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Made available in DSpace on 2021-06-25T15:38:43Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-09-16 Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Artemisinin (ART) was initially described for the control of inflammation and pain. However, the mechanisms involved with its antinociceptive effect are still poorly understood. Thus, this present study aimed to investigate the effect of ART in both free and nanocapsulated form on postoperative pain, as well as the participation of the spinal Toll-like receptor 4 (TLR4) in this process. Postoperative pain was induced using the skin/muscle incision retraction (SMIR) model in male Swiss mice. After 3 and 28 days of SMIR, the animals received an intrathecal injection of free or nanocapsulated ART, and the nociceptive threshold was evaluated by von Frey filament test. To evaluate the involvement of the microglia, astrocytes, and TLR4, minocycline (a microglia inhibitor), fluorocitrate (an astrocyte inhibitor), andLipopolysaccharide Rhodobacter sphaeroides(LPS-RS), a TLR4 antagonist, were intrathecally injected on the third day of SMIR. The levels of spinal TLR4 protein and proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), and interleukin-1-beta (IL-1 beta) were quantified by western blot and enzyme-linked immunosorbent assay, respectively. The results showed that free ART reduced postoperative pain (P < 0.001,F-5,F-30 = 7.49, 16.66% for 1000 ng dose; andP < 0.01,F-5,F-30 = 7.49, 14.58% for 500 ng dose) on the 3rd day of SMIR; while the ART nanocapsule had this effect on both the third (P < 0.001;F-5,F-30 = 4.94; 43.75, 39.58 and 72.91% for the 250, 500 and 1000 ng doses, respectively) and 28th (P < 0.05;F-5,F-30 = 7.71; 29.16 and 33.33% for the 500 and 1000 ng doses, respectively) day. The ART nanocapsule had a more potent and longer antinociceptive effect than free ART or morphine. Postoperative pain was also reduced by minocycline and LPS-RS. The ART nanocapsule also reduced the increased levels of TLR4, TNF-alpha, and IL-1 beta induced by SMIR. These data suggest that the ART nanocapsule has a potent analgesic effect on postoperative pain at the spinal level, and this response involves the inhibition of TLR4 and the proinflammatory cytokines TNF-alpha and IL-1 beta. Univ Fed Alfenas, Fac Motr Sci, Sci Motr Inst, Jovino Fernandes Sales Ave 2600, BR-37133840 Alfenas, Brazil Univ Sao Paulo, Dept Pharmacol, Sao Paulo, Brazil Univ Estadual Campinas, Fac Pharmaceut Sci, Campinas, Brazil Sao Paulo State Univ, Inst Sci & Technol, Sorocaba, Brazil Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Ribeirao Preto, Brazil Sao Paulo State Univ, Inst Sci & Technol, Sorocaba, Brazil CAPES: 001 FAPESP: 2014/16008-3

Establishing new animal models for the study of inflammation is very important in the process of discovering new drugs, since the inflammatory event is the basis of many pathological processes. Whereas rodent models have been the primary focus of inflammation research, we defend the zebrafish (Danio rerio) test as a feasible alternative for preclinical studies. Moreover, despite all the technological development already achieved by humanity, nature can still be considered a relevant source of new medicines. In this context, the aim of this work was to evaluate the anti-inflammatory effect of a substance isolated from the medicinal plant Annona crassilfora Mart, the peltatoside, in an inflammatory model of zebrafish. It was determined: (i) total leukocyte count in the coelomate exudate; (ii) N-acetyl-β-d-glucuronidase (NAG); (iii) myeloperoxidase (MPO); (iv) and the histology of liver, intestine and mesentery. Peltotoside (25, 50 and 100 μg) and dexamethasone (25 μg) were administered intracelomatically (i.c.) 30 min before carrageenan (i.c.). Pretreatment with peltatoside at three doses significantly inhibited leukocyte recruitment in the coelomic cavity, and inhibited NAG and MPO activity against the action of Cg, in a similar manner as dexamethasone. However, some microlesions in the evaluated organs were detected. The dose of 25 μg showed an anti-inflammatory effect with lower undesirable effects in the tissues. Our results suggest that the zebrafish test was satisfactory in performing our analyzes and that the peltotoside has a modulatory action in reducing leukocyte migration.

