Development of Immunotherapeutic Nanoparticles for treatment of Tuberculosis

Monesh O. Patil, Yogesh S. Mali, Paresh A. Patil*, D. R. Karnavat

Ahinsa Institute of Pharmacy, Dondaicha, Tal-Shindkheda, Dhule, MS, 425408 India.

*Corresponding Author E-mail: rcp.pareshpatil@gmail.com

ABSTRACT:

Tuberculosis (TB) is a leading infectious disease which causes for morbidity as well as mortality. This communicable infectious disease is caused by Mycobacterium tuberculosis. Nanoparticle-based drug delivery systems have considerable potential for treatment of tuberculosis (TB). The important technological advantages of nanoparticles used as drug carriers are high stability, high carrier capacity, feasibility of incorporation of both hydrophilic and hydrophobic substances, and feasibility of variable routes of administration, including oral application and inhalation.The main aim to develop these novel drug-delivery systems is to improve the patient compliance and reduce therapy time. It also reduces the dosage frequency and resolves the difficulty of low poor compliance. Nanoparticle based treatment shows convincing and promising outcomes in the treatment of tuberculosis. This article discuss various nanotechnology-based therapies which can be used for the treatment of TB

KEYWORDS: Tuberculosis, Nanotechnology, drug delivery system, Feasibility.

INTRODUCTION:

Tuberculosis (TB) is one of the fatal chronic infectious diseases caused by the strains of Mycobacterium tuberculosis, which is a small aerobic non motile bacillus. Despite all the medical advancement in therapeutics, it has been a burden for the past few decades. It is also called Koch’s bacillus (named after the discovery of Robert Koch in 1882) [1]

The TB epidemic is larger than previously estimated with a 10.4 million new incident TB cases worldwide in 2015, of which 5.9 million (54%) were among men, 3.5million (34%) among women and 1.0 million (10%) among children.

In 2015, there were an estimated 480000 new cases of multidrug resistant TB (MDR TB) and an additional 100000 people with rifampicin resistant TB [2].

Mycobacterium is an acid fast bacilli that divide very slowly in about 16 - 20 h compared to other organisms. It primarily attacks lungs (pulmonary TB), it can affect other parts of body like kidney, lymphatic system, central nervous system (meningitis), circulatory system (military TB), genitourinary system, joints and bones.

The conventional treatment of TB involves using first line agents (isoniazid INH, rifampin RIF, pyrazinamide PZA, ethambutol EMB and streptomycin) for a period of 6 months, with follow up to 1 year while the second line agents (kanamycin, amikacin, ethionamide, cycloserine) are often given as injections. These drugs when administered, majority of molecule do not reach their specific sites and accumulate in the body for a long time. Due to this long period of treatment, patient will develop multiple drug resistance, low bioavailability, low therapeutic index and severe side effects such as hepatotoxicity/nephrotoxicity/ototoxicity/ocular toxicity that has led to the emergence of MDR (Multiple Drug Resistant TB) and XDR TB (Extensive Drug Resistant TB).

One of the major problems is noncompliance to prescribed regimens, primarily because treatment of TB involves continuous, frequent multiple-drug dosing. Adherence to treatment and the outcome of therapy could be improved with the introduction of long-duration drug formulations releasing the drugs in a slow and sustained manner, which would allow reduction in frequency and dosing numbers. So we need a system that can improve the therapeutic challenges of the conventional therapy. Nanoparticle drug delivery system represents an ideal method to overcome the failure of the initial therapy, it involves encapsulating the antitubercular drug for eliciting controlled, sustained and more profound effect and circumvent the toxicities prevalent with first line chemotherapy [3]. The primary goals for research of nano-biotechnologies in drug delivery include:

· More specific drug targeting and delivery,

· Reduction in toxicity while maintaining therapeutic effects,

· Greater safety and biocompatibility, and

· Faster development of new safe medicines [4].

