reviewarticle nanotechnology-based approach in ...surfactant protein a receptors, cd14, scavenger...

Review ArticleNanotechnology-Based Approach in Tuberculosis Treatment

Mohammad Nasiruddin,1 Md. Kausar Neyaz,2 and Shilpi Das1

1Triesta Sciences, HealthCare Global Enterprises Limited, Bangalore 560 027, India2Department of Research and Education, Artemis Hospitals, Sector 51, Gurgaon 122 001, India

Correspondence should be addressed to Mohammad Nasiruddin; [email protected]

Received 1 November 2016; Accepted 28 December 2016; Published 22 January 2017

Academic Editor: Alexander S. Apt

Copyright © 2017 Mohammad Nasiruddin et al.This is an open access article distributed under the Creative CommonsAttributionLicense, which permits unrestricted use, distribution, and reproduction in anymedium, provided the originalwork is properly cited.

Tuberculosis, commonly known as TB, is the second most fatal infectious disease after AIDS, caused by bacterium calledMycobacterium tuberculosis. Prolonged treatment, high pill burden, low compliance, and stiff administration schedules are factorsthat are responsible for emergence of MDR and XDR cases of tuberculosis. Till date, only BCG vaccine is available which isineffective against adult pulmonary TB, which is themost common form of disease. Various unique antibodies have been developedto overcome drug resistance, reduce the treatment regimen, and elevate the compliance to treatment.Therefore, we need an effectiveand robust system to subdue technological drawbacks and improve the effectiveness of therapeutic drugswhich still remains amajorchallenge for pharmaceutical technology. Nanoparticle-based ideology has shown convincing treatment and promising outcomesfor chronic infectious diseases. Different types of nanocarriers have been evaluated as promising drug delivery systems for variousadministration routes. Controlled and sustained release of drugs is one of the advantages of nanoparticle-based antituberculosisdrugs over free drug. It also reduces the dosage frequency and resolves the difficulty of low poor compliance. This paper reviewsvarious nanotechnology-based therapies which can be used for the treatment of TB.

1. Introduction

Despite the remarkable advancement in medical science andtherapeutics, tuberculosis (TB) still remains the primaryfactor of mortality and socioeconomic disaster formillions ofpeople around theworld. It has plagued humankind through-out known history and human prehistory. Tuberculosis is adeadly infectious disease caused by the bacteria Mycobac-terium tuberculosis [1]. Robert Koch in 1882 was awardedNobel Prize for this remarkable discovery. Mycobacteriumtuberculosis (Mtb) is an acid-fast bacillus and intracellularpathogen, which has developed numerous strategies to avoidbeing killed bymacrophages [2, 3]. It is considered as themostsuccessful pathogen capable of persisting in host for decadeswithout causing the disease [4]. Tuberculosis is one of themain causes of mortality and morbidity globally. Accord-ing to World Health Organization (WHO), M. tuberculosis(Mtb) has infected approximately one-third of the world’spopulation, effecting more than 9 million new cases and 2million deaths annually, and the rest of the infected peopleremain asymptomatic [5]. Tuberculosis causes more deathseach year than any other infectious disease and is second

after AIDS among infectious diseases [6]. Therefore, in 1993,WHO declared tuberculosis a global health emergency [7].Mycobacterium primarily attacks the lungs, but it can attackany part of the body, like the kidney, lymphatic system, centralnervous system (meningitis), circulatory system (miliarytuberculosis), genitourinary system, joints, and bones [8].The success and failure rate to treat tuberculosis depends onvarious factors like (a) patient compliance to the treatmenttaken, (b) malnutrition, (c) smoking, (d) coexisting diseaseslike HIV, and (e) inadequate supervision by health care staffs.

The critical problemwith the current tuberculosis chemo-therapy is that when the drug is taken intravenously oradministered orally, it is distributed throughout the body viathe systemic blood circulation and a majority of moleculesdo not reach their targets and, consequently, stay in the bodycausing adverse side effects. Drugs have a short plasma-lifeand rapid clearance, which limits their effectiveness [9]. Todefeat the challenges posed by antituberculosis drugs and torecover the accomplishment rate of tuberculosis treatment,we need to have new tuberculosis drugs (Table 1), which canovercome these challenges.

HindawiTuberculosis Research and TreatmentVolume 2017, Article ID 4920209, 12 pageshttps://doi.org/10.1155/2017/4920209

https://doi.org/10.1155/2017/4920209

2 Tuberculosis Research and Treatment

Table 1: TB drugs development in pipeline.

