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Drug Delivery Systems on Leprosy Therapy: Moving Towards Eradication?

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Drug Delivery Systems on Leprosy Therapy: Moving Towards Eradication? pharmaceutics Review Drug Delivery Systems on Leprosy Therapy: Moving Towards Eradication? Luíse L. Chaves 1,2,*, Yuri Patriota 2, José L. Soares-Sobrinho 2 , Alexandre C. C. Vieira 1,3, Sofia A. Costa Lima 1,4 and Salette Reis 1,* 1 Laboratório Associado para a Química Verde, Rede de Química e Tecnologia, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal; [email protected] (A.C.C.V.); slima@ff.up.pt (S.A.C.L.) 2 Núcleo de Controle de Qualidade de Medicamentos e Correlatos, Universidade Federal de Pernambuco, Recife 50740-521, Brazil; [email protected] (Y.P.); [email protected] (J.L.S.-S.) 3 Laboratório de Tecnologia dos Medicamentos, Universidade Federal de Pernambuco, Recife 50740-521, Brazil 4 Cooperativa de Ensino Superior Politécnico e Universitário, Instituto Universitário de Ciências da Saúde, 4585-116 Gandra, Portugal * Correspondence: [email protected] (L.L.C.); shreis@ff.up.pt (S.R.) Received: 30 October 2020; Accepted: 4 December 2020; Published: 11 December 2020 Abstract: Leprosy disease remains an important public health issue as it is still endemic in several countries. Mycobacterium leprae, the causative agent of leprosy, presents tropism for cells of the reticuloendothelial and peripheral nervous system. Current multidrug therapy consists of clofazimine, dapsone and rifampicin. Despite significant improvements in leprosy treatment, in most programs, successful completion of the therapy is still sub-optimal. Drug resistance has emerged in some countries. This review discusses the status of leprosy disease worldwide, providing information regarding infectious agents, clinical manifestations, diagnosis, actual treatment and future perspectives and strategies on targets for an efficient targeted delivery therapy. Keywords: clofazimine; dapsone; nanoparticles; Mycobacterium leprae; targeting 1. Introduction Hansen’s disease or leprosy is a non-fatal old disease caused by a bacterium that affects a significant portion of the world population [1,2]. Nowadays, it is one the principal causes of non-traumatic peripheral neuropathy on a global scale [3]. In spite the advances in the political, social, and economic status of developing countries, leprosy is still endemic in many regions, mainly in South East Asia and the Americas [4]. Worldwide, between 2005 and 2014 the number of new cases (about 200,000) was stable [5], thus, in a decade, leprosy continue to be highly prevalent in many regions. In 2019, 13 countries reported more than a 1000 new cases, representing about 95% of all reported new leprosy cases [5]. Brazil, India and Indonesia, disclosed the higher levels of new cases with more than 10,000 new reports representing about 79% of new leprosy cases on a global scale [5]. New approaches have been presented to overcome the stagnation in leprosy control, going from better political commitment, reduction of patient disabilities, to the inclusion of leprosy patients [5]. 1.1. Ethiologic Agent, the Mycobacterium leprae The Mycobacterium leprae (M. leprae) belongs to the order Actinomycetales from the Mycobacteriaceae family. This bacterium is an acid-fast obligate intracellular bacillus that appears as pleomorphic rods 1 to 8 µm long and 0.3 µm large [6,7]. M. leprae replicates by binary diffusion [6,8], in about 12–13 days Pharmaceutics 2020, 12, 1202; doi:10.3390/pharmaceutics12121202 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2020, 12, x 2 of 20 Pharmaceutics 2020, 12, 1202 2 of 19 pleomorphic rods 1 to 8 µm long and 0.3 µm large [6,7]. M. leprae replicates by binary diffusion [6,8], atin 27about to 30 12◦–C[136 days]. It is at a 27 Gram-positive to 30 °C [6]. bacteriaIt is a Gram but- canpositive be di ffbacteriaerentially but stained, can be appearingdifferentially acid-fast stained, in theappearing Ziehl-Neelsen acid-fast stain in the or in Ziehl the Fite’s-Neelsen acid stain fast stainor in [8the]. M.Fite’s leprae acidcannot fast stain be grown [8]. M.in vitroleprae, whichcannot can be begrown related in tovitro its,long which doubling can be timerelated (14 days)to its [long7]. The doubling bacteria time has been(14 days) successfully [7]. The established bacteria hasin been vivo bysuccessfully inoculation es intotablished the footpad in vivo of by female inoculati Swisson mice, into the contributing footpad of to female the development Swiss mice of, contributing new antibiotic to therapiesthe development and the of study new of antibiotic drug resistance therapies [7 ].and the study of drug resistance [7]. In spitespite of of the the high high infective infective rate rate of M. of leprae M. leprae, the disease, the disease progression progression is slow due