The use of different nanotechnology-based drug delivery systems such as Polymeric Nanoparticles (PN), Solid Lipid Nanoparticles (SLNs), Liquid Crystal (LC) systems, Liposomes (LIP), Microemulsions (MEs), Nanomicelles (NAs) and metalbased nanoparticles (gold nanoparticles, silver nanoparticles, iron oxide nanoparticles) is an interesting approach to improve on the most desirable properties of a formulation [3].

What is Tuberculosis?

Tuberculosis caused by mycobacterium tuberculosis is a chronic infectious disease affecting as a killer worldwide. Mycobacterium, from the Greek “mycos”, due to their waxy appearance of their cell walls. It is the second most deadly disease after Human Immune Deficiency Virus (HIV). It is a gram positive organism that grows only inside the cells of host. It mainly attacks the lung causing pulmonary TB. Also it can infest other parts of body such as kidney, lymphatic system, central nervous system, circulatory system, bones and joints. The disease is spread when people who are sick with TB expel bacteria in to the air, for example by coughing.

Epidemiology:

In spite of the major advancement in therapeutics, tuberculosis appears to be a fatal disease in countries like Africa, Latin America and Asia. More than two billion people (about one third of the population) are estimated to be affected with tuberculosis. The TB epidemic is larger than previously estimated with a 10.4 million new incident TB cases worldwide in 2015, of which 5.9 million (54%) were among men, 3.5 million (34%) among women and 1.0 million (10%) among children. In 2015, there were an estimated 480000 new cases of multidrug resistant TB (MDR TB) and an additional 100000 people with rifampicin resistant TB. Now according to the survey TB remains as one of the top 10 causes of death worldwide in 2015 [2].

Aetiology:

The main risk factors for TB include malnutrition, poverty, other debilitating disease such as diabetes, alcoholism and immunocompromised patients (renal failure, cancer, immunocomprimised drugs). HIV infected patients has the more incidence of getting affected by TB. The risk accounts of 10% or more

Mode of Transmission:

Human beings acquire infection with tubercle bacilli by one of the following routes:

1. Inhalation of organisms present in fresh cough droplets or in dried sputum from an open case of pulmonary tuberculosis.

2. Ingestion of development the of organisms tonsillar or leads to intestinal tuberculosis. This mode of infection of human tubercle bacilli is from self-swallowing of infected sputum of an open case of pulmonary tuberculosis, or ingestion of bovine tubercle bacilli from milk of diseased cows.

3. Inoculation of the organisms into the skin may rarely occur from infected postmortem tissue.

4. Transplacental route results in development of congenital tuberculosis in foetus from infected mother and is a rare mode of transmission [1].

Pathogenesis and Immunology of TB:

The first stage of tuberculosis is initiated with inhalation of droplets generated by a person with active tuberculosis. These droplets can remain for a longer time in the air. When inhaled, a single droplet may be enough to cause the disease. Most droplets end up in the upper respiratory tract, where the microbes are killed, but a few penetrate further down. The bacteria reach the alveoli in the lungs, where the alveolar macrophages phagocytize 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 [5]. Sometimes macrophages fail to destroy the bacteria either because compounds produced by the microbe inactivate them or because phagosome-lysosome fusion mechanisms are inhibited by M. tuberculosis, thereby avoiding low pHexposure and hydrolytic surroundings of phagolysosomes [6].

