Publications by authors named "Silvia Stanisçuaski Guterres"

85 Publications

Resveratrol-Loaded Lipid-Core Nanocapsules Modulate Acute Lung Inflammation and Oxidative Imbalance Induced by LPS in Mice.

Pharmaceutics 2021 May 10;13(5). Epub 2021 May 10.

Laboratory of Inflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-360, Brazil.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are inflammatory and oxidative imbalance lung conditions with no successful pharmacological therapy and a high mortality rate. Resveratrol (RSV) is a plant-derived stilbene that presents anti-inflammatory and antioxidant effects. However, its therapeutic application remains limited due to its poor bioavailability, which can be solved by the use of nanocarriers. Previously, we demonstrated that nanoencapsulated RSV (RSV-LNC) pre-treatment, performed 4 h before lipopolysaccharide (LPS) stimulation in mice, increased its anti-inflammatory properties. In this study, we evaluated the anti-inflammatory and antioxidant effects, and lung distribution of RSV-LNCs administered therapeutically (6 h post LPS exposure) in a lung injury mouse model. The results showed that RSV-LNCs posttreatment improved lung function and diminished pulmonary inflammation. Moreover, RSV-LNC treatment enhanced the antioxidant catalase level together with a decrease in the oxidative biomarker in mouse lungs, which was accompanied by an increase in pulmonary Nrf2 antioxidant expression. Finally, the presence of RSV in lung tissue was significantly detected when mice received RSV-LNCs but not when they received RSV in its free form. Together, our results confirm that RSV nanoencapsulation promotes an increase in RSV bioavailability, enhancing its therapeutic effects in an LPS-induced lung injury model.
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http://dx.doi.org/10.3390/pharmaceutics13050683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151102PMC
May 2021

scFv-Anti-LDL(-)-Metal-Complex Multi-Wall Functionalized-Nanocapsules as a Promising Tool for the Prevention of Atherosclerosis Progression.

Front Med (Lausanne) 2021 20;8:652137. Epub 2021 Apr 20.

Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.

Atherosclerosis can be originated from the accumulation of modified cholesterol-rich lipoproteins in the arterial wall. The electronegative LDL, LDL(-), plays an important role in the pathogenesis of atherosclerosis once this cholesterol-rich lipoprotein can be internalized by macrophages, contributing to the formation of foam cells, and provoking an immune-inflammatory response. Herein, we engineered a nanoformulation containing highly pure surface-functionalized nanocapsules using a single-chain fragment variable (scFv) reactive to LDL(-) as a ligand and assessed whether it can affect the LDL(-) uptake by primary macrophages and the progression of atherosclerotic lesions in mice. The engineered and optimized scFv-anti-LDL(-)-MCMN-Zn nanoformulation is internalized by human and murine macrophages by different endocytosis mechanisms. Moreover, macrophages exhibited lower LDL(-) uptake and reduced mRNA and protein levels of and MCP1 induced by LDL(-) when treated with this new nanoformulation. In a mouse model of atherosclerosis employing mice, intravenous administration of scFv-anti-LDL(-)-MCMN-Zn nanoformulation inhibited atherosclerosis progression without affecting vascular permeability or inducing leukocytes-endothelium interactions. Together, these findings suggest that a scFv-anti-LDL(-)-MCMN-Zn nanoformulation holds promise to be used in future preventive and therapeutic strategies for atherosclerosis.
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http://dx.doi.org/10.3389/fmed.2021.652137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095373PMC
April 2021

New nanotechnological formulation based on amiodarone-loaded lipid core nanocapsules displays anticryptococcal effect.

Eur J Pharm Sci 2021 Jul 21;162:105816. Epub 2021 Mar 21.

Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Departamento de Biologia Molecular e Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Electronic address:

