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Advances in Nanocarriers As Drug Delivery Systems in Chagas Disease International Journal of Nanomedicine Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Advances in nanocarriers as drug delivery systems in Chagas disease This article was published in the following Dove Press journal: International Journal of Nanomedicine Christian Quijia Quezada1,2 Abstract: Chagas disease is one of the most important public health problems in Latin Clênia S Azevedo1 America due to its high mortality and morbidity levels. There is no effective treatment for Sébastien Charneau3 this disease since drugs are usually toxic with low bioavailability. Serious efforts to achieve Jaime M Santana1 disease control and eventual eradication have been unsuccessful to date, emphasizing the Marlus Chorilli2 need for rapid diagnosis, drug development, and a reliable vaccine. Novel systems for drug and vaccine administration based on nanocarriers represent a promising avenue for Chagas Marcella B Carneiro4 disease treatment. Nanoparticulate systems can reduce toxicity, and increase the efficacy and Izabela Marques Dourado 1 bioavailability of active compounds by prolonging release, and therefore improve the Bastos therapeutic index. Moreover, nanoparticles are able to interact with the host’s immune 1Pathogen-Host Interface Laboratory, system, modulating the immune response to favour the elimination of pathogenic micro- Department of Cell Biology, Institute of organisms. In addition, new advances in diagnostic assays, such as nanobiosensors, are Biology, University of Brasilia, Brasília, Brazil; 2Department of Drugs and beneficial in that they enable precise identification of the pathogen. In this review, we Medicines, São Paulo State University provide an overview of the strategies and nanocarrier-based delivery systems for antichagasic (UNESP), Araraquara, São Paulo, Brazil; agents, such as liposomes, micelles, nanoemulsions, polymeric and non-polymeric nanopar- 3Laboratory of Protein Chemistry and Biochemistry, Department of Cell ticles. We address recent progress, with a particular focus on the advances of nanovaccines Biology, Institute of Biology, University of and nanodiagnostics, exploring new perspectives on Chagas disease treatment. Brasilia, Brasília, Brazil; 4Electron Microscopy Laboratory, Department of Keywords: delivery systems, nanobiosensors, nanodiagnostics, nanoparticle systems, Cell Biology, Institute of Biology, nanovaccine University of Brasilia, Brasília, Brazil Introduction Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America, where between five and eight million people are infected. The disease is spreading to non-endemic countries, such as Australia, Canada, Japan, Spain and United States of America (USA).1 It is mainly transmitted by faecal contamination of Reduviidae insects through insect bites or another injury of the skin2 parasite can also be spread by blood transfusion, organ transplantation, congenital contamina- tion, and consumption of contaminated food and drinks.3 The T. cruzi biological cycle is comprised of three fundamental forms: (1) infective trypomastigotes found in mammalian blood and in the hindgut of triatomine bugs as metacyclic forms, (2) epimastigotes, the proliferative form located in the bug’s midgut, and (3) amasti- gotes that multiply by binary fission inside mammalian host cells, causing disrup- Correspondence: Izabela Marques tion and the release of new trypomastigotes into the bloodstream capable of Dourado Bastos invading any nucleated cell to begin a new reproductive cycle.4 Regarding clinical Departamento de Biologia Celular, Universidade de Brasilia, Brasília 70910- symptoms, Chagas disease can manifest both an acute phase which is asymptomatic 900, DF, Brazil in most cases and a chronic phase that is depicted by digestive and/or cardiac Tel +55 613 107 3051 5 Email [email protected] lesions. Treatment is based on the nitroheterocyclic compounds benznidazole and submit your manuscript | www.dovepress.com International Journal of Nanomedicine 2019:14 6407–6424 6407 DovePress © 2019 Quijia Quezada et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/ terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing http://doi.org/10.2147/IJN.S206109 the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Quijia Quezada et al Dovepress nifurtimox. However, in long-term therapy, both of the strategies on the treatment of Chagas disease, as well as a aforementioned induce serious side effects and cross-resis- general overview of nanovaccines and nanodiagnostics. tance. To