Made available in DSpace on 2019-10-06T15:23:08Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-02-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Aeromonas hydrophila (Ah) are rod-shaped, Gram-negative, motile aquatic bacteria that can infect fish and mammals, including humans. Due to the importance of this pathogen for fish farming and public health, the present study produced a specific immunoglobulin (Ig) Y by immunizing laying hens with Ah cell proteins. The antibody efficacy in detecting Ah was tested by direct immunofluorescence and indirect immunohistochemistry using tissues from infected Nile tilapia. The produced IgY exhibited specificity and affinity for membrane and cytoplasmic Ah proteins, which enabled detection of the intracellular localization of the bacteria and their proteins within the phagosomes of phagocytes and detection of extracellular bacteria colonizing host tissues. Thus, the findings offer a new perspective on the use of IgY for the diagnosis and analysis of Ah pathogenesis in Nile tilapia. Institute of Chemistry Sao Paulo State University (Unesp) Department of Technology School of Agrarian and Veterinary Sciences Sao Paulo State University (Unesp) Department of Preventive Veterinary School of Agrarian and Veterinary Sciences Sao Paulo State University (Unesp) Institute of Chemistry Sao Paulo State University (Unesp) Department of Technology School of Agrarian and Veterinary Sciences Sao Paulo State University (Unesp) Department of Preventive Veterinary School of Agrarian and Veterinary Sciences Sao Paulo State University (Unesp) CNPq: 140505/2016-4 CNPq: 429245/2016-5

Made available in DSpace on 2020-12-10T22:00:47Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-12-15 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) This study aimed to investigate the physical and chemical properties of mucoadhesive zein nanoparticles containing eugenol (NPZMA) and to evaluate their anesthetic effect in immersion baths, their stability in water and their effects on hemogasometric parameters of juvenile Oreochromis niloticus. Four experiments were performed: Experiment 1 characterized the nanoparticles. Experiment 2 evaluated the stability of NPZMA in water using an in vitro test with the following treatments: eugenol-80 mg L-1; NPZMA-80 mg L-1; NPZMA-40 mg L-1, NPZMA-20 mg L-1, water in natura and control (ethyl alcohol was added to the water at a proportion of 1:10 V/V). Experiment 3 tested the same treatments for time of anesthesia induction and recovery. Experiment 4 tested basal (group of non-anesthetized fish), eugenol-80 mg L-1 and NPZMA-40 mg L-1 for hemogasometric variables after two minutes of exposure. The new method for applying eugenol through mucoadhesive zein nanoparticles presented here exhibited positive loads and successful adherence to fish mucus. The method led to changes in water quality during the 60-min observation period, although it remained within the ideal range for O. niloticus. Experiment 3 revealed similar induction times for eugenol-80 mg L-1, NPZMA-80 mg L-1 and NPZMA-40 mg L-1 (P > .05). Recovery time was shortest for NPZMA-20 mg L-1 and longest for NPZMA-80 mg L-1 (P < .05). Experiment 4 found the concentrations tested to have no effects on hemogasometric variables (P > .05). The results demonstrate that mucoadhesive nanoparticles reduced the use of eugenol by 50%, as observed for NPZMA-40 mg L-1. Furthermore, this new form of eugenol application based on mucoadhesive zein nanoparticles showed good stability in water and did not alter hemogasometric parameters of juvenile O. niloticus. Univ Fed Minas Gerais, Dept Zootecnia, Lab Aquacultura, Ave Antonio Carlos 6627, BR-31270901 Belo Horizonte, MG, Brazil Univ Sao Paulo, Inst Ciencias Biol, Dept Farmacol, Ave Prof Lineu Prestes 2415, BR-05508000 Sao Paulo, SP, Brazil Inst & Ctr Pesquisas Sao Leopoldo Mandic, Rua Doutor Jose Rocha Junqueira 13, BR-13045755 Campinas, SP, Brazil Univ Estadual Paulista, Inst Ciencia & Tecnol, Ave Tres Marco,511 Alto Da Boa Vista, BR-18087180 Sorocaba, SP, Brazil Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Morfol, Ave Antonio Carlos 6627, BR-6627 Belo Horizonte, MG, Brazil Univ Estadual Paulista, Inst Ciencia & Tecnol, Ave Tres Marco,511 Alto Da Boa Vista, BR-18087180 Sorocaba, SP, Brazil CNPq: 308547/2018-7