In the second stage, mycobacterium multiplies in the macrophage, eventually causing its lysis. This results in the cellular damage which attracts the inflammatory cells and blood monocytes to the area. Monocytes differentiate into macrophages and attempt to attack the microbe which is ingested by the macrophages and grow inside the phagocyte. These macrophages again lyse and die due to phagolysosomes [7]. Two to three weeks after infection, the third stage begins. T cell immunity develops, and lymphocytes drift to the region of infection. Presentation of mycobacterial antigens to theT cells causes their stimulation, resulting in the release of sigma-interferon and other cytokines. The sigma-interferon activates macrophages to secrete IL-12, TNF-alpha, IL-8, and other proinflammatory 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 content of mycobacterial cell wall. Cell-mediated immunity is also responsible for much of the pathology of tuberculosis. Tissue damage can also take place when activated macrophages release lytic enzymes, reactive intermediates, and various cytokines. It is at this stage that the immune system, specifically the macrophages, will enclose the microorganisms inside tubercles. In between these structures, the atmospheres anoxic and acidic and prevents the growth of mycobacteria. In-between of these structures is anoxic and acidic, preventing the growth of mycobacteria. This balance between host and mycobacterium is called latency which is one of the hallmarks of TB. In the fifth and final stage, the tubercles may dissolve by many factors such as malnutrition, immunosuppression, steroid use, or HIV infection. For unknown reasons, the centers of tubercles may liquefy, providing an outstanding growth medium for the microbe which now begins to grow rapidly in the extracellular fluid. The large number of bacteria and the immune response against them eventually cause the lung tissue near the tubercles to become necrotic and form a cavity [8]. 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-sigma (IFN-sigma) and TNF, whereas CD8+ cells destroy infected macrophages and possibly Mtb by releasing different cytotoxic mediators like perforins, granzymes, and granulysin [10].In spite of our enhanced information of immune response toMtb, the type of immune response required for the effective immunity that can be induced by vaccination is not fully understood [9].

Diagnosis:

Mantoux Test:

It is a purified protein test using tuberculin protein derivative. An amount of 5 tuberculin units is injected intradermally and it should produce a raised tender, red wheal within 48 to 72 h. The area of induration of 5 mm suggests a positive test. To finalize the diagnosis of active TB disease, M. tuberculosis must be detected and isolated from sputum, gastric aspirate, spinal fluid, urine, or tissue biopsy, depending on the site of infection.

Quantiferon TB Gold Test:

In a latent infected individual there occurs the release of INF-gamma which accounts a positive test whereas the test will be negative in blood samples taken from uninfected individual. T cells stimulate release of interferon-γ. The Quantiferon TB Gold and Quantiferon-TB Gold In-Tube tests measure the interferon-γ concentrations released using an enzyme-linked immunosorbent assay [1].

Treatment:

Conventional Drug Therapy:

Drug therapy is the corner stone of patients affected with TB. It features on relieving the signs and symptoms associated with the disease, providing patient adherence to the regimen and complete cure of the disease. To accomplish these goals, treatment must be tailored to each patient’s clinical and social circumstances to ensure adherence to and completion of the treatment regimen (patient centered care). Effective treatment of TB requires a substantial period (minimum 6 months) of intensive drug therapy with at least two active bactericidal drugs. Optimization of this initial phase of treatment prevents emergence of resistance and ensures the success of TB therapy [11].

Drug Regimens:

First-Line Drugs:

In general, tuberculosis is treated with f first-line drugs as a combination therapy with isoniazid, rifampin, pyrazinamide, and ethambutol for several months. These drugs are administered orally and have outstanding effectiveness against Mtb [12].

Second-Line Drugs:

When Mtb strain is resistant to isoniazid and rifampin, two of the most powerful first-line drugs, it develops into more complex form of TB known as MDR-TB. A combination of second-line drugs used to cure MDR-TB is aminoglycosides such as amikacin and tokanamycin, polypeptides such as capreomycin, viomycin, and enviomycin, fluoroquinolones such as ciprofloxacin, levofloxacin, and moxifloxacin, and thioamides such as ethionamide, prothionamide, and cycloserine [12]. Second-line drugs aremore lethal and are more expensive than first-line drugs, and treatment may last much longer [13].

Third-Line Drugs:

The third-line drugs for treating TB include rifabutin, linezolid, thioridazine, arginine, vitamin D, and macrolides such as clarithromycin and thioacetazone [12]. Like other drugs for the treatment of TB, third-line drugs are notaseffective or their efficacyhasnot been proven [14]. Third-line drugs are also not listed by WHO. New advanced technologies like the design of carrier-based drug delivery system are under the inspection for treatment of TB. Biodegradable polymers, liposomes, and microsphere were developed in order to reduce the dose and duration of treatment [15]. The drugs are gradually released with high concentration and minimum toxicity as compared to the commonly used drugs.

