Particulate Systems for Administration of Vaccines and Therapeutics

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Silvia Andrea Moreno-Mendieta	--	2877	2023-08-24 22:35:29	\|
2	references update	Fanny Huang	Meta information modification	2877	2023-08-28 07:12:43	\|

This entry is adapted from the peer-reviewed paper 10.3390/microorganisms11081988

The use of particles to develop vaccines and treatments for a wide variety of diseases has increased, and their success has been demonstrated in preclinical investigations. Accurately targeting cells and minimizing doses and adverse side effects, while inducing an adequate biological response, are important advantages that particulate systems offer. The most used particulate systems are liposomes and their derivatives, immunostimulatory complexes, virus-like particles, and organic or inorganic nano- and microparticles.

delivery systems particulate systems tuberculosis vaccines

1. Introduction

Particulate systems are important biotechnological tools that have had an enormous impact on biomedical applications, including basic research, imaging, theranostics, and especially therapeutic or vaccine design and delivery ^[1]^[2]. The materials and preparation methods of particles define their physicochemical characteristics, such as their size, shape, and charge, which in turn define their biodistribution, targeting, release profiles, toxicity, accumulation time, and clearance ^[3]. Other properties, such as bioavailability, biodegradability, biocompatibility, and bioadhesiveness, are influenced by the intrinsic properties of the particles and their route of administration ^[4]^[5]. Currently, almost all routes of administration can be used to deliver particulate systems, including oral, transdermal, intravenous, subcutaneous, topical, intranasal, and pulmonary routes, the last of which is particularly important for tuberculosis (TB) treatment and prophylaxis because inhalable formulations are the most effective to induce a memory immune response in the lungs ^[6]^[7]^[8].

2. Particulate Systems for Tuberculosis Vaccine Development

Greater comprehension of the roles that immune cells play in response to Mycobacterium tuberculosis (Mtb) infection is of vital importance for the development of vaccines against this pathogen ^[9]. For many years, exhaustive efforts have been made to modify, improve, or find an alternative to the BCG vaccine ^[10]^[11]. This vaccine, the only anti-TB vaccine approved in humans, confers effective protection against disseminated and meningeal TB only in children, with variable protection in adults. The factors that mainly affect its protective efficacy include coinfections with viruses or parasites, comorbidities, environmental factors, intrinsic genetic factors of both mycobacteria and humans, and, importantly, the route of vaccination^[12]^[13]^[14]. After intradermal vaccination, the BCG vaccine interacts with resident epidermal macrophages, whereas Mtb interacts, in most cases, with resident alveolar macrophages (AMs) and does not suffer opsonization. Consequently, antigenic recognition, uptake, processing, and presentation are different, with implications for the induction of the T-cell memory response required for protection against lung disease ^[12]. This complex situation has justified the administration of the BCG vaccine directly into the respiratory system as a strategy to induce resident memory T cells in the lung ^[15]^[16]^[17] and the exploration of new vaccines against TB that can be administered by nasal or pulmonary routes, which favor the retention of the antigen at mucosal sites, the induction of systemic and mucosal immunity, and, importantly, the development of lung-resident memory T cells. These are important advantages of mucosal vaccination and, of course, an opportunity for the use of particulate systems ^[18]^[19].

2.1. Immune Activation Induced by Mycobacterium tuberculosis and Particulate Systems

After inhalation, mycobacteria in the deep lung (alveoli) can interact through pattern recognition receptors (PRRs) with AMs and dendritic cells (DCs). Mycobacterial endocytosis leads to the activation and maturation of these cells and the migration of DCs toward the lung-draining lymph nodes for antigenic presentation and the differentiation of T lymphocytes toward a Th1 type. Th1 cells contribute to the elimination of bacilli and create a positive feedback loop by secreting IFN-γ, which in turn activates more macrophages, enhancing the microbicidal response against Mtb by executing functions including the secretion of microbicidal factors and cytokines such as TNF-α ^[20]^[21]. In the same way, particles formulated in prophylactic or therapeutic vaccines can also interact with and activate innate immune cells, increasing their mycobactericidal performance to prevent or combat the infection. Particles can also promote endocytosis by professional phagocytes, induce the production of cytokines and microbicidal factors such as nitric oxide and reactive oxygen species (ROS) ^[22]^[23], or induce apoptosis and autophagy ^[24]^[25]^[26], which together are very important mechanisms to eliminate bacilli.

Importantly, these particulate formulations can be administered by several routes, such as parenteral, nasal, and pulmonary, protecting the antigen and supplying it to immune cells, and they can also be engineered to have intrinsic immunostimulant activity that increases the microbicidal performance of cells. In such scenarios, they can act as delivery systems, adjuvants, and immunostimulants, simultaneously or separately, which is highly desirable for the formulation of subunit vaccines against TB. For this purpose, the most used nano- and microparticles include natural and synthetic polymeric capsules and spheres (mainly of chitosan and poly(lactide-co-glycolide) (PLGA)) ^[27], followed by liposomes and derivatives, solid lipid nanoparticles (SLNs), and immune-stimulating complexes (ISCOMs) ^[28]^[29]^[30].

