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New Ways to Treat Tuberculosis Using Dendrimers As Nanocarriers

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New Ways to Treat Tuberculosis Using Dendrimers As Nanocarriers pharmaceutics Review New Ways to Treat Tuberculosis Using Dendrimers as Nanocarriers Serge Mignani 1,2,*, Rama Pati Tripathi 3,*, Liang Chen 4,5,6, Anne-Marie Caminade 5,6 ID , Xiangyang Shi 4 ID and Jean-Pierre Majoral 5,6,* 1 Université Paris Descartes, PRES Sorbonne Paris Cité, CNRS UMR 860, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologique, 45, rue des Saints Peres, 75006 Paris, France 2 CQM—Centro de Química da Madeira, MMRG, Universidade da Madeira, Campus da Penteada, 9020-105 Funchal, Portugal 3 National Institute of Pharmaceutics and Education and Research, Raibarely 226031, India 4 State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China; [email protected] (L.C.); [email protected] (X.S.) 5 Laboratoire de Chimie de Coordination du CNRS, 205 Route de Narbonne, BP 44099, 31077 Toulouse CEDEX 4, France; [email protected] 6 Université de Toulouse, UPS, INPT, 31077 Toulouse CEDEX 4, France * Correspondence: [email protected] (S.M.); [email protected] (R.P.T.); [email protected] (J.-P.M.); Tel.: +33-561-333-123 (J.-P.M.) Received: 3 July 2018; Accepted: 24 July 2018; Published: 26 July 2018 Abstract: Tuberculosis (TB) is a contagious infection that usually attacks not only the lungs, but also brain and spine. More than twenty drugs have been developed for the treatment of TB, but most of them were developed some years ago. They are used in different combinations. Isoniazid and Rifampicin are examples of the five first line TB drugs, whereas, for instance, Levofloxacin, Kanamycin and Linezolid belong to the second line drugs that are used for the treatment of drug resistant TB. Several new bicyclic nitroimidazoles (e.g., Delamanid) without mutagenic effects were developed. New TB drugs need to provide several main issues such as more effective, less toxic, and less expensive for drug resistant TB. Besides polymeric, metal-based nanoparticles, polymeric micelles and polymers, dendrimer nanostructures represent ideal delivery vehicles and offer high hopes for the future of nanomedicine. In this original review, we present and analyze the development of anti-TB drugs in combination with dendrimers. Few articles have highlighted the encapsulation of anti-TB drugs with dendrimers. Due to their unique structure, dendrimers represent attractive candidates for the encapsulation and conjugation of other anti-TB drugs presenting important drawbacks (e.g., solubility, toxicity, low bioavailability) that hinder their development, including clinic trials. Keywords: tuberculosis; dendrimers; nanocarriers 1. Introduction and State-of-the-Art in the Development of Nano-Based Drug Delivery of Anti-TB Drugs Tuberculosis (TB) is an infectious disease caused by the bacillus Mycobacterium tuberculosis, also known as Koch bacillus, surviving and replicating within human alveolar macrophages and affecting other organs [1,2]. A global view of this disease can be summarized as follows: (1) according to the latest report of the World Health Organization (WHO), more than one third of the world’s population is infected with Mycobacterium tuberculosis, and approximately 2 million deaths by TB were reported in 2017; (2) current treatments—which are generally oral—are toxic to the patient; (3) TB is a common cause of death among HIV-positive patients; (4) resistant strains, such as multi-drug Pharmaceutics 2018, 10, 0105; doi:10.3390/pharmaceutics10030105 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2018, 10, x FOR PEER REVIEW 2 of 10 Pharmaceutics 2018, 10, 0105 2 of 10 were reported in 2017; (2) current treatments—which are generally oral—are toxic to the patient; (3) TB is a common cause of death among HIV-positive patients; (4) resistant strains, such as multi-drug resistant (MDR-TB) and and extensively drug drug resistant resistant (XDR-TB), (XDR-TB), to to all all major anti-TB drugs have been observed and (5) the average cost of 6 to 32 months of treatment against TB, MDR-TB and XDR-TB is ~17,000, ~150,000 and and ~300,000 ~300,000 US US dollars, dollars, respecti respectivelyvely [3]. [3]. Typical Typical TB TB treatment follows a 6-month administration of a cocktail of four differentdifferent antibiotics:antibiotics: rifampicin (RIF), isoniazid, pyrazinamide and ethambutol. Along Along with with the the lengthy lengthy treatment treatment pe period,riod, several several side side effect effectss can can occur, occur, such as nausea, vomiting,vomiting, weight weight loss, loss, hepatotoxicity, hepatotoxicity, adverse adverse skin andskin gastrointestinal and gastrointestinal reactions reactions and immune and immuneresponses, responses, for