|Year : 2022 | Volume
| Issue : 2 | Page : 96-104
Isoniazid nano-drug delivery systems targeting macrophages for the treatment of tuberculosis
Sree Lakshmi Vemula, Mahima Tejasvni Gupta
Department of Pharmacy, Birla Institute of Technology and Science, Hyderabad, Telangana, India
|Date of Submission||09-Feb-2022|
|Date of Decision||13-May-2022|
|Date of Acceptance||18-May-2022|
|Date of Web Publication||15-Jun-2022|
Ms. Mahima Tejasvni Gupta
Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal, Hyderabad - 500 078, Telangana
Source of Support: None, Conflict of Interest: None
In the current clinical setting, the management of Mycobacterium tuberculosis remains a challenge. Isoniazid (INH) remains a drug of choice for treating tuberculosis (TB) via the conventional oral route. However, INH has low plasma levels due to its poor permeability into the bacterial cell. Furthermore, it has a short half-life of 1–4 h, indicating a brief residence in the plasma. Therefore, multiple administration frequencies at high doses are required, leading to multi-drug resistance and other side effects like nephrotoxicity. Lungs being the main target organ for TB, a pulmonary route of administration could be an alternative route to overcome such shortcomings. Due to multiple clearance mechanisms and biological barriers that restrict the entry of particles into the respiratory system, the pulmonary route of drug administration may not always be efficient. Thus, the era of nanotechnology has emerged as one of the most promising approaches to developing various drugs for overcoming such challenges. This review article highlights the anatomy and physiology of the lungs, the barriers to the pulmonary drug delivery system, and how these barriers decide the drug disposition at the target site. In addition, the various properties of the drug delivery systems such as size, shape, and charge have been discussed in the subsections, followed by various formulation-based drug delivery systems for INH, including preclinical investigation studies.
Keywords: Drug delivery system, isoniazid, Mycobacterium tuberculosis
|How to cite this article:|
Vemula SL, Gupta MT. Isoniazid nano-drug delivery systems targeting macrophages for the treatment of tuberculosis. J Prev Diagn Treat Strategies Med 2022;1:96-104
|How to cite this URL:|
Vemula SL, Gupta MT. Isoniazid nano-drug delivery systems targeting macrophages for the treatment of tuberculosis. J Prev Diagn Treat Strategies Med [serial online] 2022 [cited 2022 Aug 19];1:96-104. Available from: http://www.jpdtsm.com/text.asp?2022/1/2/96/347547
| Introduction|| |
Tuberculosis (TB) is a highly contagious disease caused by the micro-organism Mycobacterium tuberculosis (Mtb) primarily affecting the lungs. The standard treatment recommended by the World Health Organization for TB is the first-line agents such as isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZA), ethambutol for a minimum of 2–6 months administered orally and second-line agents such as levofloxacin and moxifloxacin are administered orally or parenterally. Long treatment regimens may prove to be unsustainable due to noncompliance by the patient, due to multidrug resistance, rendering the drug ineffective, and severe drug toxicity such as gastrointestinal gastritis, loss of hearing, hepatotoxicity, and bone marrow toxicity.,,,
| Isoniazid: The Needful Drug in Present Times|| |
INH is still considered a first-line drug for more than six decades due to its effectiveness in combating TB. It is a prodrug that functions only after the conversion reaction mechanism by the mycobacterial enzyme KatG., To overcome drug resistance, “drug cocktail” treatment consisting of INH along with other drugs such as PZA and ethambutol is considered., Despite its combined therapy, INH effectiveness is reduced due to the oral route of administration, which leads to adverse systemic effects. Since the lungs signify as the main target for TB treatment, the drugs can be administered directly into the lungs which minimize the risks caused by systemic effects and also increases drug concentration at the target site.,, For efficient drug delivery, these active drug particles have to be deposited on the luminal surface of the epithelial membrane and absorbed into the lungs before elimination.