2.2. In Vitro and In Vivo Evaluation of Particulate Tuberculosis Vaccines

When particles are added into a vaccine formulation, in addition to antigens and adjuvants, in vitro preclinical studies are necessary to characterize the particles’ properties, their capacity to transport and release antigens, and their stability, safety, and efficacy in the formulation in terms of the immune response induced in cell lines or primary isolates ^[31]^[32]. For instance, one of the most complete in vitro characterization studies was carried out on the subunit vaccine candidate ID93 ^[31]^[33]. The authors used the recombinant TB antigen ID93 (composed of three immune-dominant antigens and one latency-associated antigen) conjugated to a modified liposome (mGLA-LSQ). This liposome has intrinsic adjuvant properties because it contains the TLR4 agonist glucopyranosyl lipid adjuvant (GLA) and the saponin QS21. The authors demonstrated that the vaccine was stable and bioactive for 3 months, being able to induce the secretion of IL-2, INF-γ, and TNF-α in a cytokine stimulation assay using fresh whole blood from 10 healthy donors ^[33]. Most of the time, and if the formulation is successful in vitro, the next step is to test it in vivo. These studies are more robust in exploring the immune response generated after administration by different routes and are a requirement to proceed to clinical phase studies. In the last decade, most of the particulate TB vaccine candidates tested have contained polymeric particles that encapsulate, accompany, or present the antigen on their surfaces and have been administered by the parenteral or mucosal routes.

In contrast to the growing number of preclinical phase studies conducted with particulate TB vaccine formulations, progression to clinical phase trials is scarce. Ongoing clinical trials of new TB vaccines were recently reviewed by Saramago et al. . Based on their review, and in researchers' search, only two particulate vaccine candidates have progressed to clinical studies: ID93+GLA-SE and GamTBvac. Coler et al., conducted a randomized, double-blind phase I study in 60 healthy non-TB-exposed non-vaccinated adults. The purpose was to evaluate two dose levels of the ID93 antigen, administered intramuscularly alone or in combination with two different doses of the GLA-SE adjuvant. The vaccine was safe and well tolerated under all regimes and induced antigen-specific IgG responses in subjects that also received the adjuvant. The use of the adjuvant also enhanced the magnitude and cytokine profile of polyfunctional CD4⁺ T cells ^[34]. Tkachuk et al., in 2020, conducted a phase II study with 180 healthy volunteers previously vaccinated with BCG and immunized subcutaneously twice at 8-week intervals with their vaccine, GamTBvac. This was a particulate system composed of a multi-antigen fusion protein (the TB antigens Ag85A-ESAT6-CFP10 and a dextran-binding domain) immobilized on dextran NPs and a CpG adjuvant. The vaccine was also safe and well tolerated and induced antigen-specific IFN-γ release, augmented Th1 cytokine-expressing CD4⁺ T cells, and a higher IgG response in vaccinated subjects ^[35].

3. Disadvantages of Conventional Treatments for Tuberculosis and Opportunities for Particulate Formulations

After infection, the main objective is to target the mycobacteria that are present inside macrophages, which the immune system is unable to eliminate. It would also be relevant to target the bacteria that are present inside neutrophils or DCs, with therapeutic agents. However, most of the WHO-recommended drugs for TB treatment, which show variable permeability, are administered by oral or intravenous routes, implying that they are present at high concentrations in serum but not in the lungs. This partially explains their lower effectiveness in pulmonary disease treatment and their higher toxicity . Additionally, Mtb not only survives inside the cells but also in the granuloma, the complex multicellular structure formed as a result of the host immune response, and drugs must also permeate these structures and reach the mycobacteria that are contained within them . Importantly, prolonged treatments for drug-susceptible TB (6 months of isoniazid and rifampicin, with the addition of pyrazinamide and ethambutol in the initial 2 months) and drug-resistant TB (between 9 and 24 months depending on the strain) become very toxic, increase secondary adverse effects, and therefore decrease patient adherence to the treatment scheme ^[36].

One way to overcome or at least partially resolve these problems is to use engineered carriers for the directed administration of TB drugs, such as liposomes, solid lipid nanoparticles (SLNs), and polymeric micro- and nanoparticles . The physicochemical characteristics of these particles, mainly but not exclusively the size, surface charge, and functionalization, are crucial in the design and must be considered together with the route of administration. Particularly for the treatment of TB, the inhalation route is of interest to target resident AMs loaded with bacteria. In this regard, several investigations have been developed to find the ideal characteristics that a particle must have to reach this cell population and deliver its load . Another important advantage of this route of administration is that it mimics the course of bacterial spread: because the AMs are the first cells to phagocytize Mtb and drug-containing particles upon inhalation, they traffic them to the lung interstitium and travel to the site at which the bacteria tend to migrate, which can guarantee the directed and controlled release of anti-TB drugs and, consequently, a more precise dosage with fewer side effects ^[37].