Cryptococcus neoformans is the etiological agent of cryptococcal meningoencephalitis. The recommended available treatment has low efficiency, with high toxicity and resistance as recurrent problems. In the search of new treatment protocols, the proposal of new pharmacological approaches is considered an innovative strategy, mainly nanotechnological systems considering fungal diseases. The antiarrhythmic drug amiodarone has demonstrated antifungal activity against a range of fungi, including C. neoformans. Here, considering the importance of calcium storage mediated by transporters on cryptococcal virulence, we evaluated the use of the calcium channel blocker amiodarone as an alternative therapy for cryptococcosis. C. neoformans displayed high sensitivity to amiodarone, which was also synergistic with fluconazole. Amiodarone treatment influenced some virulence factors, interrupting the calcium-calcineurin signaling pathway. Experiments with murine cryptococcosis models revealed that amiodarone treatment increased the fungal burden in the lungs, while its combination with fluconazole did not improve treatment compared to fluconazole alone. In addition, we have developed different innovative nanotechnological formulations, one of which combining two drugs with different mechanisms of action. Lipid-core nanocapsules (LNC) loaded with amiodarone (LNC), fluconazole (LNC) and both (LNC) were produced to achieve a better efficacy in vivo. In an intranasal model of treatment, all the LNC formulations had an antifungal effect. In an intraperitoneal treatment, LNC showed an enhanced anticryptococcal effect compared to the free drug, whereas LNC or LNC displayed no differences from the free drugs. In this way, nanotechnology using amiodarone formulations could be an effective therapy for cryptococcal infections.
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http://dx.doi.org/10.1016/j.ejps.2021.105816DOI Listing
July 2021

Folic Acid-Doxorubicin-Double-Functionalized-Lipid-Core Nanocapsules: Synthesis, Chemical Structure Elucidation, and Cytotoxicity Evaluation on Ovarian (OVCAR-3) and Bladder (T24) Cancer Cell Lines.

Pharm Res 2021 Feb 19;38(2):301-317. Epub 2021 Feb 19.

Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Av. Ipiranga 2752, Porto Alegre, 90610-000, Brazil.

Purpose: Folic acid-doxorubicin-double-functionalized-lipid-core nanocapsules (LNC-CS--Zn-DOX-FA) were prepared, characterized, and evaluated in vitro against ovarian and bladder cancer cell lines (OVCAR-3 and T24).

Methods: LNC-CS--Zn-DOX-FA was prepared by self-assembly and interfacial reactions, and characterized using liquid chromatography, particle sizing, transmission electron microscopy, and infrared spectroscopy. Cell viability and cellular uptake were studied using MTT assay and confocal microscopy.

Results: The presence of lecithin allows the formation of nanocapsules with a lower tendency of agglomeration, narrower size distributions, and smaller diameters due to an increase in hydrogen bonds at the surface. LNC--CS-Zn-DOX-FA, containing 98.00 ± 2.34 μg mL of DOX and 105.00 ± 2.05 μg mL of FA, had a mean diameter of 123 ± 4 nm and zeta potential of +12.0 ± 1.3 mV. After treatment with LNC--CS-Zn-DOX-FA (15 μmol L of DOX), T24 cells had inhibition rates above 80% (24 h) and 90% (48 h), whereas OVCAR-3 cells showed inhibition rates of 68% (24 h) and 93% (48 h), showing higher cytotoxicity than DOX.HCl. The fluorescent-labeled formulation showed a higher capacity of internalization in OVCAR-3 compared to T24 cancer cells.

Conclusion: Lecithin favored the increase of hydrogen bonds at the surface, leading to a lower tendency of agglomeration for nanocapsules. LNC-CS--Zn-DOX-FA is a promising therapeutic agent against tumor-overexpressing folate receptors.
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http://dx.doi.org/10.1007/s11095-021-02989-yDOI Listing
February 2021

Innovative hydrogel containing polymeric nanocapsules loaded with phloretin: Enhanced skin penetration and adhesion.

Mater Sci Eng C Mater Biol Appl 2021 Jan 28;120:111681. Epub 2020 Oct 28.

Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. Electronic address:

Dermatological applications of phloretin are restricted by its poor aqueous solubility. Nanotechnology has been proposed as strategy to increase the apparent drug solubility in aqueous media. This study aimed to develop, characterize, and evaluate the antitumoral effects and safety of polymeric nanocapsules containing phloretin (NCPhl). Further, to incorporate NC-Phl in an innovative semi-solid formulation (HG-NCPhl) to evaluate its performance using porcine skin model. NC-Phl was prepared and the effects in MRC5, HACAT, and SK-mel28 cells were evaluated. Hydrogels were prepared with Lecigel ® and characterized for their nanotechnological properties, adhesion (in vitro washability), and penetration/permeation studies in porcine skin. NC-Phl had a cytotoxic effect against Sk-Mel-28 cells and the population doubling time was increased upon treatment with NC-Phl for longer culture periods; notably when cells were treated for 72 h and then followed for 7 days after the treatment was removed (p < 0.05). HG-NC-Phl was considered adhesive and had a higher capacity to penetrate all skin layers compared with HG-Phl (p < 0.05). The innovative hydrogel HGNC-Phl promoted a drug-reservoir in the stratum corneum and higher penetration of the flavonoid into the epidermis. Therefore, this approach can be considered as a platform to establish versatile dermatological solutions for both cosmeceutics and melanoma therapy.
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http://dx.doi.org/10.1016/j.msec.2020.111681DOI Listing
January 2021

Dermatopharmacokinetic and pharmacodynamic evaluation of a novel nanostructured formulation containing capsaicinoids for treating neuropathic pain.