Hence, one needs to understand the process of absorption through this route due to its constrained anatomical and physiological barriers in the pulmonary system. Nanotechnology is the most promising passage for the effective delivery of drugs. The drug properties such as particle size, shape, and charge also play an important role in crossing the barriers.,,,, This review article discusses the anatomy and physiology of healthy lungs and TB-infected lungs, the types and effects of biological barriers on drug deposition at the target site, and the properties of the delivery system. Further, we discussed the recent updates on various INH delivery systems in both preclinical and clinical investigations.
| Anatomy and Physiology of the Lungs|| |
The respiratory system consists of a pair of lungs that facilitate gaseous exchange. Two layers of thin serous membranes cover the lung's surface called the pleura. These layers converge at the hilum, creating the space between the layers called the pleural hollow that secretes the pleura fluid to lubricate and decrease the friction between the layers of the lungs during contraction and relaxation of the lungs. The bronchi are further branched into small bronchioles carrying a tiny air sac at their tip called alveoli that facilitate gaseous exchange. This mechanism of gaseous exchange of oxygen and carbon dioxide into and out of the lungs is called breathing or pulmonary ventilation.
| Pulmonary Route of Drug Administration|| |
Thia route involves drug administration through the mouth and nose directly into the lungs via aerosol (inhalation). The aerosol dosage form is the most commonly used inhalation technique that provides uniform distribution and better drug penetration. Drug absorption by this route involves gravitational sedimentation, inertial impaction, and diffusion, which greatly depends on the nature of the drug and particulate systems. Further, it depends on the particles' other geometric properties, such as the electrical charge and particle shape. However, all these properties are greatly influenced by the lungs' anatomical and physiological barriers, which may block the entry of the particulate systems due to its natural defense mechanism to block foreign particles.
| Pulmonary Barriers Affecting the Delivery of Drugs|| |
One of the greatest challenges for delivering drugs into the lungs is the permeation of the molecules to the target site across the alveolar and epithelial barriers, consisting mucus layer, epithelial layer, basement membrane, and the capillary endothelium, of which, the alveolar region is the most targeted tissue for any drug delivery. [Figure 1] for diagramatic representaion of the various pumonary barriers.
|Figure 1: Biological Barriers of Human lung: (a) The surfactant above the pseudostraified cells of the airways facilitate in mucociliary clearance ,(b) the surfact over the alveolar surface facilitate in macrophage clearance|
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Air blood barrier (alveolar barrier)
The blood-air barrier is a thin tissue; expanding over 600 nm − 2 μm, allowing sufficient oxygen diffusion. This alveolar barrier facilitates in gaseous exchange across the alveoli. The surfactant layer between the alveolar and epithelial layers significantly increases the gas exchange mechanism in the blood capillaries and the alveolar region as it reduces the surface tension., Due to the mucus/surfactant layer, the molecules need to be solubilized and stabilized to cross the barrier. In addition, the cilia facilitate in washing out the drug particles by the mucociliary mechanism. Thus, this improves permeation and reduces drug loss.
The epithelial barrier consists of ciliated cells, mucous-secreting cells, and undifferentiated basal cells. A mucosal epithelium surface protects the subepithelial tissue from toxins and pathogens. It facilitates maintaining the homeostasis of the lungs. The tight epithelial barrier is composed of pneumocytes connected by tight junctions that restrict the entry of particles <100 nm via passive diffusion., It acts as physical and immunological barriers affecting the interaction between cytokines and growth factors with their receptors.
| Delivery System Properties across Pulmonary Tissues|| |
Recent studies have been reported to understand the permeation properties of delivery systems with different molecular sizes, shapes, and charges. The following section deals with the permeation studies of delivery systems with different properties.
A particulate system is defined as a substance of size ranging from 0.001 to 100 μm, delivered through inhalation via aerosol or any liquid suspension. The mechanism of drug deposition into the lungs based on the particle size is of four types: diffusion, sedimentation, impaction, and interception., Fine particles smaller than 0.5 μm undergo a diffusion through Brownian motion More Details facilitating drug deposition at the alveolar region.,, Particles ranging between 1 and 5 μm undergo sedimentation due to gravitational forces, particle velocity, and aerodynamic size. Aerosol particles on inhalation pass through the humid airways, leading to the formation of micro-sized particles that eventually deposit in the bronchiolar region. The particles of size >5 μm undergo impaction for drug deposition in the bronchioles. Dry powder inhalation and metered dose inhalators are commonly used by the impaction mechanism. If the particles are inhaled slowly, they get deposited for longer periods inside the alveolar region. It has been reported that drug particles of tobramycin and pentamidine which are of small particle size of < 200 nm, reside in the lungs for a long time. [Figure 2] for diagramatic representation.