3.1. In Vitro Evaluation of Particulate Tuberculosis Drug Delivery Systems

In the same way as for evaluating particulate vaccines, in vitro assays are also required for the preclinical investigation of anti-TB treatments formulated with particles. Each study has its limitations and advantages, but they are essential in determining the safety and efficacy of these systems. In vitro studies are also very important to standardize and achieve particles with an optimal aerodynamic diameter for pulmonary delivery, ensuring deposition in the apical and deep regions of the lung. These studies are also critical in characterizing the physicochemical properties, stability, loading efficiency, and release of anti-TB drugs, as exemplified in the works of Garg et al. and Desai et al. ^[38]^[39]. Additionally, they allow us to evaluate the phagocytosis of loaded particles, their intracellular accumulation, and their cytotoxicity, because the main objective is to induce lower cytotoxicity than that induced by free drug administration ^[40]^[41]^[42]^[43]^[44].

Novel tools such as the in silico stochastic lung model have also been developed to correlate with in vitro studies and to predict the amount of drug deposited quantitatively in the lungs. Mukhtar et al., who reported the fabrication and characterization of a chitosan/hyaluronic acid nanoparticle and isoniazid suspension, predicted, with this model, that a very low fraction of particles was exhaled, while the particle deposition was high in the lung–bronchial and acinar regions, correlating with their in vitro observations ^[45].

Interestingly, several authors have also evaluated in vitro drug-free microparticles as a strategy to reduce the bacillary load in infected cell lines. For instance, Lawlor et al. reported the use of PLGA particles to reduce the bacillary load in THP-1-derived macrophages infected with the H37Rv strain. Without altering cell viability and without modifying proinflammatory cytokine secretion, they demonstrated that the particles induced NF-kB activation and autophagy in a dose-dependent manner, which in turn increased the killing performance of macrophages ^[25]. Bai et al., used curcumin particles to treat human alveolar and THP-1-derived macrophages before infection with the H37Rv strain, and curcumin also reduced the bacillary load through the induction of autophagy and caspase-3-dependent apoptosis ^[24]. Machelart et al., using beta cyclodextrin NPs, demonstrated that they were efficiently captured by bone-marrow-derived macrophages and bone-marrow-derived dendritic cells and were able to impair Mtb replication and induce apoptosis in infected macrophages ^[26].

Although less frequent, the study of inorganic particles that have a direct microbicidal effect is also of interest. Gold and silver NPs have been functionalized with variable ligands, such as citrate or polyallylamine hydrochloride A, to effectively reduce the cell viability of mycobacteria ^[46]. The antimycobacterial properties of gold have been supported by auranofin, a gold-based antirheumatic drug that inhibits bacterial thioredoxin reductase, making replicating and nonreplicating mycobacteria susceptible to oxidative species; consequently, gold has become a suitable material to develop particles for the treatment of TB ^[47]^[48].

3.2. In Vivo Evaluation of Particulate Tuberculosis Drug Delivery Systems

In vivo studies conducted to evaluate particulate TB drugs are performed with antibiotic-loaded particles (against drug-sensitive and drug-resistant Mtb strains) and are useful in showing prolonged drug release, long-term antibacterial effects, reduced toxicity, and the prevention of infection relapse. There is agreement that, for inhalable formulations, the most appropriate materials are natural or synthetic polymers, and those made from polysaccharides are especially promising. Wu et al. evaluated the in vivo toxicity and release properties of an inhalable preparation of chitosan nanogel particles loaded with genipin, isoniazid, and rifampicin. They demonstrated enhanced antimycobacterial activity in mice infected with the resistant H37Rv strain ^[49]. Machelart et al., with their beta-cyclodextrin NPs administered by direct aerosolization, were also able to decrease the Mtb burden in the lung after infection, and the authors proposed that this observation was a result of AMs’ reprogramming by these particles, which had intrinsic immunostimulant properties ^[26].

Grehna et al., showed that after the pulmonary administration of spray-dried locust bean gum MPs loaded with isoniazid and rifabutin, lung infection and mycobacterial growth rate values were decreased in the spleens and livers of infected mice. The short-term treatment regimen (five times per week) that the authors used was more effective than the oral coadministration of both antibiotics, even at lower doses. Additionally, they highlighted that polysaccharide-based particles are promising for pulmonary administration because they contain sugar units that are recognized by surface receptors expressed by AMs ^[50]. Singh et al. in 2021 also developed a dry powder for inhalation, composed of 25% isoniazid, 25% rifabutin, and 50% biodegradable polymer poly(L-lactide). The authors demonstrated the efficacy, safety, and tolerability of the inhalable particles in three TB models (high-dose intravenous and low-dose aerosol infection in mice and low-dose aerosol infection in guinea pigs). They were also able to prevent the relapse of infection four weeks after stopping the treatment, using the combination strategy of half the oral dose of antibiotics with inhalable particles ^[51]. Antonov et al. showed that encapsulated levofloxacin in PLGA MPs achieved greater bacterial clearance than the free drug orally administered after infecting mice with the H37Rv strain. The particles demonstrated suitable biocompatibility and release kinetics ^[52].