Int J Pharm 2021 Mar 23;596:120294. Epub 2021 Jan 23.

Pharmaceutical Sciences Graduate Program, College of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.

The in vivo skin penetration by dermal microdialysis and the pharmacological efficacy of a chitosan hydrogel containing capsaicinoids-loaded nanocapsules (CHNC) was evaluated in this study. Such gel has previously been proven to control capsaicinoids release and decrease the drugs side effects in humans. The nanocapsules containing capsaicinoids had an average size around 150 nm, with a low polydispersity index, positive zeta potential, and high encapsulation efficiency of the drugs. The CHNC showed intact nanocapsules, a slightly acid pH value, and a pseudoplastic behavior suitable for topical application. Microdialysis experiments showed a 1.6-fold increase in the concentration of capsaicinoids in the dermis (after 12 h of its application) when CHNC was administered compared to a chitosan hydrogel containing capsaicinoids in hydroethanolic solution (CHET) and the commercial cream. The CHNC showed antiallodynic and antihyperalgesic effects from 6 h to 96 h after treatment initiation, whereas CHET and the commercial cream showed antiallodynic and antihyperalgesic effects only at 48 h and 96 h after treatment initiation, respectively. CHNC and the commercial cream maintained antihyperalgesic activity for 6 days after treatment interruption. For mechanical allodynia, the antinociceptive effect was maintained for 48 h after treatment interruption only with CHNC. In conclusion, CHNC is a promising formulation for treating peripheral neuropathic pain.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120294DOI Listing
March 2021

Docosahexaenoic acid nanoencapsulated with anti-PECAM-1 as co-therapy for atherosclerosis regression.

Eur J Pharm Biopharm 2021 Feb 6;159:99-107. Epub 2021 Jan 6.

LADAF, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address:

Atherosclerosis is a non-resolving inflammatory condition that underlies major cardiovascular diseases.Recent clinical trial using an anti-inflammatory drug has showna reduction of cardiovascular mortality, but increased the susceptibility to infections. For this reason, tissue target anti-inflammatory therapies can represent a better option to regress atherosclerotic plaques. Docosahexaenoic acid (DHA) is a natural omega 3 fatty acidcomponentof algae oil and acts asaprecursor of several anti-inflammatory compounds, such the specialized proresolving lipid mediators(SPMs). During the atherosclerosis process, the inflammatory condition of the endothelium leads to the higher expression of adhesion molecules, such as Endothelial Cell Adhesion Molecule Plate 1 (PECAM-1 or CD31), as part of the innate immune response. Thus, the objective of this study was to develop lipid-core nanocapsules with DHA constituting the nucleus and anti-PECAM-1 on their surface and drive this structure to the inflamed endothelium. Nanocapsules were prepared by interfacial deposition of pre-formed polymer method. Zinc-II was added to bind anti-PECAM-1 to the nanocapsule surface by forming an organometallic complex. Swelling experiment showed that the algae oil act as non-solvent for the polymer (weight constant weight for 60 days, p > 0.428) indicating an adequate material to produce kinetically stable lipid-core nanocapsules (LNC). Five formulations were synthesized: Lipid-core nanocapsules containing DHA (LNC-DHA) or containing Medium-chain triglycerides (LNC-MCT), multi-wall nanocapsules containing DHA (MLNC-DHA) or containing MCT (MLNC-MCT) and the surface-functionalized (anti-PECAM-1) metal-complex multi-wall nanocapsules containing DHA (MCMN-DHA-a1). All formulations showed homogeneous macroscopic aspects without aggregation. The mean size of the nanocapsules measured by laser diffraction did not show difference among the samples (p = 0.241). Multi-wall nanocapsules (MLNC) showed a slight increase in the mean diameter and polydispersity index (PDI) measured by DLS, lower pH and an inversion in the zeta-potential (ξP) compared to LNCs. Conjugation test for anti-PECAM-1 showed 94.80% of efficiency. The mean diameter of the formulation had slightly increased from 160 nm (LCN-DHA) and 162 nm (MLNC-DHA) to 164 nm (MCMN-DHA-a1) indicating that the surface functionalization did not induce aggregation of the nanocapsules. Biological assays showed that the MCMN-DHA-a1 were uptaken by the HUVEC cells and did not decrease their viability. The surface-functionalized (anti- PECAM-1) metal-complex multi-wall nanocapsules containing DHA (MCMN-DHA-a1) can be considered adequate for pharmaceutical approaches.
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http://dx.doi.org/10.1016/j.ejpb.2020.12.016DOI Listing
February 2021

Incorporation of amoxicillin-loaded microspheres in mineral trioxide aggregate cement: an study.

