Int J Mycobacteriol. 2018;7(1):84–88.
11. Qasim M, Lim DJ, Park H, et al. Nanotechnology for diagnosis and treatment of TB. J Nanosci Nanotechnol. 2014;14(10):7374–7387.
12. Singh J, Garg T, Rath G, et al. Advances in nanotechnology-based carrier systems for targeted delivery of bioactive drug molecules with special emphasis on immunotherapy in drug resistant tuberculosis. Drug Deliv. 2016;23(5):1676–1698.
13. Çağdaş M, Sezer AD, Bucak S. Liposomes as Potential Drug Carrier Systems for Drug Delivery. Application of Nanotechnology in Drug Delivery. 2014.
14. Zolnik BS, González FA, Sadrieh N, et al. Nanoparticles and the Immune System. Endocrinology. 2010;151(2):458-465.
15. Bhatt K, Salgame P. Host innate immune response to Mycobacterium tuberculosis. J Clin Immunol. 2007;27(4):347–362.
16. Shivangi, Meena LS. A Novel Approach in Treatment of Tuberculosis by Targeting Drugs to Infected Macrophages Using Biodegradable Nanoparticles. Appl Biochem Biotechnol. 2018;185(3):815–821.
17. Vergne I, Chua J, Singh SB, et al. Cell biology of Mycobacterium tuberculosis Annu Rev Cell Dev Biol. 2004;20:367–394.
18. Griffiths G, Nystrom B, Suraj B, et al. Nanobead-based interventions for the treatment and prevention of tuberculosis. Nat Rev Microbiol. 2010;8(11):827–834.
19. Houchin ML, Topp EM. Chemical Degradation of Peptides and Proteins in PLGA: A Review of Reactions and Mechanisms. J Pharm Sci. 2008;97(7):2395–2404.
20. Schwendeman SP. Recent advances in the stabilization of proteins encapsulated in injectable PLGA delivery systems. Crit Rev Ther Drug Carrier Syst. 2002;19(1):73–98.
21. Makadia HK, Siegel SJ. Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier. Polymers (Basel). 2011;3(3):1377–1397.
22. Ramchandani M, Robinson D. In vitro and in vivo release of ciprofloxacin from PLGA 50:50 implants. J Control Release. 1998;54(2):167–175.
23. Yang YY, Chung TS. Morphology, drug distribution, and in vitro release profiles of biodegradable polymeric microspheres containing protein fabricated by double-emulsion solvent extraction/evaporation method. 2001;22(3):231–241.
24. Lawlor C1, Kelly C, O'Leary S, et al. Cellular targeting and trafficking of drug delivery systems for the prevention and treatment of MTb. Tuberculosis (Edinb). 2011;91(1):93–97.
25. Lawlor C, O'Sullivan MP, Rice B, et al. Therapeutic aerosol bioengineering of targeted, inhalable microparticle formulations to treat Mycobacterium tuberculosis (MTb). J Mater Sci Mater Med. 2012;23(1):89–98.
26. Ramakrishnan L. Revisiting the role of the granuloma in tuberculosis. Nat Rev Immunol. 2012;12(5):352–66.
27. Lawlor C, O'Connor G1, O'Leary S, et al. Treatment of Mycobacterium tuberculosis-Infected Macrophages with Poly (Lactic-Co Glycolic Acid) Microparticles Drives NFκB and Autophagy Dependent Bacillary Killing. PLoS One. 2016;11(2):e0149167.
28. Podinovskaia M, Lee W, Caldwell S, et al. Infection of macrophages with Mycobacterium tuberculosis induces global modifications to phagosomal function. Cell Microbiol. 2013;15(6):843–859.
29. Shafik N, Kondel R, Malhotra S. Tuberculosis and nanotechnology where shall the twain meet? J Postgrad Med Edu Res. 2013;47(4):188–192.
30. Meena J, Singh M, Sahare PD, et al. Interaction of Nanoparticles in Biological Systems and their Role in Therapeutical Treatment of Tuberculosis and Cancer. Journal of Luminescence and Applications. 2014;1(1):7–22.
31. Shive MS, Anderson JM. Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv Drug Deliv Rev. 1997;28(1):5–24.
32. Poecheim J, Barnier Quer C, Collin N, et al. Ag85A DNA Vaccine Delivery by Nanoparticles: Influence of the Formulation Characteristics on Immune Responses. Vaccines (Basel). 2016 Sep;4(3). pii: E32.
33. Tanwar M, Meena J, Meena LS. Nanoparticles: scope in drug delivery- Book title: Advanced Biomaterials and Biodevices, (Advanced Materials Book Series).14:487–452.