In contrast to the growing number of preclinical phase studies conducted with particulate formulations for TB treatment, progression to clinical phase trials is also scarce and, based on researchers search, there are no polymeric formulations at this stage of investigation. Srichana et al., demonstrated the safety of a dry powder formulation with liposomes containing four anti-tuberculosis drugs (isoniazid, rifampicin, pyrazinamide, and levofloxacin) administered via inhalation to 40 healthy adults. After successfully passing this clinical phase I trial ^[53], the formulation was evaluated for approximately eight weeks in 44 adult patients with active pulmonary TB. Although the treatment did not increase Mtb sputum culture conversion after two months, the percentage of patients having adverse side effects was significantly lower. The main results were decreased cough at 4 weeks of treatment, substantially reduced hemoptysis at 2 weeks of treatment, and lower incidences of nausea and vomiting ^[54].

3.3. Opportunities for Particulate Systems for Tuberculosis Theranostics

Recent studies have focused their attention on theranostics as means to combine early diagnosis and the administration of targeted treatments in a single system. Particulate systems applied to TB theranostics must be developed with a favorable aerodynamic diameter for pulmonary delivery, to maximize drug delivery while avoiding toxic systemic side effects and potentially shortening the treatment duration. These systems are composed of a biocompatible metal organic framework (MOF) as a drug carrier, which usually has synergistic therapeutic activity and one or several anti-TB drugs ^[55]. The MOF delivers its cargo upon activation by endogenous stimuli such as pH, redox, or ATP or by exogenous stimuli such as temperature, ions, pressure, light, humidity, or a magnetic field ^[56]. Recently, Jiménez-Rodríguez et al. successfully encapsulated RIF in liposomes and silver nanoparticles to develop a luminescent biomarker for its evaluation as a TB theranostic. The particles permitted early diagnosis and treatment, and, due to their optical properties, the authors highlighted their utility in pharmacokinetic studies ^[57].

An emerging opportunity for TB theranostics is the tracking of complex structures such as granulomas and encapsulating various anti-TB drugs for directed administration. In latent TB that can become active TB, this strategy is a priority because granulomas contribute to the persistence and/or spread of the bacilli present inside them. For this reason, in recent studies, the use of sophisticated systems to localize and treat early granulomas has been explored. Liao et al. designed a TB granuloma imaging-guided photodynamic therapy (PDT) using an aggregation-induced emission carrier. After exposure to white light, the carrier generated ROS and simultaneously released rifampicin. With this system, the authors were able to perform an early diagnosis ex vivo using a granuloma tail model in mice and control the drug-sensitive and drug-resistant bacteria in vitro ^[58]^[59]. However, these strategies are in the preliminary stage of investigation and their efficacy and safety levels need to be further studied and characterized.