Although current anti-TB drugs are effective, urgent strategies must be developed in order to accomplish delivery of these drugs. In this context, nanotechnology is one of the most promising passages for development of more decisive and more effective drug delivery systems for treatment of TB along with the potent strategy for the development and delivery of next-generation TB vaccines.

Nanotechnology-based drug delivery system has ability to improve tolerability of noxious chemotherapies, sustained and controlled drug release, and eventually increased bioavailability. Desired particle size required for drug localization upon administration by inhalation is between 50 and 200nm.

Phagocytic escape by slow release from lungs and mucociliary clearance without inducing any immune responses are promising key factors of nanosized particles. Rapid drug absorption through the pulmonary epithelia and high lung bioavailability facilitate the lowering of drug doses and also maintaining therapeutic concentration. Combination of smaller dose with absence of first pass metabolism and prevention of gastrointestinal tract is estimated to reduce to systemic side effects and increased tolerability. The novel design of anti-TB antibiotics, which is currently followed to deal with the resistant strains of mycobacterium, is designed as such to shorten the treatment course and limit drug communications with other anti-TB and anti-HIV drugs [16]. If managed properly, first-generation anti-TB drugs can still show better efficacy. In this context, nanotechnology has emerged as a promising area to rise above the limitations of some of the following factors: (a) increased patient conformity and devotion to regimes, (b) main technological margins, and (c) targetingbacterial reservoirs (e.g., alveolar macrophages) [17].

Liposomes:

Liposomes are miniature closed vesicles consisting of phospholipid bilayer enfolding an aqueous section [18]. They have been broadly studied as a promising drug delivery model for bioactive compounds because of their sole ability to encapsulate both hydrophilic and hydrophobic drugs. To examine better chemotherapeutic efficacy in animal models like mice, liposomes have been evaluated for the constant delivery of anti-TB drugs [17,19]. Few drugs like amphotericin B (fungal infection) and doxorubicin (breast cancer) have been approved for human use [20,21]. When administered, phagocytic cells promptly recognize these carriers and vacant them from the blood stream. In order to avoid removal/clearance and broaden circulation times, liposomes are usually PEGylated. An established work discovered the incorporation of gentamicin into liposomes and evaluated the antimicrobial activity compared to that of the free drug inamouse model of dispersed M. avium complex infection [22]. It was seen that the encapsulated drug considerably reduced the bacterial load in liver and spleen; however, sterilization was not found. Similar outcome was obtained with diverse liposome-entrapped second-line antibiotics [23,24]. Vigorous take-up by alveolar macrophages is effective against intracellular pathogens with two main advantages of using liposomes [25]. As liposomes are susceptible to intestinal lipases, they must be administered by either respiratory means or intravenous route. Nonspecific uptake by mononuclear phagocyte system (MPS) of liver and spleen can be reduced by the inclusion of PEG in the liposomal formulations [26,27]. Upon administering Mtb infected mice twice a week for 6 weeks, it was observed that liposomes encapsulated drugs (rifampicin or isoniazid alone) were more powerful in clearing mycobacterial infection when compared to thefree drugs. Dose was fruitfully reduced to one weekly administration for 6 weeks when these two front-line ATDs were co-administered in liposomes. As per histopathological examination, no hepatotoxicity was reported and was supported by levels of serum albumin, alanine aminotransferase, and alkaline phosphatase [28]. WhenINH and rifampin encapsulated in the lung specific stealth liposome were used against Mtb infection, it was revealed that liposome encapsulated drugs at and below therapeutic concentration were more effective than free drugs against TB [26].