Discovery PreclinicaldevelopmentClinical development

Phase 1 Phase 2 Phase 3Existing drugsredeveloped orrepurposed for TB

Linezolid,rifapentine

Gatifloxacin,moxifloxacin

New drugsdevelopedspecifically for TB

Nitroimidazole,riminophenazines, translocase-1inhibitor, InhA inhibitor, GyrBinhibitor, LueRS inhibitor,pyrazinamide analogues,

diarylquinoline, spectinamides

CPZEN-45,SQ641, SQ609,DC159a, Q201

AZD5847

Bedaquiline(TMC-207),PA-824,SQ-109,

PNU-100480

Delamanid(OPC67683)

The clinical management of tuberculosis still remainsa difficult task. A large number of tuberculosis endemicareas are being covered for antitubercular treatment (ATT)under directly observed treatment. Short course (DOTS) pro-gram of World Health Organization (WHO) has not beencompletely successful in controlling TB and major burden indeveloping countries of Indian subcontinent and Africa [10].

The major problems associated with treatment of TBare long duration of treatment and continuous and frequentmultiple drugs dosing which leads to low or noncomplianceof patients to current therapy. Low compliance of patientsis the main contributory factor in the reemergence of thedisease and the development of multidrug-resistant (MDR)tuberculosis and more severe form called extensively drug-resistant (XDR) tuberculosis [11]. Moreover, the prevalenceof multidrug-resistant tuberculosis (MDR-TB and XDR-TB)is increasing in developing countries. That causes a challengeto the medical sciences and became matter of great concern.AIDS is again amajor contributor to the increasing incidenceof tuberculosis, providing fertile grounds for Mtb to grow inan immunocompromised host [12].The alarmof spread of theMDR and XDR strains and the lack of successful treatmentoptions strengthen the need to developnew and effective anti-TB drugs to overcome the problemof drug resistance, shortenthe treatment course, and better compliance [13].

2. Different Forms of TB

There are two forms of TB, latent TB and active TB. In latentTB, bacteria remain dormant in body. This phase can last formuch longer time. It is usually treated by taking onemedicinefor 9 months. And, in the active TB, bacteria multiply andspread in the body, thereby causing damage to the tissue [8].

3. Multidrug-ResistantTuberculosis (MDR-TB)

This is onerous form of tuberculosis (TB) defined byresistance to at least two of the standard four drug anti-TBmedicines (first-line antituberculosis drugs) [23]. Inadequateor inconsistent treatment has allowed MDR-TB to emergeand spread quickly. Today, the treatment for drug-resistantTB takes almost two years and, in addition, the treatment is so

complex, expensive, and toxic thatMDR-TB patients struggleto live [24]. Treatment of MDR-TB consists of second-linedrugs. Many second-line drugs are lethal and have harsh sideeffects. Treatment for MDR-TB is administered for 2 yearsor more than that and involves daily injections. All thesecomponents hold a significant challenge to governments andhealth care departments. World Health Organization aimsto treat 80% of the MDR-TB cases by 2015. Without unique,simple, and inexpensive treatments for MDR-TB, this is nextto impossible. WHO predicted that more than 2 million peo-ple would have developed MDR-TB between 2011 and 2015[25].

4. Extensively Drug-Resistant TB (XDR-TB)

XDR-TB poses a major risk to public health. This is morebrutal form of MDR-TB and is characterized by resistance toany fluoroquinolone and at least one of the three injectablesecond-line drugs [26]. This makes this XDR-TB treatmentextremely problematic. In the year 2006, XDR-TB outbrokein KwaZulu-Natal, South Africa; 52 out of 53 people whocontracted the disease died within few months [24]. 70% ofXDR-TB patients were estimated to die within a month ofdiagnosis. Estimation by WHO suggested that roughly 5% ofMRD-TB cases are XDR-TB.

5. Drug Regimens

5.1. First-Line Drugs. In general, tuberculosis is treated withfirst-line drugs as a combination therapy with isoniazid,rifampin, pyrazinamide, and ethambutol for several months.These drugs are administered orally and have outstandingeffectiveness against Mtb [27].