References

Wallis, J.; Shenton, D.P.; Carlisle, R.C. Novel Approaches for the Design, Delivery and Administration of Vaccine Technologies.. Clin. Exp. Immunol. 2019, 196, 189–204.
Batty, C.J.; Bachelder, E.M.; Ainslie, K.M. Historical Perspective of Clinical Nano and Microparticle Formulations for Delivery of Therapeutics. . Trends Mol. Med. 2021, 27, 516–519..
Zhao, Z.; Ukidve, A.; Krishnan, V.; Mitragotri, S. Effect of Physicochemical and Surface Properties on in vivo Fate of Drug Nanocarriers. . Adv. Drug Deliv. Rev. 2019, 143, 3-21.
Chenthamara, D.; Subramaniam, S.; Ramakrishnan, S.G.; Krishnaswamy, S.; Essa, M.M.; Lin, F.; Qoronfleh, M.W. Therapeutic Efficacy of Nanoparticles and Routes of Administration. . Biomater. Res. 2019, 21, 20.
Vasquez-Martínez, N.; Guillen, D.; Moreno-Mendieta, S.A.; Sanchez, S.; Rodríguez-Sanoja, R. The Role of Mucoadhesion and Mucopenetration in the Immune Response Induced by Polymer-Based Mucosal Adjuvants. . Polymers 2023, 15, 1615.
Khan, A.; Sayedahmed, E.E.; Singh, V.K.; Mishra, A.; Dorta-Estremera, S.; Nookala, S.; Canaday, D.H.; Chen, M.; Wang, J.; Sastry, K.J.; et al.et al. A Recombinant Bovine Adenoviral Mucosal Vaccine Expressing Mycobacterial Antigen-85B Generates Robust Protection against Tuberculosis in Mice. . Cell Reports Med. 2021, 2, 100372.
Nagpal, P.S.; Kesarwani, A.; Sahu, P.; Upadhyay, P. Aerosol Immunization by Alginate Coated Mycobacterium (BCG/MIP) Particles Provide Enhanced Immune Response and Protective Efficacy than Aerosol of Plain Mycobacterium against M.tb. H37Rv Infection in Mice. . BMC Infect. Dis. 2019, 19, 568.
Gomez, M.; Archer, M.; Barona, D.; Wang, H.; Ordoubadi, M.; Bin Karim, S.; Carrigy, N.B.; Wang, Z.; McCollum, J.; Press, C.; et al.et al. Microparticle Encapsulation of a Tuberculosis Subunit Vaccine Candidate Containing a Nanoemulsion Adjuvant via Spray Drying. . Eur. J. Pharm. Biopharm. 2021, 163, 23–37.
Sia, J.K.; Rengarajan, J. Immunology of Mycobacterium tuberculosis Infections.. Microbiol. Spectr. 2019, 7, 3-22.
Zhang, Y.; Yang, J.; Bai, G. Cyclic Di-AMP-Mediated Interaction between Mycobacterium tuberculosis DcnpB and Macrophages Implicates a Novel Strategy for Improving BCG Vaccination. . Pathog. Dis. 2018, 76, fty008.
Cotton, M.F.; Madhi, S.A.; Luabeya, A.K.; Tameris, M.; Hesseling, A.C.; Shenje, J.; Schoeman, E.; Hatherill, M.; Desai, S.; Kapse, D.; et al.et al. Safety and Immunogenicity of VPM1002 versus BCG in South African Newborn Babies: A Randomised, Phase 2 Non-Inferiority Double-Blind Controlled Trial. . Lancet Infect. Dis. 2022, 22, 1472–1483.
Moliva, J.I.; Turner, J.; Torrelles, J.B. Immune Responses to Bacillus Calmette-Guérin Vaccination: Why Do They Fail to Protect against Mycobacterium tuberculosis? . Front. Immunol. 2017, 8, 407.
Orgeur, M.; Brosch, R. Evolution of Virulence in the Mycobacterium tuberculosis Complex. . Curr. Opin. Microbiol. 2018, 41, 68–75.
Boahen, C.K.; Moorlag, S.J.C.F.M.; Jensen, K.J.; Matzaraki, V.; Fanucchi, S.; Monteiro, I.; de Bree, C.; Fok, E.T.; Mhlanga, M.; Joosten, L.A.B.; et al.et al. Genetic Regulators of Cytokine Responses upon BCG Vaccination in Children fromWest Africa. . J. Genet. Genom. 2023, 50, 434–446.
Perdomo, C.; Zedler, U.; Kühl, A.A.; Lozza, L.; Saikali, P.; Sander, L.E.; Vogelzang, A.; Kaufmann, S.H.E.; Kupz, A. Mucosal BCG Vaccination Induces Protective Lung-Resident Memory T Cell Populations against Tuberculosis. . MBio 2016, 7, e01686-16..
Wang, Y.; Yang, C.; He, Y.; Zhan, X.; Xu, L. Ipr1 Modified BCG as a Novel Vaccine Induces Stronger Immunity than BCG against Tuberculosis Infection in Mice. . Mol. Med. Rep. 2016, 14, 1756–1764.