|Figure 2: Particle size determines the particles' deposition site in the lung|
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Any type of aerosol possess an electrical charge when released from any device like a nebulizer or metered-dose inhaler device. Drug particles possessing electrostatic charge have increased deposition in the lungs.,, Clinical investigation showed that the aerosol deposition in the lungs was increased due to the charge.,, Particles of size lesser than 5 μm can penetrate better into the narrower airways and alveolar regions by generating electrostatic charges that facilitate its deposition into the alveolar walls. In a study, smaller particles' net charge can be increased up to 200 electrons for better particle deposition in the alveolar region. On the other hand, more charge is required to increase for larger particles to achieve a desirable deposition effect.
The particle shape affects the absorption in the lungs. It has been reported that needle-shaped particles increase the adhesion of the drug in the lungs., Similarly, the benefits of highly fine particle fraction benefits were observed with pollen-shaped particles with less drug loss. In a study, immunoglobulin G anisotropic polystyrene particles of various shapes such as a sphere, rectangular disc, elliptical disc, and oblate ellipsoid have been developed. When macrophages were attached to the minor axis or flat surface of the elliptical disc, phagocytosis did not happen even after 2 h. Rectangular discs and oblate ellipsoids, show the same results except for sphere-shaped particles, as phagocytosis occurred immediately. On further investigation of the same study under in vitro conditions, it was observed that no phagocytosis effect occurred in worm-like structures due to low curvature, unlike those of spherical structures. Thus, phagocytosis was observed only when the worm-like structure was aligned to the major axis as it possessed large curvatures.
| Formulation-based Drug Delivery Systems: Preclinical Investigations|| |
The variation in the size of microparticles and nanoparticles offers them the ability to encapsulate more drugs and improve the drug's bioavailability when administered orally. Thus, the smaller the particle size, the larger the absorption ability of the encapsulated particle into the targeted tissues. This subsection will discuss various formulation-based drug delivery systems on INH concerning the preclinical studies. [Figure 3] for diagramatic representation of various nanoparticles administered for INH delivery.
|Figure 3: Schematic illustration of INH various delivery systems used for tuberculosis treatment. INH: Isoniazid|
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Solid lipid nanoparticles
Solid lipid nanoparticles (SLNs) are the most used colloidal systems. They offer improved stability, bioavailability, and capacity to hold both lipophilic and hydrophilic drugs, and to increase the lymphatic transport of drugs. In a study, SLNs encapsulated INH of different charges were investigated for relative bioavailability. Results showed that particle size decides the permeation and retention of the particle into the lungs. Its charge also determines the circulation time, metabolism, and clearance as the plasma proteins stick with the SLNs to form soft halo-like structures which present them to the mononuclear phagocyte system in the liver and spleen to promote their quick elimination.
The same group recently investigated the acute toxicity study of INH-loaded COMBI-SLNs. Results showed excellent bioavailability and three times LD50 higher than INH alone. Similarly, results from behavioral and hematological tests of the selected low, medium, and high doses showed no adverse effect of hepatotoxicity or peripheral neuropathy. In a study, SLNs encapsulated INH with Technitium 99 in Wistar rats showed that the labeled INH could retain in the body for a longer time compared to free INH. This encapsulated INH-SLNs could improve the level of INH to the lungs with less frequency of dosing than INH alone.
The role of mannose receptors on the surface of alveolar macrophages is one of the vital targets to enhance local drug delivery for anti-TB agents. Fluorescent mannosylated SLN showed high efficiency for internalization compared to free SLNs. In addition, the uptake study showed that it was decreased when used with the pre-incubated cells with mannose. This indicates the receptor-dependence internalization of the mannosylated SLN could be a future platform for targeting the alveolar macrophages for anti-TB treatment.