Restor Dent Endod 2020 Nov 7;45(4):e50. Epub 2020 Oct 7.

Department of Dental Materials, School of Dentistry, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.

Objectives: In this study, we investigated the potential of amoxicillin-loaded polymeric microspheres to be delivered to tooth root infection sites via a bioactive reparative cement.

Materials And Methods: Amoxicillin-loaded microspheres were synthesized by a spray-dray method and incorporated at 2.5% and 5% into a mineral trioxide aggregate cement clinically used to induce a mineralized barrier at the root tip of young permanent teeth with incomplete root development and necrotic pulp. The formulations were modified in liquid:powder ratios and in composition by the microspheres. The optimized formulations were evaluated for physical and mechanical eligibility. The morphology of microspheres was observed under scanning electron microscopy.

Results: The optimized cement formulation containing microspheres at 5% exhibited a delayed-release response and maintained its fundamental functional properties. When mixed with amoxicillin-loaded microspheres, the setting times of both test materials significantly increased. The diametral tensile strength of cement containing microspheres at 5% was similar to control. However, phytic acid had no effect on this outcome ( > 0.05). When mixed with modified liquid:powder ratio, the setting time was significantly longer than that original liquid:powder ratio ( < 0.05).

Conclusions: Lack of optimal concentrations of antibiotics at anatomical sites of the dental tissues is a hallmark of recurrent endodontic infections. Therefore, targeting the controlled release of broad-spectrum antibiotics may improve the therapeutic outcomes of current treatments. Overall, these results indicate that the carry of amoxicillin by microspheres could provide an alternative strategy for the local delivery of antibiotics for the management of tooth infections.
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http://dx.doi.org/10.5395/rde.2020.45.e50DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691264PMC
November 2020

Pequi ( Cambess)-Loaded Nanoemulsion, Orally Delivered, Modulates Inflammation in LPS-Induced Acute Lung Injury in Mice.

Pharmaceutics 2020 Nov 11;12(11). Epub 2020 Nov 11.

Laboratory of Inflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-360, Brazil.

Pequi is a Brazilian fruit used in folk medicine for pulmonary diseases treatment, but its oil presents bioavailability limitations. The use of nanocarriers can overcome this limitation. We developed nanoemulsions containing pequi oil (pequi-NE) and evaluated their effects in a lipopolysaccharide (LPS)-induced lung injury model. Free pequi oil or pequi-NE (20 mg/kg) was orally administered to A/J mice 16 and 4 h prior to intranasal LPS exposure, and the analyses were performed 24 h after LPS provocation. The physicochemical results revealed that pequi-NE comprised particles with mean diameter of 174-223 nm, low polydispersity index (0.11 ± 0.01), zeta potential of -7.13 ± 0.08 mV, and pH of 5.83 ± 0.12. In vivo evaluation showed that free pequi oil pretreatment reduced the influx of inflammatory cells into bronchoalveolar fluid (BALF), while pequi-NE completely abolished leukocyte accumulation. Moreover, pequi-NE, but not free pequi oil, reduced myeloperoxidase (MPO), TNF-α, IL-1β, IL-6, MCP-1, and KC levels. Similar anti-inflammatory effects were observed when LPS-exposed animals were pre-treated with the nanoemulsion containing pequi or oleic acid. These results suggest that the use of nanoemulsions as carriers enhances the anti-inflammatory properties of oleic acid-containing pequi oil. Moreover, pequi's beneficial effect is likely due its high levels of oleic acid.
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http://dx.doi.org/10.3390/pharmaceutics12111075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696187PMC
November 2020

Dermatological applications of the flavonoid phloretin.

Eur J Pharmacol 2020 Dec 21;889:173593. Epub 2020 Sep 21.