Bull, N.C.; Stylianou, E.; Kaveh, D.A.; Pinpathomrat, N.; Pasricha, J.; Harrington-Kandt, R.; Garcia-Pelayo, M.C.; Hogarth, P.J.; McShane, H. Enhanced Protection Conferred by Mucosal BCG Vaccination Associates with Presence of Antigen-Specific Lung Tissue-Resident PD-1 + KLRG1 - CD4+ T Cells. . Mucosal. Immunol. 2019, 12, 555–564.
Counoupas, C.; Ferrell, K.C.; Ashhurst, A.; Bhattacharyya, N.D.; Nagalingam, G.; Stewart, E.L.; Feng, C.G.; Petrovsky, N.; Britton, W.J.; Triccas, J.A.; et al. Mucosal Delivery of a Multistage Subunit Vaccine Promotes Development of Lung-Resident Memory T Cells and Affords Interleukin-17-Dependent Protection against Pulmonary Tuberculosis. . NPJ Vaccines 2020, 5, 105.
Gomez, M.; McCollum, J.; Wang, H.; Ordoubadi, M.; Jar, C.; Carrigy, N.B.; Barona, D.; Tetreau, I.; Archer, M.; Gerhardt, A.; et al.et al. Development of a Formulation Platform for a Spray-Dried, Inhalable Tuberculosis Vaccine Candidate. . Int. J. Pharm. 2021, 593, 120121.
O’Garra, A.; Redford, P.S.; McNab, F.W.; Bloom, C.I.; Wilkinson, R.J.; Berry, M.P.R. The Immune Response in Tuberculosis. . Annu. Rev. Immunol. 2013, 31, 475–527.
de Martino, M.; Lodi, L.; Galli, L.; Chiappini, E. Immune Response to Mycobacterium tuberculosis: A Narrative Review. . Front. Pediatr. 2019 , 7, 350.
Counoupas, C.; Pinto, R.; Nagalingam, G.; Britton,W.J.; Petrovsky, N.; Triccas, J.A. Delta Inulin-Based Adjuvants Promote the Generation of Polyfunctional CD4+ T Cell Responses and Protection against Mycobacterium tuberculosis. . Infect. Sci. Rep. 2017, 7, 8582.
Tkachuk, A.P.; Gushchin, V.A.; Potapov, V.D.; Demidenko, A.V.; Lunin, V.G.; Gintsburg, A.L. Multi-Subunit BCG Booster Vaccine GamTBvac: Assessment of Immunogenicity and Protective Efficacy in Murine and Guinea Pig TB Models. . PLoS ONE 2017, 12, e0176784.
Bai, X.; Oberley-Deegan, R.E.; Bai, A.; Ovrutsky, A.R.; Kinney,W.H.; Weaver, M.; Zhang, G.; Honda, J.R.; Chan, E.D. Curcumin Enhances Human Macrophage Control of Mycobacterium tuberculosis Infection. . Respirology 2016, 21, 951–957.
Lawlor, C.; O’Connor, G.; O’Leary, S.; Gallagher, P.J.; Cryan, S.A.; Keane, J.; O’Sullivan, M.P. Treatment of Mycobacterium tuberculosis-Infected Macrophages with Poly(Lactic-Co-Glycolic Acid) Microparticles Drives NFKB and Autophagy Dependent Bacillary Killing. . PLoS ONE 2016, 11, e0149167.
Machelart, A.; Salzano, G.; Li, X.; Demars, A.; Debrie, A.S.; Menendez-Miranda, M.; Pancani, E.; Jouny, S.; Hoffmann, E.; Deboosere, N.; et al.et al. Intrinsic Antibacterial Activity of Nanoparticles Made of -Cyclodextrins Potentiates Their Effect as Drug Nanocarriers against Tuberculosis. . ACS Nano 2019, 13, 3992–4007.
Khademi, F.; Derakhshan, M.; Yousefi-Avarvand, A.; Tafaghodi, M. Potential of polymeric particles as future vaccine delivery systems/adjuvants for parenteral and non-parenteral immunization against tuberculosis: A systematic review. . Iran. J. Basic Med. Sci. 2018, 21, 116–123.
Rajput, A.; Mandlik, S.; Pokharkar, V. Nanocarrier-Based Approaches for the Efficient Delivery of Anti-Tubercular Drugs and Vaccines for Management of Tuberculosis. . Front. Pharmacol. 2021, 12, 749945.
Duong, V.T.; Skwarczynski, M.; Toth, I. Towards the development of subunit vaccines against tuberculosis: The key role of adjuvant. . Tuberculosis 2023, 139, 102307.
Pabreja, S.; Garg, T.; Rath, G.; Goyal, A.K. Mucosal Vaccination against Tuberculosis Using Ag85A-Loaded Immunostimulating Complexes. . Artif. Cells Nanomed. Biotechnol. 2016, 44, 532–539.
Kramer, R.M.; Archer, M.C.; Orr, M.T.; Dubois Cauwelaert, N.; Beebe, E.A.; Huang, P.W.D.; Dowling, Q.M.; Schwartz, A.M.; Fedor, D.M.; Vedvick, T.S.; et al.et al. Development of a Thermostable Nanoemulsion Adjuvanted Vaccine against Tuberculosis Using a Design-of-Experiments Approach. . Int. J. Nanomed. 2018, 13, 3689–3711.