Malaria affects more than 200 million people annually around the world, killing a child every 2 min. Artemether (ART) and lumefantrine (LUM) are the gold standard choice to treat uncomplicated Plasmodium falciparum malaria; however, they are hydrophobic compounds with low oral bioavailability. Microneedle (MN) arrays consist of micron-sized needles on one side of a supporting base and have the ability to bypass the skin's stratum corneum barrier in a minimally invasive way, creating temporary channels through which drugs can diffuse, including those with poor water solubility. Herein, we report the development of dissolving MNs (DMNs) containing ART (MN-ART) and LUM (MN-LUM) as an alternative treatment regimen for malaria in low-resource settings. To incorporate the drugs into the MNs, nanosuspensions (NSs) for both molecules were developed separately to enhance drug solubility. The NSs were freeze-dried and the powder form was incorporated directly in an aqueous polymeric blend with poly-vinyl-pyrrolidone for MN-ART and a sodium hyaluronate hydrogel for MN-LUM. The in vivo bioavailability studies were performed using a MN reapplication scheme (1 × a day for 3 days), illustrating that an extended-release profile was achieved for both drugs when MNs were applied intradermally, and when compared to conventional oral treatment. The ART-LUM oral treatment was used as a positive control. For antimalarial activity, studies with animals infected with 106 Plasmodium yoelii 17XNL (12 days) were also conducted using female C57BL/6JUnib mice, demonstrating a 99.5% reduction in parasitemia by day 12 post-infection. By abolishing the infection, MN-ART and MN-LUM may serve as a promising controlled intradermal delivery device for antimalarial drugs to be explored in endemic areas.

Made available in DSpace on 2021-06-25T10:13:13Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-12-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) In order to understand events and mechanisms present in the pathophysiology of tilapia's chronic inflammation and based on the immunomodulatory activity attributed to cyclophosphamide which is widely used to suppress immune responses in human medicine, the present study investigated the effects of cyclophosphamide (CYP) treatment on the modulation of foreign body inflammatory reaction in Nile tilapia (Oreochromis niloticus) with round glass coverslip implanted in the subcutaneous tissue (9 mm of diameter). Forty tilapia (151 ± 10,2 g) were randomly distributed in 5 aquariums (n = 8) with a capacity of 250 L of water each, to compose two treatments (sampled 3 and 6 days post-implantation): implanted/untreated (control) and implanted/treated with 200 mg of CYP kg−1 of b.w., through i.p. route. A fifth group (n = 8) was sampled without any stimulus (naive) to obtain reference values. CYP-treated tilapia showed decrease in macrophage accumulation, giant cell formation and Langhans cells on the glass coverslip when compared to control fish. The treatment with CYP resulted in decrease of leukocyte and thrombocyte counts. Decrease in alpha-2-macroglobulin, ceruloplasmin, albumin and transferrin levels, as well as increase in haptoglobin, complement C3 and apolipoprotein A1 were observed in tilapias during foreign body inflammation. Blood levels of complement C3, alpha-2-macroglobulin, ceruloplasmin and transferrin were modulated by treatment with CYP. Therefore, the treatment with 200 mg of CYP kg−1 of b.w. in tilapia resulted in an anti-inflammatory effect by suppressing the dynamics between leukocytes in the bloodstream and macrophage accumulation with giant cell formation in the inflamed focus, as well as by modulating APPs during foreign body reaction. Department of Pharmacology Institute of Biomedical Science University of São Paulo (USP) Department of Preventive Veterinary Medicine São Paulo State University (UNESP) Veterinary College Federal University of Rondonia (UNIR) Department of Graduate Program in Health Sciences Federal University of Roraima (UFRR) Laboratório de Bioquímica de Peptídeos UNIFESP Laboratory of Animal Pharmacology and Toxicology Brasil University Department of Preventive Veterinary Medicine São Paulo State University (UNESP) FAPESP: 2012/12256-7 FAPESP: 2013/11675-9 CNPq: 432830/2016-2 CNPq: 477816/2013-4