5.2. Second-Line Drugs. When Mtb strain is resistant toisoniazid and rifampin, two of the most powerful first-linedrugs, it develops into more complex form of TB known asMDR-TB. A combination of second-line drugs used to cureMDR-TB is aminoglycosides such as amikacin and kanamy-cin, polypeptides such as capreomycin, viomycin, and envio-mycin, fluoroquinolones such as ciprofloxacin, levofloxacin,and moxifloxacin, and thioamides such as ethionamide,prothionamide, and cycloserine [27]. Second-line drugs are

Tuberculosis Research and Treatment 3

more lethal and are more expensive than first-line drugs, andtreatment may last much longer [8].

5.3. Third-Line Drugs. The third-line drugs for treating TBinclude rifabutin, linezolid, thioridazine, arginine, vitaminD, and macrolides such as clarithromycin and thioacetazone[27]. Like other drugs for the treatment of TB, third-linedrugs are not as effective or their efficacy has not been proven[28]. Third-line drugs are also not listed by WHO. Newadvanced technologies like the design of carrier-based drugdelivery system are under the inspection for treatment of TB.Biodegradable polymers, liposomes, and microsphere weredeveloped in order to reduce the dose and duration of treat-ment [29]. The drugs are gradually released with high con-centration and minimum toxicity as compared to the com-monly used drugs.

Although current anti-TB drugs are effective, urgentstrategies must be developed in order to accomplish deliveryof these drugs. In this context, nanotechnology is one of themost promising passages for development of more decisiveand more effective drug delivery systems for treatment ofTB along with the potent strategy for the development anddelivery of next-generation TB vaccines.

Nanotechnology-based drug delivery system has abil-ity to improve tolerability of noxious chemotherapies, sus-tained and controlled drug release, and eventually increasedbioavailability. Desired particle size required for drug local-ization upon administration by inhalation is between 50 and200 nm.

Phagocytic escape by slow release from lungs and muco-ciliary clearance without inducing any immune responsesare promising key factors of nanosized particles. Rapiddrug absorption through the pulmonary epithelia and highlung bioavailability facilitate the lowering of drug doses andalso maintaining therapeutic concentration. Combination ofsmaller dose with absence of first pass metabolism and pre-vention of gastrointestinal tract is estimated to reduce to sys-temic side effects and increased tolerability. The novel designof anti-TB antibiotics, which is currently followed to deal withthe resistant strains of mycobacterium, is designed as such toshorten the treatment course and limit drug communicationswith other anti-TB and anti-HIV drugs [30]. If managedproperly, first-generation anti-TB drugs can still show betterefficacy. In this context, nanotechnology has emerged as apromising area to rise above the limitations of some of the fol-lowing factors: (a) increased patient conformity and devotionto regimes, (b) main technological margins, and (c) targetingbacterial reservoirs (e.g., alveolar macrophages) [31].

6. Pathogenesis and Immunology of TB

The first stage of tuberculosis is initiated with inhalationof droplets generated by a person with active tuberculosis.These droplets can remain for a longer time in the air. Wheninhaled, a single droplet may be enough to cause the disease.Most droplets end up in the upper respiratory tract, wherethe microbes are killed, but a few penetrate further down.The bacteria reach the alveoli in the lungs, where the alve-olar macrophages phagocytose them. Several receptors are

involved in the uptake process including mannose receptors,Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4),surfactant protein A receptors, CD14, scavenger receptors,complement receptors, and immunoglobulin receptors [32].Sometimes macrophages fail to destroy the bacteria eitherbecause compounds produced by the microbe inactivatethem or because phagosome-lysosome fusion mechanismsare inhibited by M. tuberculosis, thereby avoiding low pHexposure and hydrolytic surroundings of phagolysosomes[33].