Najafi, A.; Ghazvini, K.; Sankian, M.; Gholami, L.; Amini, Y.; Zare, S.; Khademi, F.; Tafaghodi, M. T Helper Type 1 Biased Immune Responses by PPE17 Loaded Core-Shell Alginate-Chitosan Nanoparticles after Subcutaneous and Intranasal Administration. . Life Sci. 2021, 282, 119806.
Adeagbo, B.A.; Akinlalu, A.O.; Phan, T.; Guderian, J.; Boukes, G.; Willenburg, E.; Fenner, C.; Bolaji, O.O.; Fox, C.B. Controlled Covalent Conjugation of a Tuberculosis Subunit Antigen (ID93) to Liposome Improved in vitro Th1-Type Cytokine Recall Responses in Human Whole Blood. . ACS Omega 2020, 5, 31306–31313.
Coler, R.; Day, T.; Ellis, R.; Piazza, F.M.; Beckmann, A.; Vergara, J.A.; Rolf, T.; Lu, L.L.; Alter, G.; Hokey, D.; et al.et al. The TLR-4 agonist adjuvant, GLA-SE, improves magnitude and quality of immune responses elicited by the ID93 tuberculosis vaccine: First-in-human trial. . NPJ Vaccines 2018, 3, 34.
Tkachuk, A.P.; Bykonia, E.N.; Popova, L.I.; Kleymenov, D.A.; Semashko, M.A.; Chulanov, V.P.; Fitilev, S.B.; Maksimov, S.L.; Smolyarchuk, E.A.; Manuylov, V.A.; et al.et al. Safety and Immunogenicity of the GamTBvac, the Recombinant Subunit Tuberculosis Vaccine Candidate: A Phase II, Multi-Center, Double-Blind, Randomized, Placebo-Controlled Study. . Vaccines 2020, 8, 652.
Sant´Anna, F.M.; Araújo-Pereira, M.; Schmaltz, C.A.S.; Arriaga, M.B.; de Oliveira, R.V.C.; Andrade, B.B.; Rolla, V.C. Adverse Drug Reactions Related to Treatment of Drug-Susceptible Tuberculosis in Brazil: A Prospective Cohort Study. . Front. Trop. Dis. 2022, 2, 748310.
Cohen, S.B.; Gern, B.H.; Delahaye, J.L.; Adams, K.N.; Courtney, R.; Winkler, J.; Sherman, D.R.; Gerner, M.Y.; Kevin, B. Alveolar Macrophages Provide an Early Mycobacterium tuberculosis Niche and Initiate Dissemination. . Cell Host Microbe 2018, 24, 439–446.
Garg, T.; Goyal, A.K.; Rath, G.; Murthy, R.S.R. Spray-Dried Particles as Pulmonary Delivery System of Anti-Tubercular Drugs: Design, Optimization, in vitro and in vivo Evaluation. . Pharm. Dev. Technol. 2016, 21, 951–960.
Desai, S.K.; Mondal, D.; Bera, S. Polyurethane-Functionalized Starch Nanocrystals as Anti-Tuberculosis Drug Carrier. . Sci. Rep 2021, 11, 8331.
Moretton, M.A.; Cagel, M.; Bernabeu, E.; Gonzalez, L.; Chiappetta, D.A. Nanopolymersomes as Potential Carriers for Rifampicin Pulmonary Delivery.. Colloids Surf. B Biointerfaces 2015, 136, 1017–1025.
Alves, A.D.; Cavaco, J.S.; Guerreiro, F.; Lourenço, J.P.; Rosa Da Costa, A.M.; Grenha, A. Inhalable Antitubercular Therapy Mediated by Locust Bean Gum Microparticles. . Molecules 2016, 21, 702.
Rodrigues, S.; Alves, A.D.; Cavaco, J.S.; Pontes, J.F.; Guerreiro, F.; Rosa da Costa, A.M.; Buttini, F.; Grenha, A. Dual Antibiotherapy of Tuberculosis Mediated by Inhalable Locust Bean Gum Microparticles. . Int. J. Pharm 2017, 529, 433–441.
Adeleke, O.A.; Hayeshi, R.K.; Davids, H. Development and Evaluation of a Reconstitutable Dry Suspension Containing Isoniazid for Flexible Pediatric Dosing. . Pharmaceutics 2020, 12, 286.
Rodrigues, S.; Cunha, L.; Kollan, J.; Neumann, P.R.; Rosa da Costa, A.M.; Dailey, L.A.; Grenha, A. Cytocompatibility and Cellular Interactions of Chondroitin Sulfate Microparticles Designed for Inhaled Tuberculosis Treatment.. Eur. J. Pharm. Biopharm. 2021, 163, 171–178.
Mukhtar, M.; Pallagi, E.; Csóka, I.; Benke, E.; Farkas, Á.; Zeeshan, M.; Burián, K.; Kókai, D.; Ambrus, R. Aerodynamic Properties and in Silico Deposition of Isoniazid Loaded Chitosan/Thiolated Chitosan and Hyaluronic Acid Hybrid Nanoplex DPIs as a Potential TB Treatment. . Int. J. Biol. Macromol. 2020, 165, 3007–3019.
Zhou, Y.; Kong, Y.; Kundu, S.; Cirillo, J.D.; Liang, H. Antibacterial Activities of Gold and Silver Nanoparticles against Escherichia coli and Bacillus Calmette-Guérin. . J. Nanobiotechnol 2012, 10, 19.