Made available in DSpace on 2021-06-25T11:04:32Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-09-01 Mucoadhesive polymeric nanocapsules have attracted interest of researchers from different fields from natural sciences because of their ability to interact with the mucosa and increase drug permeation. Anesthesia by immersion causes absorption through the skin and gills of fish, so it is important to evaluate the exposure of these organs to drug nanosystems. Benzocaine (BENZ) is one of the most popular anesthetic agents used in fish anesthesia, but it has drawbacks because of its low bioavailability, resulting in weak absorption after immersion. Here we describe method developed for preparing and characterizing chitosan-coated PLGA mucoadhesive nanoparticles containing BENZ (NPMAs) for zebrafish immersion anesthesia. We determined the lowest effective concentration, characterized the interaction of the mucoadhesive system with fish, measured the anesthetic efficacy, and evaluated possible toxic effects in embryos and adults exposed to the nanoformulations. This study opens perspectives for using nanoformulations prepared with BENZ in aquaculture, allowing reduction of dosage as well as promoting more effective anesthesia and improved interaction with the mucoadhesive system of fish. Department of Pharmacology University of São Paulo-ICB/USP Laboratório Integrado de Biociências Translacionais (LIBT) Instituto de Biodiversidade e Sustentabilidade (NUPEM) Universidade Federal do Rio de Janeiro (UFRJ) Department of Morphology ICB-UFMG Aquiculture Laboratory (Laqua) UFMG Department of Preventive Veterinary Medicine São Paulo State University Department of Postgraduate in Health Sciences PROCISA Federal University of Roraima (UFRR) Institute of Chemistry São Paulo State University (Unesp) Laboratory of Animal Pharmacology and Toxicology Brasil University Department of Clinical and Toxicological Analyses Faculty of Pharmacy-UFMG Laboratory of Applied Immunology Federal University of São Carlos School of Veterinary Medicine Department of Clinic and Veterinary Surgery UFMG Faculty of Medicine São Leopoldo Mandic Institute of Science and Technology of Sorocaba São Paulo State University Department of Preventive Veterinary Medicine São Paulo State University Institute of Chemistry São Paulo State University (Unesp) Institute of Science and Technology of Sorocaba São Paulo State University

Morphological nuclear alterations are indicative of DNA damage and have been considered excellent markers of exposure to several pollutants in aquatic environments. Flow cytometry is a powerful technique for measuring cell phenotypes in large numbers of cells in a short period of time. This technique is suited to the study of cell populations and subset identification as a function of its high-throughput and multi-parameter characteristics. We used the quantification of erythrocyte nuclear alterations to compare the techniques of imaging flow cytometry and light microscopy. The comparison used blood samples of the fish Oreochromis niloticus assayed using cadmium as a nuclear alteration-inducing agent. The results showed that imaging flow cytometry has higher sensitivity than light microscopy for detecting and quantifying erythrocytic nuclear alterations. We conclude that imaging flow cytometry can produce fast and reliable results and could potentially be useful in studies involving fish erythrocytes under normal and impacted environmental conditions.