In the second stage, mycobacterium multiplies in themacrophage, eventually causing its lysis. This results in thecellular damage which attracts the inflammatory cells andblood monocytes to the area. Monocytes differentiate intomacrophages and attempt to attack the microbe which isingested by the macrophages and grow inside the phagocyte.These macrophages again lyse and die due to bacterial load[34]. Two to threeweeks after infection, the third stage begins.T cell immunity develops, and lymphocytes drift to the regionof infection. Presentation of mycobacterial antigens to theT cells causes their stimulation, resulting in the release of𝛾-interferon and other cytokines. The 𝛾-interferon activatesmacrophages to secrete IL-12, TNF-𝛼, IL-8, and other proin-flammatory cytokines. Fast growth of the Mtb stops and,at this stage, the host cell develops cell-mediated immunity.Those that are outside of cells are resistant to antibody-activated complement attack due to the high lipid contentof mycobacterial cell wall. Cell-mediated immunity is alsoresponsible for much of the pathology of tuberculosis. Tissuedamage can also take place when activated macrophagesrelease lytic enzymes, reactive intermediates, and variouscytokines. It is at this stage that the immune system, specif-ically the macrophages, will enclose the microorganismsinside tubercles. In between these structures, the atmosphereis anoxic and acidic and prevents the growth of mycobac-teria. In-between of these structures is anoxic and acidic,preventing the growth ofmycobacteria.This balance betweenhost and mycobacterium is called latency which is one of thehallmarks of TB. In the fifth and final stage, the tubercles maydissolve by many factors such as malnutrition, immunosup-pression, steroid use, orHIV infection. For unknown reasons,the centers of tuberclesmay liquefy, providing an outstandinggrowth medium for the microbe which now begins to growrapidly in the extracellular fluid.The large number of bacteriaand the immune response against them eventually cause thelung tissue near the tubercles to become necrotic and form acavity [35]. Most tuberculosis infections stop at stage three.

It is an established fact that a cell-mediated immuneresponse involves CD4+ (helper) and CD8+ (cytotoxic) Tcells and both play significant role in protection against TB.Antibacterial activity of macrophages is enhanced by theCD4+ (helper) T cells by releasing cytokines like interferon-𝛾 (IFN-𝛾) and TNF, whereas CD8+ cells destroy infectedmacrophages and possibly Mtb by releasing different cyto-toxicmediators like perforins, granzymes, and granulysin [2].In spite of our enhanced information of immune response toMtb, the type of immune response required for the effectiveimmunity that can be induced by vaccination is not fullyunderstood [36].


7. Nanotechnology-Based Therapies

Over the past few years, the budding use of nanotechnology-based therapy has been researched for replacing theadministration of antibiotics or other drugs in the free formwith an access using drugs that are encapsulated with nano-particle [13].

8. Nanoparticles and Tuberculosis

Nanobead delivery has a remarkable feature of slow, sus-tained, and controlled release from a biodegradable particle.Different animal models have been tried out to develop anantibiotic therapy based on polymer technology against M.tuberculosis but unfortunately not a single model stands upto the expectation or imitates all the features of human TB[31].

The sizes of nanoparticles which are defined as submicron(


Table2:Th

erapeutic

efficacy

ofnano

particle-based

antitub

erculard

rugdeliverysyste

ms.

Delivery

syste

mDrug:

carrier

ratio

Use

oforganic

solvents

Drugencapsulation

efficiency

Mod

eof

delivery

Animalmod

el

Durationof

susta

ined

drug

release(days)

Sterilizing

effectinlung

sandspleen

References

Plasma

Organ

Synthetic

(i)PL

Gnano

particles

1:1for

each

drug

Dichlorom

ethane

60–70%

Oral

Aerosol

Subcutaneous

Mice

Guineap

igs

Mice

6–8

6–8 32

9–11

9–11 36

5do

sese

very

10d

5do

sese

very

10d

Sing

leinjection

[14,15]

[16] [17]

(ii)L

ectin

functio

nalized

PLGnano

particles

1:1for

each

drug

Dichlorom

ethane

60–70%

Oral

Aerosol

Guineap

igs

Guineap

igs

6–14

6–14

15 153do

sesfortnightly

3do

sesfortnightly

[14]

[15]

Natural

(i)Lipo

somes

RIF0.22

:1IN

H0.14:1

Chloroform

,methano

l35–4

5%8–12%

Intravenou

sAe

rosol

Mice,Guinea

pigs

Guineap

igs

5–7 2

7 52do

sese

very

week

singled

osee

very

5–7days

[15,18]

[19]

(ii)S

olid

lipid

nano

particles

1:1for

each

drug

Aceton

e,ethano

l40–50%

Oral

Aerosol

Mice

Guineap

igs

8 510 7

5do

sese

very

10d

7do

sesw

eekly

[20] [21]

(iii)Alginate

nano

particles

7.5:1fore

ach

drug

No

70–80%

Oral

Aerosol

Mice/Guinea

pigs

Guineap

igs

8–11

8–11

15 153do

sesfortnightly

3do

sesfortnightly

[22]

[22]


The lasting circulation of drugs encapsulated in wheatgerm agglutinin-grafted nanoparticles may be because of thefact that lectins improve prolonged adhesion of the particlesto the intestinal shell to permit an increase in the time intervalfor absorption and also increase in the concentration gradientbetween serosal and luminal sides of the membrane [36].