Liposomes (LPs) have been known as one of the oldest and simplest delivery systems to incorporate first-line drugs for the anti-TB study. These are composed of phospholipid bilayer as the main building block with an aqueous core at its center. The structure of LPs can be compared to a soap bubble which is a spherical vesicle with a diameter varying from 0.02 to 2.5 μm. LPs are recognized by the phagocytic cells in the bloodstream and are cleared off quickly. To increase their residence time in the bloodstream, LPs are usually PEGylated. LPs offer a significant advantage as nanoparticles since they are very similar in structure to the bilayer of the cell membrane. Thus, LPs can easily interact and incorporate into the cells and facilitate in easy transfer and release of the drugs into the cells. In a study, INH was encapsulated and characterized in LPs using soybean lecithin. The average size of the INH-LPs was found to be in the range of 813 nm. This was due to an increase in the proportion of phospholipids during the purification process of soybean lecithin, which is promising for the targeted anti-TB activity. Later, the group extended the study by incorporating a complex system of INH-hydrazone-phthalocyanine conjugate in gamma-cyclodextrin. Using a simple heating method, the formulation was further characterized in the in vitro study at an acidic medium (4.4) and neutral (7.4) pH medium. The results show that the complex had a slow-releasing ability in the neutral medium compared to the acidic medium. This showed that the above complex delivery system could be a promising carrier for INH. Lately, the group has continued the study by grafting a phthalocyanine with cyclodextrin complex to the INH-LPs. On encapsulation with RIF (Rif-complex-LPs), the complex was released at a higher level for both INH and RIF at 6.4 pH than the neutral pH of 7.4. Moreover, the cytotoxicity study with HeLa cell lines showed no toxicity, and Rif-Complex-LPs were internalized by peripheral lung fibroblast and epithelial cells. Therefore, Rif-Complex-LPs are excellent carriers for the lung targeted delivery system.
Microparticles are polymeric spherical-shaped particles of size ranging from 1 to 1000 μm, which can be produced naturally or synthetically from biodegradable polymers such as chitosan, poly (lactic) acid, and others. These particles are preferable due to their higher stability and increased capacity to load the drugs., Microparticles are often used as pulmonary drug delivery systems as they deposit easily deep inside the lungs and do not form agglomerates. In a study, microparticles incorporated with INH and INH methanesulfonate were prepared by the precipitation method with a compressed anti-solvent process. The study aims at delivering the drug and targeting the alveolar macrophages. The size of the microparticle range between 1 and 3 μm bearing a spherical shape and coated with cationic hydrophobic ions to understand the release kinetics of the drug. Furthermore, the in vivo rat model was used to investigate how the microparticles can target the alveolar microparticles. These microparticles showed sustained and targeted INH delivery to the alveolar macrophages. These results suggest that polymeric microparticles could be useful for treating pulmonary TB. Thereby the frequency of dosing and toxicity can be reduced. Similarly, microparticles encapsulated with INH and INH polymeric particles (INH-PM) were investigated for pulmonary drug delivery. The study compares the drug deposition of INH and INH-PM into the lungs by performing a cascade impaction study. The in vitro release study showed that the INH microparticles prepared from poly-ɛ-caprolactone exhibited control release characteristics in the lungs. In contrast, the results of cascade impaction suggest the inhaled characteristics of INH and INH-PM of particle sizes ranging from 1.9 to 4 μm provide a deep deposition into the lungs.
Polymeric micelles are another form of nanocarriers developed in contact with water, where amphiphilic polymers give rise to polymeric micelles. They are self-assembled to core-shell nanostructures., A comparison study on micelles containing polymers of ethylene Oxide-Propylene oxide and Pluronics was performed. Results showed that micelles enhance anti-mycobacterial activity. The study was further investigated in caco2 monolayer cell lines for the permeability study, which shows better absorption and permeability into the cells than free drugs. Similarly, another study reported on the polymeric micelles encapsulated with Hydroxyl methyl PZA, INH, and Rifampin, tested against various strains of Mtb. Results showed that the polymeric micelles give promising results as anti-mycobacterial activity. In another study, INH and RIF were encapsulated in polymeric micelles containing polyethylene glycol-poly-L-lactic acid (PLA) tested against Mtb showed good activity.