Harbut, M.B.; Vilchèze, C.; Luo, X.; Hensler, M.E.; Guo, H.; Yang, B.; Chatterjee, A.K.; Nizet, V.; Jacobs,W.R.; Schultz, P.G.; et al.et al. Auranofin Exerts Broad-Spectrum Bactericidal Activities by Targeting Thiol-Redox Homeostasis. . Proc. Nat. Acad. Sci. USA 2015, 112, 4453–4458.
Frei, A.; Verderosa, A.D.; Elliott, A.G.; Zuegg, J.; Blaskovich, M.A.T. Metals to Combat Antimicrobial Resistance. . Nat. Rev. Chem. 2023, 7, 202–224.
Wu, T.; Liao, W.; Wang, W.; Zhou, J.; Tan, W.; Xiang, W.; Zhang, J.; Guo, L.; Chen, T.; Ma, D.; et al.et al. Genipin-Crosslinked Carboxymethyl Chitosan Nanogel for Lung-Targeted Delivery of Isoniazid and Rifampin. . Carbohydr. Polym 2018, 197, 403–413.
Grenha, A.; Alves, A.D.; Guerreiro, F.; Pinho, J.; Simões, S.; Almeida, A.J.; Gaspar, M.M. Inhalable Locust Bean Gum Microparticles Co-Associating Isoniazid and Rifabutin: Therapeutic Assessment in a Murine Model of Tuberculosis Infection. . Eur. J. Pharm. Biopharm. 2020, 147, 38–44.
Singh, A.K.; Verma, R.K.; Mukker, J.K.; Yadav, A.B.; Muttil, P.; Sharma, R.; Mohan, M.; Agrawal, A.K.; Gupta, A.; Dwivedi, A.K.; et al.et al. Inhalable Particles Containing Isoniazid and Rifabutin as Adjunct Therapy for Safe, Efficacious and Relapse-Free Cure of Experimental Animal Tuberculosis in One Month. . Tuberculosis 2021, 128, 102081.
Antonov, E.N.; Andreevskaya, S.N.; Bocharova, I.V.; Bogorodsky, S.E.; Krotova, L.I.; Larionova, E.E.; Mariyanats, A.O.; Mishakov, G.V.; Smirnova, T.G.; Chernousova, L.N.; et al.et al. PLGA Carriers for Controlled Release of Levofloxacin in Anti-Tuberculosis Therapy. . Pharmaceutics 2022, 14, 1275.
Srichana, T.; Ratanajamit, C.; Juthong, S.; Suwandecha, T.; Laohapojanart, N.; Pungrassami, P.; Padmavathi, A.R. Evaluation of Proinflammatory Cytokines and Adverse Events in Healthy Volunteers upon Inhalation of Antituberculosis Drugs. . Biol. Pharm. Bull 2016, 39, 1815–1822.
Laohapojanart, N.; Ratanajamit, C.; Kawkitinarong, K.; Srichana, T. Efficacy and Safety of Combined Isoniazid-Rifampicin- Pyrazinamide-Levofloxacin Dry Powder Inhaler in Treatment of Pulmonary Tuberculosis: A Randomized Controlled Trial. . Pulm. Pharmacol. Ther. 2021, 70, 102056.
Luz, I.; Stewart, I.E.; Mortensen, N.P.; Hickey, A.J. Designing Inhalable Metal Organic Frameworks for Pulmonary Tuberculosis Treatment and Theragnostics: Via Spray Drying.. Chem. Commun 2020, 56, 13339–13342.
Cai, W.; Wang, J.; Chu, C.; Chen, W.; Wu, C.; Liu, G. Metal–Organic Framework-Based Stimuli-Responsive Systems for Drug Delivery. . Adv. Sci. 2019, 6, 1801526.
Jiménez-Rodríguez, R.; Douda, J.; Mota-Díaz, I.I.; Luna-Herrera, J.; Romera-Ibarra, I.C.; Casas-Espínola, J.L. Theragnostic Liposomes for the Diagnosis and Treatment of Tuberculosis. . MRS Adv. 2023, 8, 67–70.
Li, B.; Tan, Q.; Fan, Z.; Xiao, K.; Liao, Y. Next-Generation Theranostics: Functionalized Nanomaterials Enable Efficient Diagnosis and Therapy of Tuberculosis. . Adv. Ther 2020, 3, 1900189.
Liao, Y.; Li, B.; Zhao, Z.; Fu, Y.; Tan, Q.; Li, X.; Wang, W.; Yin, J.; Shan, H.; Tang, B.Z.; et al.et al. Targeted Theranostics for Tuberculosis: A Rifampicin-Loaded Aggregation-Induced Emission Carrier for Granulomas Tracking and Anti-Infection. . ACS Nano 2020, 14, 8046–8058.

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.

Upload a video for this entry

Information

Subjects: Biotechnology & Applied Microbiology

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Alejandra Barrera-Rosales

Romina Rodríguez-Sanoja

Rogelio Hernández-Pando

Silvia Moreno-Mendieta

View Times: 251

Update Date: 28 Aug 2023

Table of Contents

Video Upload Options

Confirm