11. Pulmonary Delivery of ATD Nanomedicine

Pulmonary TB is themost ubiquitous formof the disease, andthe respiratory path represents a unique means of deliveringATDs directly to the lungs. Reduction of systemic toxicity andaccomplishing higher drug concentration at the chief site ofinfection are the promising advantages of direct delivery ofdrug to the lungs. Inhalable NPs possess an enhanced abilityofmucosal adherence, particle delivery, and net drug deliveryto the lungs [18, 48].

12. Intravenous Delivery ofATD Nanomedicine

There are three injectable routes of drug delivery. Amongthese, intravenous administration of drugs results in imme-diate availability of all the drug molecules and increasesbioavailability. Other routes like subcutaneous and intramus-cular routes also provide similar bioavailability as comparedto intravenous route [49].

A single subcutaneous injection of PLG nanoparticlesloaded with RMP, INH, and PZA resulted in sustainedtherapeutic drug levels in plasma for 32 days and in lungsor spleen for 36 days. This produced complete sterilizationof organs of Mtb infected mice and demonstrated bettertherapeutic efficacy as compared with daily oral free drugs(35 doses) [19]. This demonstrates the better efficacy ofnanoparticles compared to microparticles. Microparticleswith diameter of more than 1 𝜇m cannot be administered viaintravascular route; however, nanoparticles are small enoughto pass through [50].

Clofazimine is a new promising anti-TB drug for myco-bacterial infection. However, use of this drug was limitedbecause of its less solubility. To defeat this problem, a novelapproach was applied. Clofazimine was formulated as ananosuspension (particle size, 385 nm). Upon intravenousadministration of this formulation, a significant reductionof colony-forming unit count in the liver, spleen, and lungsof mice infected with M. avium was observed [51]. Theeffects of the clofazimine nanocrystalline were found to besimilar to the liposomal formulation used as a control inthis study. This study clearly demonstrates the importanceof nanotechnology to overcome the solubility problems andtoxicity of drugs [52].

13. Liposome-Based Drug Delivery Systems

Liposomes are miniature closed vesicles consisting of phos-pholipid bilayer enfolding an aqueous section [53].They havebeen broadly studied as a promising drug delivery model forbioactive compounds because of their sole ability to encap-sulate both hydrophilic and hydrophobic drugs. To examine

better chemotherapeutic efficacy in animal models like mice,liposomes have been evaluated for the constant deliveryof anti-TB drugs [31, 54]. Few drugs like amphotericin B(fungal infection) and doxorubicin (breast cancer) have beenapproved for human use [55, 56].

When administered, phagocytic cells promptly recognizethese carriers and vacant them from the blood stream. Inorder to avoid removal/clearance and broaden circulationtimes, liposomes are usually PEGylated. An established workdiscovered the incorporation of gentamicin into liposomesand evaluated the antimicrobial activity compared to thatof the free drug in a mouse model of dispersed M. aviumcomplex infection [57]. It was seen that the encapsulateddrug considerably reduced the bacterial load in liver andspleen; however, sterilization was not found. Similar outcomewas obtained with diverse liposome-entrapped second-lineantibiotics [58–60].

Vigorous take-up by alveolar macrophages is effectiveagainst intracellular pathogens with two main advantagesof using liposomes [61]. As liposomes are susceptible tointestinal lipases, they must be administered by either res-piratory means or intravenous route. Nonspecific uptake bymononuclear phagocyte system (MPS) of liver and spleencan be reduced by the inclusion of PEG in the liposomalformulations [21, 62].

Upon administering Mtb infected mice twice a week for6 weeks, it was observed that liposomes encapsulated drugs(rifampicin or isoniazid alone) were more powerful in clear-ingmycobacterial infectionwhen compared to the free drugs.Dose was fruitfully reduced to one weekly administrationfor 6 weeks when these two front-line ATDs were coadmin-istered in liposomes. As per histopathological examination,no hepatotoxicity was reported and was supported by levelsof serum albumin, alanine aminotransferase, and alkalinephosphatase [63].

When INHand rifampin encapsulated in the lung specificstealth liposome were used against Mtb infection, it wasrevealed that liposome encapsulated drugs at and belowtherapeutic concentrationweremore effective than free drugsagainst TB [21].