Programa de Pós-Graduação Em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. Electronic address:

Botanical molecules are known to have the ability to counteract ultraviolet radiation-induced skin damage. The interest in the development of natural compound-based products for the prevention of solar ultraviolet radiation-induced skin photoaging, melasma, and photocarcinogenesis has been increasing. Recently, the flavonoid phloretin has attracted the attention of researchers in the dermatological field for application in cosmetics and therapeutics. In addition to its antioxidant activity, phloretin has been shown to have properties such as anti-aging and depigmenting effects. In this study, we review the dermatological treatments with phloretin for conditions such as melasma, photoaging, acne, and melanoma. Phloretin has been shown to inhibit elastase and matrix metalloproteinase-1 activity, to reduce cellular tyrosinase activity and melanin content, and induce apoptosis in B16 mouse melanoma 4A5 cells. An in vivo study showed that phloretin, applied topically to the dorsal skin of mice, suppressed the 12-O-tetradecanoylphorbol 13-acetate-induced expression of COX-2, a critical molecular target of many chemopreventive, as well as anti-inflammatory agents. Phloretin can penetrate the skin; nevertheless, its penetration profile in different skin layers has not yet been evaluated. Despite its health benefits, phloretin application has been limited because of its photoinstability and poor aqueous solubility, among other limitations. Therefore, we reviewed the recent advances in pharmaceutical applications such as the use of nanotechnology, in order to improve the cutaneous availability of phloretin. In this review, we also focus on the oral application, product development challenges, and recent progress and future research directions on phloretin.
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http://dx.doi.org/10.1016/j.ejphar.2020.173593DOI Listing
December 2020

Taste-masked nanoparticles containing Saquinavir for pediatric oral administration.

Mater Sci Eng C Mater Biol Appl 2020 Dec 4;117:111315. Epub 2020 Aug 4.

Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul (UFRGS), Avenida Ipiranga, 2572, Porto Alegre, RS 90610-000, Brazil; Programa de Pós-Graduação em Ciências Farmacêuticas, UFRGS, Avenida Ipiranga, 2752, Porto Alegre, RS 90610-000, Brazil.. Electronic address:

This research has aimed to improve the stability and taste-masking properties by developing nanostructured dosage forms containing Saquinavir. Liquid formulations were developed using Eudragit RS100® and Pullulan as polymers. The physicochemical characteristics, stability, in vitro drug release, morphology, mucoadhesion and taste masking capacity were evaluated. The Saquinavir-nanoparticles had average diameters between 136 and 158 nm, with a Span below 1.4. These formulations presented a drug content above 80%, a high encapsulation efficiency (>97%), slightly acidic pH levels, low dynamic viscosity and controlled drug release. Electron microscopy revealed irregular spherical nanoparticles. The formulations prepared with higher amounts of Eudragit RS100® had greater mucoadhesion. Both polymers were able to improve drug stabilization, taste-masking properties and protection against drug cytotoxicity. The Saquinavir-nanoparticles exhibited stability and control releasing properties, thus making it a promising liquid dosage form with taste-masking properties intended for application in pediatric treatment.
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http://dx.doi.org/10.1016/j.msec.2020.111315DOI Listing
December 2020

Otoliths-composed gelatin/sodium alginate scaffolds for bone regeneration.

Drug Deliv Transl Res 2020 12;10(6):1716-1728

Tiradentes University, Av. Murilo Dantas, 300, Aracaju, 49010-390, Brazil.

Evidence that otoliths, mineral-rich limestone concrescences present in the inner ear of bone fishes, can accelerate bone formation in vivo has been previously reported. The goal of this work was the development, characterization, and evaluation of the cytocompatibility of otoliths-incorporated sodium alginate and gelatin scaffolds. Cynoscion acoupa-derived otoliths were characterized by X-ray fluorescence spectrometry (FRX), particle size, free lime, and weight loss by calcination. Furthermore, otoliths were incorporated into sodium alginate (ALG/OTL-s) or gelatin (GEL/OTL-s) scaffolds, previously developed by freeze-drying. Then, the scaffolds were characterized by thermogravimetric analysis (TGA/DTG), differential scanning calorimetry (DSC), infrared spectroscopy with Fourier transform (FTIR), swelling tests, and scanning electron microscopy (SEM). Cytotoxicity assays were run against J774.G8 macrophages and MC3T3-E1 osteoblasts. Data obtained from TGA/DTG, DSC, and FTIR analyses confirmed the interaction between otoliths and the polymeric scaffolds. SEM showed the homogeneous porous 3D structure rich in otolith micro-fragments in both scaffolds. Swelling of the GEL/OTL-s (63.54 ± 3.0%) was greater than of ALG/OTL-s (13.36 ± 9.9%) (p < 0.001). The viability of J774.G8 macrophages treated with both scaffolds was statistically similar to the group treated with DMEM only (p > 0.05) and significantly higher than that treated with Triton-X (p < 0.01) at 72 h. Both scaffolds showed approximately 100% growth of MC3T3-E1 osteoblasts by 24 h, similarly to control (p > 0.05). However, by 48 h, only ALG/OTL-s showed growth similar to control (p > 0.05), whereas GEL/OTL showed a significantly lower growth index (p < 0.05). In conclusion, the physicochemical profiles suggest proper interaction between the otoliths and the two developed polymeric 3D scaffolds. Moreover, both materials showed cytocompatibility with J774.G8 macrophages but the growth of MC3T3-E1 osteoblasts was higher when exposed to ALG/OTL-s. These data suggest that sodium alginate/otoliths scaffolds are potential biomaterials to be used in bone regeneration applications. Graphical abstract.
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http://dx.doi.org/10.1007/s13346-020-00845-xDOI Listing
December 2020