date, research into the production of Chagas disease vaccines has been conducted. The main difficulties General aspects have been finding a protective antigen and generating Physical characteristics of the nanocarriers attenuated parasites that will not trigger pathology in the Some physical characteristics can influence nanocarrier long-term.6 Therefore, in the absence of vaccines, control functions and thus can be strategically explored to control measures for Chagas disease remain limited to diagnosis the Chagas disease, especially against intracellular para- and treatment.5 sites, which are the most difficult forms to eliminate. Nanocarriers has demonstrated important results in These main characteristics are: 1) size of the particles: terms of increasing the efficacy and decreasing the toxicity this feature improves greater bioavailability and circula- of drugs, antigens, and adjuvants currently used against tion time (release, aggregation and transport of the drug), some diseases. The use of nanocarriers against pathogens ranging from 1 to 100 nm or micrometric size (μm).9–11 2) provides a greater ability to overcome biological barriers, Solubility: nanostructures can encapsulate insoluble or maintenance of drug integrity in biological media, with poorly soluble drugs, and the use of them can eliminate higher specificity to target cells and tissues together with the need for toxic organic solvents.12 3) Shape: it can prolonged drug release in comparison to conventional influence interactivity, cellular uptake, retention, biocom- drugs.7 Moreover, nanodiagnostic systems have been patibility, transport and drug loading capacity. The main developed to improve the accuracy of sample preparation shapes are spheres, discs, hemispheres, cylinders, cones, and detection of infectious pathogens by means of a sim- and tubes.10,11 4) Surface area: provides more reactivity as ple, quick, accurate and inexpensive technique.8 the particle size decreases in comparison to larger mole- In this review, we provide an overview of synthetic cules (bulk solids), in addition, they are responsible for the methods, physical characteristics and delivery systems improved water solubility and bioavailability.10 5) Net based on nanocarriers for various antitrypanosomal agents, charge: it can influence the retention in the tissue, the through liposomes, micelles, mesoporous silica nanoparti- circulation half-life and the uptake. In fact, cationic parti- cles, polymeric and non-polymeric nanoparticles (Figure 1). cles can have better uptake in the electrostatic interaction In this context, we highlight new perspectives and innovative with the membrane,13,14 compared to particles with nega- tive charges that have longer circulation half-life.15 The interactions of nanoparticles with their biological environment (molecules, cells, organs) depend on a com- plex interaction between controllable particle properties and largely uncontrollable properties of the surrounding media. Particle size, surface charge, polydispersity index, shape, and surface chemistry are key factors that deter- mine the performance criteria, including the degree of protein adsorption, cell absorption, biodistribution patterns and mechanisms.16 Regarding Chagas disease, these nano- materials must show a high volume of distribution and longer circulation time in the body compared to the avail- able drugs (Nifurtimox or Benznidazole). It has been shown that highly cationic nanoparticles are eliminated from the circulation more rapidly than highly anionic nanoparticles.17 In contrast, neutral nanoparticles, as well as those with a slight negative charge, show significantly longer circulating half-lives, since the negative nature of Figure 1 Nanomaterials used against Chagas disease. Strategies and application of cell membranes allows them to be highly absorbed by nanocarrier-based drug delivery systems, such as liposomes, micelles, mesoporous cells.18–22 Similarly, the size of the nanoparticle, with an silica nanoparticles, polymeric and non-polymeric nanoparticles to optimize the delivery of antitrypanosomal agents. average of less than 200 nm, enables a longer lifetime in 6408 submit your manuscript | www.dovepress.com International Journal of Nanomedicine 2019:14 DovePress Dovepress Quijia Quezada et al the bloodstream, by avoiding interactions with the mono- Gonzalez-Martin et al29 synthesized the same allopur- nuclear phagocyte system and controlling drug delivery.23 inol-loaded polyether cyclic nanoparticles and showed that the pyrazolopyrimidine
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