14. Microemulsions as Potential Anti-TBDrug Delivery Systems

The concept of microemulsions was first introduced by Hoarand Schulman in 1943 [64]. Danielsson and Lindman [65]have correctly defined microemulsion as follows: “micro-emulsion is a system of water, oil and an amphiphile (surfac-tant and co-surfactant) which is a single optically isotropicand thermodynamically stable liquid solution.”

Microemulsions in recent years have gained a lot ofattention for the development and design of new drugdelivery systems because of their thermodynamic stability,high diffusion and absorption rates, ease of preparation, andhigh solubility [66, 67]. They aid in the improvement of drugbioavailability [68], resistance against enzymatic hydrolysis,and reduced toxicity [69]. The droplets of microemulsionsare very small and they are thermodynamically stable.In stable microemulsions, the droplet diameter is usually


within the range of 10–100 nm and hence these systems arealso termed as nanoemulsions [70]. Microemulsions havewide applications in colloidal drug delivery systems for thepurpose of drug targeting and controlled release. Thereare three different types of microemulsions depending oncomposition: (a) oil-in-water (o/w), (b) bicontinuous, and (c)water-in-oil (w/o) microemulsion [71].

Mehta et al. studied the use of tween-based microemul-sion systems for potential application as a drug carrier for theanti-TB drug rifampicin [72]. They formulated microemul-sion composed of oleic acid + phosphate buffer (PB) + Tween80 + ethanol and examined its potential as a delivery systemfor an antitubercular drug.They studied numerous structuralfeatures with various physiochemical methods such as elec-tron microscopy, NMR, optical microscopy, and dissolutionand release kinetics and concluded that microemulsions con-taining Tween 80were successful, since they encapsulated theanti-TB drugs (RIF, INH, and PZA) in different combinationsby means of conductivity and viscosity, with no precipitationor phase separation [72]. In another study, Kumar performedthe inclusion of INH in O/Wmicroemulsion or W/Omicro-emulsion comprising TX100 : AcOH (1 : 1), followed by cetyl-trimethylammonium dichromate (CTADC), chloroform,and water; this microemulsion system presents the opportu-nity of sustained release, increasing drug solubility and bio-availability [73]. Talegaonkar et al. studied ameans of concen-trating RIF by microemulsion for oral drug delivery in orderto make this drug more efficient, which was composed of areaction product of a castor oil and ethylene oxide [74]. Thisstudy established that RIF was effective andmay likely prevailover the problem, since lowering the dose lessens the toxicity.

15. Solid Lipid Nanoparticle-Based Anti-TBDrug Delivery System

Liposomal degradation by intestinal lipases forbids their useby oral route.The SLNs are a nanocrystalline nanosuspensionin water and can be administered orally with many positivekey points like extensive steadiness and better encapsulationeffectiveness than liposomes and polymeric nanoparticlesand the formation process also involves nominal amounts oforganic solvents. In SLN, in order to produce lipid nanopar-ticles, the drug is mainly entrapped in solid lipid matrix [75].The main hallmarks of SLNs are superior tolerability (due totheir origin from physiological lipids), scaling up feasibility,the ability to incorporate hydrophobic or hydrophilic drugs,and an improved stability of incorporated drugs [76].

When compared to liposomes and polymeric nanoparti-cles, SLNs have longer/higher stability and enhanced encap-sulation efficiency and involve minimal quantity of organicsolvents, respectively. A single oral administration of ATD-loaded SLNs to mice resulted in drug identification in theplasma from 3 hrs and lasted up to 8th day [41]. At eachtime peak, plasma drug concentrations were at or abovethe least inhibitory concentration (MIC90), whereas freedrugs were cleared from the circulation within 12 hrs of oraladministration [77].

The chemotherapeutic prospective of the formulationwaspredicted via the respiratory route in Guinea pigs. It was seen

that a prolonged drug release was preserved for 5 days inplasma and for 7 days in organs. Seven doses of the formu-lation resulted in complete clearance of bacilli in replacing 46conventional doses [42]. Further, ATD-loaded SLN was alsoevaluated via oral course and better results were obtained asthe drug level could be retained in plasma for 8 days and inorgans for 9-10 days. InM. tuberculosisH37Rv infected mice,to achieve complete sterilization in the lungs/spleen, 5 oraldoses at every 10th day of drug-loaded SLNs were sufficient,whereas free drug needed administration of 46 daily oraldoses to get the same result. SLN-based antitubercular drugmajorly reduced the dosing rate of recurrence and improvedbioavailability [41].