instance, for ininstance, the case in of the RIF. case In addition, of RIF. In RIF addition, interacts RIF with interacts isoniazid, with which isoniazid, is also which a major is alsoanti-TB a major drug, anti-TB leading drug, to the leading corresponding to the corre insolublesponding hydrazine insoluble derivative hydrazine [4 ].derivative [4]. The main drugs used (not an exhaustive list) for the treatment of TB are as follows: (1) first-line first-line agents: rifampicinrifampicin (RIF), (RIF), isoniazid isoniazid (INH), pyrazinamide(INH), pyrazinamide (PZA), thambutol (PZA), (ETB)thambutol and aminoglycosides; (ETB) and aminoglycosides;(2) bacteriostatic second-line(2) bacteriostatic drugs: second-line P-aminosalicylic drugs: P-aminosalicylic acid, cycloserine acid, and cycloserine other drugs and such other as drugsclofazimine, such as amoxicillin, clofazimine, clarithromycin, amoxicillin, clarithrom rifabutinycin, and thioacetazonerifabutin and (Figurethioacetazone1). Many (Figure of these 1). drugsMany ofare these generics drugs [5 ].are generics [5]. Figure 1. MainMain treatments to tack tacklele tuberculosis (o: oral, iv:: intravenous intravenous administration). administration). There is no doubt that TB remains a major global health problem, and new treatments to combat There is no doubt that TB remains a major global health problem, and new treatments to combat the crisis of drug resistance in TB are urgently needed. To this end, several new bicyclic the crisis of drug resistance in TB are urgently needed. To this end, several new bicyclic nitroimidazoles nitroimidazoles without mutagenic effects were developed, such as OPC-67683 (delamanid, Otsuka without mutagenic effects were developed, such as OPC-67683 (delamanid, Otsuka Pharmaceuticals) Pharmaceuticals) and PA-824 (pretonamid, PathoGenesis) (Figure 2). Delamanid was approved by and PA-824 (pretonamid, PathoGenesis) (Figure2). Delamanid was approved by the European the European Medicines Agency (EMA) in 2014 for pulmonary multi drug-resistant TB in adult Medicines Agency (EMA) in 2014 for pulmonary multi drug-resistant TB in adult patients [6,7], patients [6,7], whereas pretonamid (Figure 2) is currently in Phase II/III clinical trials for the treatment whereas pretonamid (Figure2) is currently in Phase II/III clinical trials for the treatment of TB. of TB. Recently, the Global Alliance for TB drug development and the University of Auckland Recently, the Global Alliance for TB drug development and the University of Auckland advanced advanced TBA-6354 to Phase I, but the drug showed neurotoxicity in healthy volunteers [8,9]. In 2012, TBA-6354 to Phase I, but the drug showed neurotoxicity in healthy volunteers [8,9]. In 2012, the FDA the FDA granted accelerated approval to the diarylquinonoline derivative, SirturoTM (bedaquiline, granted accelerated approval to the diarylquinonoline derivative, SirturoTM (bedaquiline, TMC-2017) TMC-2017) for treatment in adults of multidrug-resistant tuberculosis. It is the first new anti-TB drug for treatment in adults of multidrug-resistant tuberculosis. It is the first new anti-TB drug to be to be approved after 1998 (Rifapentine) [10]. This drug was the first to be introduced specifically for approved after 1998 (Rifapentine) [10]. This drug was the first to be introduced specifically for the the treatment of multidrug-resistant tuberculosis in combination with other drugs such as Delamanid treatment of multidrug-resistant tuberculosis in combination with other drugs such as Delamanid combination for the treatment of patients with pulmonary extensively drug-resistant tuberculosis combination for the treatment of patients with pulmonary extensively drug-resistant tuberculosis [11]. [11]. Pharmaceutics 2018, 10, 0105 3 of 10 Pharmaceutics 2018, 10, x FOR PEER REVIEW 3 of 10 FigureFigure 2. ChemicalChemical structures structures of Rifampicin (RIF), Isoniazid (INH), Delamanid, and Pretonamid. Nanotechnology represents a multidisciplinary field encompassing various domains such as Nanotechnology represents a multidisciplinary field encompassing various domains such chemistry, materials, biology, physics, diagnosis and engineering, including the synthesis of as chemistry, materials, biology, physics, diagnosis and engineering, including the synthesis of nanodevices. The pharmaceutical industry adopts nanotechnology throughout the R&D process [12]. nanodevices. The pharmaceutical industry adopts nanotechnology throughout the R&D process [12]. Thus, nanoformulations and nanocarriers have made a significant impact on the delivery of Thus, nanoformulations and nanocarriers have made a significant impact on the delivery of therapeutic agents and diagnostics through the development of several nanodevices such as therapeutic
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