Nanotubes are hollow tubular-shaped structures that resemble empty carbon tube. These are made from carbon, with a diameter of an approximate size of <100 nm. It has been reported that carbon nanotubes have more capability to penetrate deep inside the tissues and overcome most of the biological barriers. In a study, INH was loaded into halloysite nanotubes and investigated for the release study and cytotoxicity. Results showed that the release study gives a uniform and prolonged release of INH from the delivery system and that there was no interference in the biological function of INH by the nanotubes. These findings suggested that they could provide an effective treatment for wound-healing TB ulcers. Recently, another study was reported on a novel method of multi-wall carbon nanotubes incorporated with INH prepared by a reflux system process for anti-tubercular activity. Results showed that the formulation exhibited a better activity at lower concentrations than the parent drug INH alone against the Mtb strains.
PNPs are one of the most common drug delivery systems opted for anti-TB drugs due to their incredible drug solubility, stability, and specific targeting. These are some of the best techniques for drug encapsulation due to their stability, ability to administer through different routes, and flexibility to load either/hydrophilic or hydrophobic drugs. Two systems can be produced based on their production process: nanocapsules and nanospheres. Nanocapsules are prepared by solubilizing the drug in aqueous or oily solvents and are encapsulated in a polymeric membrane. Nanospheres are composed of solid matrices of variable porosity, in which the active molecules are homogeneously distributed throughout the nanosphere and dispersed at the molecular level. A few of the early dosage forms developed using nanotechnology for the controlled release of INH incorporate INH in polymers such as poly (methyl methacrylate), poly (vinyl chloride), and carbomer. Further, Eudragit S was also used as capsulation material for sustained release. Apart from this, polymers such as PLA, PGA, and PLG ([PLA], [PLGA]) have exceptional biocompatibility, biodegradability, and mechanical strength. Hence, all these polymers facilitate sustaining persistent plasma levels of INH
In the previous study, sustained release of RIF, INH, and PZA from orally administered poly (lactide-glycolide) (PLG) nanoparticles. Within 9–11 days of administration of the drug, the therapeutic dose was attained in the tissues and complete clearance of the bacterial infection was observed after five doses for every 10th day in the mice. To improve the efficiency of the nanoparticles, the surface of the nanoparticles is modified using wheat germ agglutinin. Lecithin grafted PLGA NPs in the above case helped in the sustained release of the drug and the plasma life of the drug extended up to 6–14 days. Lecithins provide added advantages such as enhancing mucoadhesion, faster biorecognition by glycosylated structures in the intestine, and increased serum half-life of the drug. Following this, the author experimented with the same nanoparticles of the same three drugs via the pulmonary route. The drug release rate was comparatively lower through the pulmonary route. However, agglutinin surface-modified NPs were given three doses every 14 days for 45 days, which has increased the efficacy of the drug with decreased drug dose and duration. In another study, a mesoporous silica nanoparticle (MSNP) drug delivery system was reported which was prepared with polyethylene (PEI) and included cyclodextrin PH based which works only at acidic pH to release INH into the Mtb infected macrophages. It was tested against toxicity and observed that the PEI-coated MSNP showed better bactericidal activity against the Mtb-infected macrophages as compared to INH alone. [Table 1] briefly describes the recent applications of the above mentioned nanoparticles. [68,]
|Table 1: Various Nano drug delivery systems available for isoniazid formulation|
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| Conclusion|| |
The management of TB remains a challenge due to multi-drug resistance. INH is a drug of choice which is still considered to date for the management of TB or in combination with first-line agents. However, despite its advantages, INH is associated with limitations like poor drug penetration into the bacteria cell due to hydrophilicity. Therefore, with the emergence of pulmonary drug delivery systems of INH, such as SLNs, LPs, nanoparticles, micelles, and nanotubes, there seem to be promising results against these limitations. The delivery systems have shown potent results and improvement of drug efficacy to penetrate inside the lungs. Numerous efforts are going on to develop potent INH delivery systems for effective delivery of INH into the lungs to treat TB.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]