16. Niosomes-Based Anti-TB DrugDelivery System

Niosomes are thermodynamically stable liposomes like col-loidal particles formed by self-assembly of nonionic sur-factants and hydrating mixture of cholesterol in aqueousmedium resulting in multilamellar systems, unilamellar sys-tems, and polyhedral structures [78, 79]. They are vesicularsystems analogous to liposomes which can be used as carriersof amphiphilic and lipophilic drugs. Niosomes hold all thecharacteristics of liposomes except that they are composed ofa surfactant bilayer with its hydrophilic ends exposed on theoutside and inside of the vesicle to the aqueous phase, whilehydrophobic chains face each other within the bilayer [80].The bilayer system in niosomes is composed of unchargedsingle-chain nonionic surface-active agents, while double-chain phospholipids (neutral or charged) are seen in theliposomal structures.The sizes of niosomes lie in nanometricscale and aremicroscopic.Theparticle size ranges from 10 nmto 100 nm.Niosomes have drawn a lot of interest in the field ofmodern drug delivery systems due to their significant featuressuch as biodegradability, biocompatibility, chemical stability,low production cost, easy storage and handling, and lowtoxicity [81].

Niosomes are one of the most promising carriers that canbe used in targeted drug delivery systems through diverseprincipal schemes of drug targeting. The potential of nio-somes to deliver drugs in a controlled/sustained manner indifferent applications and therapies has led to bioavailabilitydevelopment and continuous therapeutic effect over a longerphase of time [82].

Karki et al. formulated a niosomal drug delivery system ofantitubercular agents such as isoniazid that has exceptionalpotential for development into a low dose performed witheffective treatment for tuberculosis [83]. Niosomes can alsobe used as orally controlled release systems. For exam-ple, antitubercular hydrophilic drugs such as isoniazid andpyrazinamide which are orally active showed sustained drugrelease from the tyloxapol niosome membrane [84].

Rani et al. prepared niosomes of rifampicin and gati-floxacin by lipid hydration technique [85]. They studied thebactericidal activities of the niosomal formulation by theBACTEC radiometric technique using the resistant strain (RF8554) and sensitive strain (H37Rv) of Mycobacterium tuber-culosis which showed inhibition and reduced growth index.


This means that rifampicin and gatifloxacin niosomes pro-vided extensive release of drugs, which was optimum toprovide a decreased dose, fewer days of treatment, and morepatient compliance [85].

Thomas and Bagyalakshmi concluded that all three poly-mers such as Brij-35, Tween 80, and Span-80 used for thesuccessful formulation of pyrazinamide niosomes helpedavoid hepatotoxicity by keeping the cholesterol content con-stant. FTIR results showed that this drug and the polymerused were compatible. It was seen that Span-80 formulationhad the highest percentage release when compared to otherformulations [86].

17. Alginate-Based Anti-TB DrugDelivery System

Guluronic acid and mannuronic acid are the natural copoly-mer of alginic acid. For the supportive treatment of reflexesophagitis, US Food and Drug Administration authorizedthe oral use of alginate. Alginate is a naturally occurringbiopolymer which has been getting louder application invarious fields. It serves numerous purposes like disintegratingand binding agent in tablets, solidifying and suspending agentin water-miscible gels, creams, and lotion, and stabilizer foremulsions. It has various applications such as solidifyingagent, gelling agent, and colloidal stabilizer in food and bever-age industries.There are other diverse properties whichmakealginate an ultimate drug delivery model. These consist of (1)aqueous backgroundwithin thematrix, (2) adhesive interfacewith intestinal epithelium, (3) drug encapsulation processwithout the use of organic solvent, (4) high gel porosity per-mitting high diffusion rate of macromolecules, (5) capacity tocontrol this porosity with easy coating measures using poly-cations, (6) biodegradation of the system under physiologicalconditions, (7) sustained drug release, and (8) being nontoxic.For all the rationales mentioned above, alginate is utilizedas a carrier for the controlled discharge of several moleculesof clinical concern including indomethacin [87], gentamicin[88], insulin [89], anticancer drugs [90], and ATDs [91–93].