is slow to the due long to incubation the long periodincubation of the period bacteria of the [9]. bacteria This intracellular [9]. This intracellular pathogen infects pathogen preferentially infects preferentially the skin, nasal the mucosa skin, nasal and peripheralmucosa and nerves, peripheral exhibiting nerves tropism, exhibiting for reticuloendothelialtropism for reticuloendothelial and peripheral and nervous peripheral system nervous cells, particularlysystem cells, Schwann particularly cells (SCs)Schwann and macrophagescells (SCs) and [6, 10macrophages]. Upon entry [6,10 to the]. Upon cells, M.entry leprae to reorganizethe cells, M. in aggregatesleprae reorganize called in globi aggregates [9]. M. leprae calledtargets globi SCs[9]. M. by leprae the attachment targets SCs to by laminin- the attachmentα2 and adhesins to laminin and- to2 peripheraland adhesins nerve and surface to peripheral cell receptors nerve (α surface-dystroglycan cell receptors and ErbB2) (-dystroglycan [1,3]. Upon internalization and ErbB2) [1,3 by]. the Upon SCs, theinternalization bacteria triggers by the the SCs, differentiation the bacteria into triggers immature the differentiation cells, suitable for into its immature proliferation cells, [1]. suitable As previously for its mentioned,proliferationM. [1]. leprae As replicatespreviously slowly mention anded after, M. its leprae recognition replicates by T slowly cells, initiates and after a chronic its recognition inflammatory by T reactioncells, initiates [6]. Figure a chronic1 illustrates inflammatory the interaction reaction between [6]. FigureM. leprae 1 illustratesand laminin- the interactionα2 glycoprotein between in SCs. M. Demyelinationleprae and laminin and- disability2 glycoprotein mediated in SCs by loss. Demyelination of axonal conductance and disability are the mediated consequences by loss of ofM. axonal leprae SCconductance infection [ 3are,6, 9the]. consequences of M. leprae SC infection [3,6,9]. Figure 1. IInteractionnteraction bet betweenween M. leprae and Schwann cells, mediated by the laminin-laminin-α2 present in the basal laminalamina of myelinatedof myelinated and non-myelinatedand non-myelinated Schwann-cell–axon Schwann-cell units.–axon Reproduced units. Reproduced with permission with frompermission [8], Elsevier, from [8], 2000. Elsevier, 2000. Apart ofof thethe SCs, SCs,M. M. leprae lepraecan can successfully successfully survive survive inside inside macrophages macrophages [11]. [11]. It is It well-known is well-known that mycobacteria,that mycobacteria, in general, in general, have developed have developed the ability the to ability block theto fusionblock the between fusion maturated between phagosomematurated withphagosome the lysosome with the in macrophages,lysosome in macrophages, which is essential which for is pathogen essential destruction, for pathogen antigen destruction, processing antigen and presentationprocessing and for presentation effective recognition for effective by therecognition adaptive by immune the adaptive system immune [10]. It hassystem been [10]. demonstrated It has been thatdemonstratedM. leprae usesthat aM. mechanism leprae uses similara mechanism to other similar mycobacteria to other mycobacteria to avoid this fusionto avoid in this which fusion a host in protein,which a namelyhost protein tryptophan, namely aspartate-containing tryptophan aspartate coat-containing protein (TACO,coat protein also known(TACO,as also CORO1A known oras coronin-1),CORO1A or lead coronin the phagosome-1), lead the to phagosome escape immune to escape system immune detection system [10,11 detection]. Therefore, [10,11 CORO1A]. Therefore, has beenCORO1A considered has been an essential considered host an protein essential that allowshost protein the intracellular that allows survival the intracellular of mycobacteria survival [10,11 of]. mycobacteriaLikewise, [10,11 lipid metabolism]. has been proven to have a crucial role in the survival of M. leprae bacilli in theLikewise, hostile intracellular lipid metabolism environment has been of macrophage proven to orhave SCs a [10crucial]. In fact,role skinin the lesions survival of severe of M. clinical leprae diseasebacilli in manifestations the hostile intracellular are characterized environment by heavily of macrophage containing or SCs infected [10]. In macrophages fact, skin lesions (also of known severe asclinical Virchow disease cells) manifestations [12]. These cells are present characterized a typically by heavily “foamy” containing appearance, infected which macrophages is in part derived (also fromknown a classicalas Virchow lipid-droplet cells) [12]. marker, These cells called present adipose a typically differentiation-related “foamy” appearance protein,, which highly is positive in part forderived infected from dermal a classical lesions lipid cells-droplet
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