The present study evaluated whether a natural dietary additive, dried Artemisia annua leaves, may be useful to control Rhipicephalus (Boophilus) microplus on naturally infested cattle. Twenty heifers of the Canchim breed, weighing around 250 kg, were divided into two equally sized experimental groups: 1) control animals and 2) animals receiving 200 g/day of dried A. annua leaves for two months. Before treatment began, the animals were homogeneously distributed in control and treatment groups based on their pre-treatment weight and tick infestation level. Counts of engorged female ticks then occurred weekly during the two-month experimental period. We also monitored cattle weight gain and packed cell volume (PCV). Artemisinin (0.96%) was quantified in the plant material by high-performance liquid chromatography with refractive index detector (HPLC-IR). No statistical differences between the control and treatment groups were observed for engorged female counts (log averages of 1.3 ticks and 1.4 ticks per animal, respectively), daily cattle weight gain (0.910 kg and 0.888 kg, respectively) or PCV (33.5% and 33.0%, respectively). We conclude that the oral supplementation of cattle feed with dried A. annuna leaves did not control natural infestation of R. (B.) microplus. The hypothesis of artemisinin’s action on cattle ticks by ingestion through the animals’ blood was not confirmed at the evaluated dose.

Made available in DSpace on 2019-10-06T16:39:48Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-10-15 Nanoparticles to delivery drugs and immunomodulatory substances in fish have been widely studied by several research groups. In general, these nanoparticles are polymers, ceramic, fullerenes and metal derivates which can be toxic to fish and other aquatic organisms. We reported for the first time a nanostructured system composed of proteins obtained from pacamã fish (Lophiosilurus alexandri) mucus. We identified and characterized the formation of nanoparticles with 210.8 nm and zeta potential of −13.4 (mV). These characteristics suggest a possible application of this material as a biocompatible coating. These nanoparticles are biodegradable, metabolizable and can be easily manipulated; as well as they can easily undergo surface modification to transport biomolecules, thus exhibiting greater versatility. Our study suggests that these nanoparticles from fish mucus could be used to delivery drugs and to modulate the immune system, since they demonstrated to be biocompatible coating. Universidade Brasil Campus Itaquera Faculdade de Medicina São Leopoldo Mandic Departamento de Morfologia Universidade Federal de Minas Gerais Universidade Estadual Paulista Instituto de Ciência e Tecnologia de Sorocaba Laboratório de Bioquímica de Peptídeos Universidade Federal de São Paulo Laboratório de Farmacologia e Toxicologia Animal Descalvado/SP Universidade Brasil Departamento de Medicina Veterinária Preventiva Universidade Estadual Paulista- Unesp Jaboticabal Departamento de Zootecnia Universidade Federal de Minas Gerais Escola de Veterinária Laboratório de Aquacultura Universidade Estadual Paulista Instituto de Ciência e Tecnologia de Sorocaba Laboratório de Farmacologia e Toxicologia Animal Descalvado/SP Universidade Brasil Departamento de Medicina Veterinária Preventiva Universidade Estadual Paulista- Unesp Jaboticabal

Made available in DSpace on 2019-10-06T17:05:31Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-12-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Acute-phase protein (APPs) serum levels have been studied in many human diseases, and their components contribute to host defense during the evolution of infectious diseases by acting as part of the innate immune system. Based on the importance of establishing new experimental models, the present investigation evaluated the modulation of APPs following inflammatory stimulus by the inoculation of Aeromonas hydrophila in tilapias. Fish were sampled 6 and 24 hours post-infection. Tilapias presented increase of positive APPs such as ceruloplasmin, haptoglobin, alpha-2-macroglobulin and complement C3, as well as decrease of negative APPs such as albumin and transferrin. The protein response of tilapias during the course of bacterial infection showed correlation with the kinetics of cellular accumulation in the inflamed focus with significant increase of granulocytes, thrombocytes, lymphocytes and macrophages. However, granulocytes were the predominant cells, associated with increment in the reactive oxygen species (ROS) production. Showing responses similar to those observed in humans, the modulation of APPs and the kinetics of cellular accumulation in the exudate demonstrate the feasibility of this alternative experimental model for advances and studies to understand changes in pathophysiological mechanisms of acute inflammatory reaction due to bacterial infection. Department of Preventive Veterinary Medicine São Paulo State University (UNESP) Department of Pharmacology and Morphology ICB-UFMG Immunoregulation Unit of the Special Laboratory of Applied Toxicology (CEPID/FAPESP) Butantan Institute Laboratório de Bioquímica de Peptídeos UNIFESP Veterinary College Federal University of Rondonia Laboratory of Animal Pharmacology and Toxicology Brasil University Department of Preventive Veterinary Medicine São Paulo State University (UNESP)