González-Rodŕıguez et al. have developed ATD-loadedalginate nanoparticles by means of ionotropic gelation withfairly high encapsulation efficiency ranging between 80 and90% for rifampicin, 70 and 90% for isoniazid and pyraz-inamide, and 88 and 95% for ethambutol [94]. After oraladministration of this formulation, drugs were observed inplasma for 7, 9, 11, and 12 days for ETB, RIF, INH, and PYZ,respectively, and in tissues until day 15, in contrast to freedrugs which were cleared from blood after 12 to 24 hrs andwere detectable in tissues only until day 1 [94]. Oral adminis-tration of 3 dosages fortnightly in Mtb infected mice showedthe complete clearance of bacilli from the organs as comparedto 45 dosages of free drugs [95] which were comparableto the results obtained in Guinea pigs by the oral and therespiratory route [96, 97]. Therefore, these results advocatethe supremacy of alginate NPs over other PLG NPs [43].

In another study, important observations were madewhen chitosan was added to the alginate. Alginate supple-mentedwith chitosan resulted in improved pharmacokineticsand therapeutic efficacy and reduced the drug dose to half

[98]. Another advantage of alginate NP is that it allows moreloading of drugs with lower consumption of polymer.

However, there is some alarm/unease that the organicsolvents used to suspend polymer may have detrimental sideeffects. On the basis of this, alginate, a water-soluble poly-mer which is free from organic solvent and may be preferred,has been used effectively againstM. tuberculosis in the courseof oral and aerosol administration in mice and Guinea pigs[43]. Being hydrophilic in character, alginate avoids swiftclearance by the mononuclear phagocyte system on intra-venous administration. This reports a long circulation half-life. This system shows obvious advantages over the estab-lished neutral polymers or liposomes.

Alginate NPs have been developed and stabilized withpoly(L-lysine)-chitosan, encapsulating ATDs (RIF, INH,PZA, and EMB). The ratio for drug to polymer was kept at7.5 : 1, whichwas considered to be better than PLGNPs, wherethe ratio was 1 : 1. Thus, the alginate formulation allocatesmore loading of the drug with minor consumption of thepolymer. The formulation provides a persistent release for 7–11 days in plasma and 15 days in the organs following a singleoral dose [99].

18. Conclusions and Future Perspective

In developing and underdeveloped countries, infectious dis-eases are foremost issues of health concern. Particularly inthe developing countries, almost one-third of the destitutepopulation does not have proper access to vital medicines.Tuberculosis has a very big impact on developing nations. Inthis scenario, for the effective control of theTB, drug-resistantTB acts as a major challenge. The aim is to find an answer tothis by creating or producing better and more effective drugsthat lessen the period of treatment, reduce drug toxicity, andhave longer bioavailability. Till now, apart from few drugslike quinolones and rifamycins, no major contributions havebeen made to the ATD therapy and certainly an effectiveTB vaccine has also remained equally elusive. The goal is tofind out a solution to eradicate the transmission of causativeorganism but this is difficult, multifarious, and thorny due tothe difficulty of diagnosis, multidrug resistance, and patients’low compliance to treatment. A number of new anti-TBprospective drugs are in channel but the major drawbacksassociated with these drugs include lack of rigorous researchwork, high cost, difficulty in aiming MDR and dormantbacilli, and drugs toxicity. These are the reasons which stim-ulate for the search of new and unique alternative therapeuticdrug. It was observed that nanoparticle-based therapy couldoffer a potential advantage over conventional therapy for TB,which has a great potential to diminish the drug regimenand improve patient’s compliance. The use of nanoparticlesis one of the promising steps taken presently to improvevaccination against TB. Advancements in the nanoparticle-based delivery systems represent a commercial, practical, andmost promising substitute for potential TB chemotherapy.The superior drug bioavailability and therapeutic usefulnessare even at low therapeutic doses of the formulation andperiod of chemotherapy can also be reduced. All theseaspects are vital in substantially curtaining the expenditure


of treatment, reducing interactions with anti-HIV drugs,and improved management of MDR-TB and latent TB. Theabove facts imply the conclusion that nanoparticles havetremendous potential for the treatment of TB.Their foremostadvantages such as long shelf life, dipping of dosing fre-quency, and enhancement of drug bioavailabilitymakeDOTSmore convenient and reasonable. Oral and inhalation routesof drug administration are another reason why it makesnanoparticles more feasible. To conclude, the success of thistechnology will depend on the toxicological profiles linkedwith understanding the fate of polymeric components ofnanocarriers in the body. Based on this opinion, drug carriersmade from natural polymers like alginate and chitosan sug-gest a smart outlook but still they require more explorations.Appropriate clinical studies should be done in order to findout whether or not nanoparticle-based drug delivery systemmight bemuch anticipated solution for improving the patientcompliance in TB chemotherapy.

Competing Interests

The authors declare that there are no competing interests.

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