Solid lipid nanoparticles (SLN):

In SLN, the drug is mainly entrapped in solid lipid matrix to produce lipid nanoparticles of size range 50-1000 nm and they produced using hot or cold high pressure homogenization technique. It is noteworthy that the solid lipid nanoparticles display important advantages, such as the composition (physiologic compounds) and the possibility of large-scale production favored by the feasibility to avoid organic solvents in the manufacturing process [29]. A sterilizing effect was achieved after administration of solid lipid nanoparticles [30]. No tubercle bacilli could be detected in the lungs/spleen after seven doses of treatment of infected guinea pigs with drug loaded solid lipid nanoparticles. Pandey R., developed RIF, INH and PYZ loaded SLN by using emulsion solvent diffusion technique and tested against experimental tuberculosis. SLN formulations following a single oral administration to mice maintained therapeutic drug concentrations in plasma till 8 days and in the organs rich in MPS (lungs, liver and spleen) for 10 days as compared to free drugs which were cleared within 1–2 days. In M. tuberculosis H37Rv infected mice, 5 oral doses at every 10th day of drug loaded SLNs were sufficient to completely suppress bacterial load in the lungs/spleen whereas free drug required administration of 46 daily oral doses to get same effect. SLN incorporated antitubercular drug significantly reduced the dosing frequency and improved bioavailability [30].

Dendrimers:

Dendrimers represent a novel class of structurally controlled three dimensional macromolecules that radiate from a central core and are mainly derived from a branches-upon-branches structural design. Dendrimers are well defined, highly branched macromolecules. Kumar et al. developed mannosylated fifth generation (5G) PPI dendrimeric nanoparticles for delivery of RIF to macrophages. Drug encapsulation mainly depend on hydrophobic interactions and hydrogen bonding contributing to the physical binding of the drug to the core. High haemolysis levels were observed for amine-terminated dendrimers. Mannose on surface significantly reduced the haemolytic toxicity of the nanocarriers from 15.6 to 2.8%. RIF-containing dendrimers reduced haemolytic effect of free RIF from 9.8 to 6.5%. A similar effect was observed in epithelial cell line of kidney when tested for viability; encapsulation significantly improved the survival of the cells from approx. 50% (free RIF) to 85% (RIF dendrimers). The phagocytic uptake of RIF and RIF-loaded dendrimers in alveolar macrophages harvested from rat lungs showed a clear increasein the intracellular concentration of the antibiotic [31]. A more recent reports investigated 4G and 5G PEGylated-PPI dendrimers for sustain the delivery of RIF. PEGylation resulted in a significant increase in drug entrapment for 4th and 5th generation derivatives. PEG-grafted dendrimers showed low haemolytic activity (13%) as composed the NH2-terminated ones (1420%) [32]. Researchers from Monash Institute of Pharmaceutical Science (Melbourne, Australia) developed PEGylated Polysinedendrimers in collaboration with Star pharma Holdings Ltd for cancer, HIV, tuberculosis and lymphatic disease conditions.

Micelles:

Micelles are submicroscopic aggregates (20-80 nm) of surfactant molecules resulting in liquid colloid. Jiang et al., synthesized thermoresponsive poly(ε-caprolactone-coglycolide) poly (ethylene glycol)-poly(ε-caprolactone-coglycolide) (P(CL-GA)–PEG-P(CL-GA)) block copolymers having micelle- forming and gelation properties. They can be used for development of drug depot system. The sol–gel transition temperature was optimized by selecting optimized GA/CL ratio and length of the hydrophobic segments.RIF sustained release was obtained over 32 days from 25% gel matrix [33]. INH-poly (ethyleneglycol)–poly (aspartic acid) conjugates were studied for sustain release of the drug. A 5.6-fold increase in anti-tuberculosis activity against M. tuberculosis was found for micelle-forming prodrug as compared to the free drug [34]. Similar attempts were made to incorporate PYZ and RIF in micelles (<100 nm) aiming to minimize renal filtration and prolonging mean residence times in the blood stream with improved antimicrobial activity [35,36]. INH lipid derivatives was designed by Jin et al. to reduce the resistance. The new amphiphilic molecules resulted in formation of monolayers at the air/water interface. Flexible medium-long tails formed self assembling nano-sized vesicles whereas short lipid tail-derivatives resulted in weak hydrophobic interactions. Lipid vesicles showed increased penetration of the drug into the pathogen leading to promising antibacterial activity against Mycobacterium [37].