Made available in DSpace on 2020-12-10T17:03:14Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-12-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) In order to understand the pathophysiology of melanomcrophage centers (MMCs) formation during the tilapia defense response to bacterial infections, the present study evaluated the response, in terms of area, number and pigment constitution, of splenic MMCs of Oreochromis niloticus subjected to intraperitoneal (i.p.) infection with Aeromonas hydrophila and Mycobacterium marinum. Eighty-four fish (396.9 +/- 21.0 g) were randomly distributed into twelve plastic tanks (300 L), to constitute three treatments with 28 animals each: control group (inoculated with PBS); Infected with A. hydrophila (1 x 10(7) UFC mL(-1)); Infected with M. marinum (1 x 10(6) UFC mL(-1)). The spleen was collected in seven fish per treatment on the 3rd, 7th, 14th and 21st day post-infection (DPI). The results revealed the participation of MMCs in the defense response of tilapia during bacterial infection by A. hydrophila and M. marinum, since there was an increase in the number and size of these cell aggregates. Variation of pigment accumulation with significant increase of hemosiderin, in infected tilapias by A. hydrophila, bacteria responsible for causing hemolytic anemia in fish was also found. On the other hand, M. marinum-infected tilapia had high amount of melanin in MMCs. In general, mycobacterial infections are notoriously difficult to treat, being characterized as a chronic disease. These findings demonstrate different strategies of fish response during the evolution of these bacterial diseases. Sao Paulo State Univ, Jaboticabal Campus, Sao Paulo, SP, Brazil Fed Univ Rondonia, Dept Vet Med, Rolim de Moura Campus, Rolim De Moura, Rondonia, Brazil Brasil Univ, Sao Paulo, SP, Brazil Biol Inst Sao Paulo, TB Lab, Sao Paulo, Brazil Sao Paulo State Univ, Jaboticabal Campus, Sao Paulo, SP, Brazil FAPESP: 13/01838-8

Made available in DSpace on 2021-06-25T12:42:32Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-04-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Instituto Federal Goiano Although carbon nanotubes' (CNTs) toxicity in different experimental systems (in vivo and in vitro) is known, little is known about the toxic effects of carbon nanofibers (CNFs) on aquatic vertebrates. We herein investigated the potential impact of CNFs (1 and 10 mg/L) by using Physalaemus cuvieri tadpoles as experimental model. CNFs were able to induce nutritional deficit in animals after 48-h exposure to them, and this finding was inferred by reductions observed in body concentrations of total soluble carbohydrates, total proteins, and triglycerides. The increased production of hydrogen peroxide, reactive oxygen species and thiobarbituric acid reactive substances in tadpoles exposed to CNFs has suggested REDOX homeostasis change into oxidative stress. This process was correlated to the largest number of apoptotic and necrotic cells in the blood of these animals. On the other hand, the increased superoxide dismutase and catalase activity has suggested that the antioxidant system of animals exposed to CNFs was not enough to maintain REDOX balance. In addition, CNFs induced increase in acetylcholinesterase and butyrylcholinesterase activity, as well as changes in the number of neuromasts evaluated on body surface (which is indicative of the neurotoxic effect of nanomaterials on the assessed model system). To the best of our knowledge, this is the first report on the impact of CNFs on amphibians; therefore, it broadened our understanding about ecotoxicological risks associated with their dispersion in freshwater ecosystems and possible contribution to the decline in the populations of anurofauna species. Univ Fed Goias, Postgrad Program Biotechnol & Biodivers, Goiania, Go, Brazil Goiano Fed Inst, Biol Res Lab, Urutai Campus,Rodovia Geraldo Silva Nascimento 2, BR-75790000 Urutai, Go, Brazil Sao Paulo State Univ, Morphol Dept, Reprod & Mol Biol Grp, Botucatu, SP, Brazil Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Sao Paulo, Brazil Goiano Fed Univ, Postgrad Program Cerrado Nat Resources Conservat, Urutai Campus, Urutai, Brazil Univ Fed Uberlandia, Postgrad Program Ecol & Nat Resources Conservat, Uberlandia, MG, Brazil Sao Paulo State Univ, Morphol Dept, Reprod & Mol Biol Grp, Botucatu, SP, Brazil CNPq: 426531/2018-3 CNPq: 23219.000002.2021-81 Instituto Federal Goiano: 23219.000002.2021-81 CNPq: 307743/2018-7