Solubilization of RIF within polymeric micelles of various linear and branched PEOPPO was studied and found to increased about 2 fold depending upon RIF entrapment. Other studied amphiphilic block copolymers of different molecular weight further improved the solubilization of RIF by 5 to 7 fold [38]. Furthermore, drug-loaded stereocomplex micelles were developed by Chen et al. using the specific assembly of enantiomeric poly (ethylene glycol)poly(L-lactide) (MPEG-PLLA) and poly(ethylene glycol)-poly(D-lactide) (MPEG-PDLA) block copolymers (1:1 ratio of L-PLA- and D-PLAcontaining block copolymers). An increase in the length of the PLA segment resulted in lower CMC values and larger nano-aggregates. Developed stereocomplexes showed improved RIF loading and encapsulation efficiency than enantionerically pure micelles. Stereo complex released t50% between 4-8 hours and t100% after 48 h, which can be further manipulated according to polymer molecular weight [39].PLA-modified chitosan oligomers sphericalmicelles (154 to 181nm) were prepared by Wu et al. Developed RIF chitosan oligomer micelles showed initial burst drug release of 35% within 10 h followed by more sustained drug release till 5th day suggesting suitability of carrier for prolonged anti-TB activity with reduced toxic effects [40]. Pulmonary tuberculosis causes lung fibrosis and alveolar collapse due to a dysfunction of pulmonary surfactant. Nanoparticles of pulmonary surfactant (surface tension of approx. 25-30mN/m) canbe employed as delivery agents for the anti-tubercular drugs to the infected lung tissue. Anti-tubercular drug loaded surfactants nanoparticles for inhalation therapy wereproposed by Chimoteet al. These nanoparticles act as anti-atelectatic agents and can stabilize the alveoli integrity by preventing alveolar collapse thereby allowing drug to reach the diseased alveoli uniformly in a non-invasive manner. Such nanoparticulate aerosols would be a significant improvement over existing therapies in pulmonary tuberculosis [41,42].

Nanoemulsions:

Nanoemulsion, many times referred as miniemulsions or sub-micronemulsions by dispersing mainly oil in water. Thermodynamically stablenanoemulsion (mean particle size of 80.9nm andpolydispersity index of 0.271) of ramipril, were developed for oral administration. In vitro drug release showed that drug release till 24 h from nanoemulsion and was highly significant (p<0.01) as compared to marketed capsule formulation and drug suspension. The relative bioavailability of ramipril nanoemulsion to that of conventional capsule was 229.62% and to drug suspension was 539.49 suggesting the use of developed ramipril nanoemulsion for pediatric and geriatric patients [43]. In another study, they investigated effect of Labrasolon self-nanoemulsification efficiency of ramipril nanoemulsion [44]. Ahmed et al., developed various parenteral o/w nanoemulsions of RIF (47 and 115nm) using GRAS listed excipients (US-FDA). The entrapment efficiency was found to be 99% with excellent stability over 3 months with slight increase in particle size and showed initial burst drug release of 40 to 70% after 2 h [45]. Mehta et al. performed physicochemical analysis of INH microemulsions and confirmed the release of drug from microemulsion was non-Fickian [46]. In another study, the same group studied the changes in the microstructure of Tween 80-based microemulsion in the presence of anti-TB drugs viz. INH, PYZ (pyrazinamide), and RIF [46].

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Received on 31.03.2020 Modified on 18.04.2020

Asian J. Pharm. Res. 2020; 10(3):226-232.

DOI: 10.5958/2231-5691.2020.00039.8