Doxorubicin (DOX) is an anthracycline antibiotic widely used in the treatment of cancer, however, it is associated with the occurrence of adverse reactions that limits its clinical use. In this context, the encapsulation of DOX in micelles responsive to pH variations has shown to be a strategy for tumor delivery of the drug, with the potential to increase therapeutic efficacy and to reduce the toxic effects. In addition, radiolabeling nanoparticles with a radioactive isotope is of great use in preclinical studies, since it allows the in vivo monitoring of the nanostructure through the acquisition of quantitative images. Therefore, this study aimed to develop, characterize, and evaluate the antitumor activity of a pH-sensitive micelle composed of DSPE-PEG2000, oleic acid, and DOX. The micelles had a diameter of 13 nm, zeta potential near to neutrality, and high encapsulation percentage. The critical micellar concentration (CMC) was 1.4 × 10−5 mol L-1. The pH-sensitivity was confirmed in vitro through a drug release assay. Cytotoxicity studies confirmed that the encapsulation of DOX into the micelles did not impair the drug cytotoxic activity. Moreover, the incorporation of DSPE-PEG2000-DTPA into the micelles allowed it radiolabeling with the technetium-99 m in high yield and stability, permitting its use to monitor antitumor therapy. In this sense, the pH-sensitive micelles were able to inhibit tumor growth significantly when compared to non-pH-sensitive micelles and the free drug. in vivo toxicity evaluation in the zebrafish model revealed significantly lower toxicity of pH-sensitive micelles compared to the free drug. These results indicate that the developed formulation presents itself as a promising alternative to potentiate the treatment of tumors.

In recent years, artemisinin (ART) and its derivatives have highlighted according to their effects on highly aggressive cancers, as well as treatment of malaria and leishmaniasis, besides presenting anti-inflammatory and antibacterial activity. It has also been shown that ART compounds have the ability to modulate the immune response by regulating cell proliferation and cytokine release. These effects may be beneficial and improve the treatment of cancer and parasitic diseases by increasing therapeutic success, but it has some pharmacological limitations such as low bioavailability, short half-life and limited tissue access. Nanotechnology has been explored during the last decades, notably in the design of drug carrier systems which includes polymeric, lipid and inorganic nanoparticles, cyclodextrins inclusion complexes, liposomes, carbon nanotubes, among others. These nanostructured drug delivery systems bring benefits both increased therapeutic efficacy and reduced toxicity. This review article aims to give an overview of the current progress in nanostructured drug carriers used for encapsulation of ART and its derivatives yielding examples of successful outcomes. The data collection suggests future applications of ART and derivatives encapsulated in nano delivery systems in clinical trials and prospects for use of ART loaded nanosystems in immunomodulatory responses.