Intranasal administration of budesonide-loaded nanocapsule microagglomerates as an innovative strategy for asthma treatment.

Drug Deliv Transl Res 2020 12;10(6):1700-1715

Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Av. Ipiranga 2752, Porto Alegre, 90610-000, Brazil.

The co-existence with rhinitis limits the control of asthma. Compared with oral H receptor antagonists, intranasal corticosteroids have been demonstrated to provide greater relief of all symptoms of rhinitis and are recommended as first-line treatment for allergic rhinitis. Intrinsic limitations of nasal delivery, such as the presence of the protective mucous layer, the relentless mucociliary clearance, and the consequent reduced residence time of the formulation in the nasal cavity, limit budesonide efficacy to the treatment of local nasal symptoms. To overcome these limitations and to enable the treatment of asthma via nasal administration, we developed a budesonide-loaded lipid-core nanocapsule (BudNC) microagglomerate powder by spray-drying using a one-step innovative approach. BudNC was obtained, as a white powder, using L-leucine as adjuvant with 75 ± 6% yield. The powder showed a bimodal size distribution curve by laser diffraction with a principal peak just above 3 μm and a second one around 0.45 μm and a drug content determined by HPLC of 8.7 mg of budesonide per gram. In vivo after nasal administration, BudNC showed an improved efficacy in terms of reduction of immune cell influx; production of eotaxin-1, the main inflammatory chemokine; and arrest of airways remodeling when compared with a commercial budesonide product in both short- and long-term asthma models. In addition, data showed that the results in the long-term asthma model were more compelling than the results obtained in the short-term model. Graphical abstract.
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http://dx.doi.org/10.1007/s13346-020-00813-5DOI Listing
December 2020

Erlotinib-Loaded Poly(ε-Caprolactone) Nanocapsules Improve In Vitro Cytotoxicity and Anticlonogenic Effects on Human A549 Lung Cancer Cells.

AAPS PharmSciTech 2020 Aug 10;21(6):229. Epub 2020 Aug 10.

Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Avenida Ipiranga, 2752/405, Porto Alegre, RS, 90610-000, Brazil.

Lung cancer is the most frequent type of cancer and the leading cause of cancer-related mortality worldwide. This study aimed to develop erlotinib (ELB)-loaded poly(ε-caprolactone) nanocapsules (NC) and evaluated their in vitro cytotoxicity in A549 cells. The formulation was characterized in relation to hydrodynamic diameter (171 nm), polydispersity index (0.076), zeta potential (- 8 mV), drug content (0.5 mgmL), encapsulation efficiency (99%), and pH (6.0). NC presented higher cytotoxicity than ELB in solution against A549 cells in the MTT and LIVE/DEAD cell viability assays after 24 h of treatment. The main mechanism of cytotoxicity of NC was the induction of apoptosis in A549 cells. Further, a significant decrease in A549 colony formation was verified after NC treatment in comparison with the unencapsulated drug treatment. The reduction in clonogenic capacity is very relevant as it can reduce the risk of tumor recurrence and metastasis. In conclusion, erlotinib-loaded PCL nanocapsules are promising nanoparticles carriers to increase the efficacy of ELB in lung cancer treatment.
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http://dx.doi.org/10.1208/s12249-020-01723-yDOI Listing
August 2020

Semi-Mechanistic Pharmacokinetic Modeling of Lipid Core Nanocapsules: Understanding Quetiapine Plasma and Brain Disposition in a Neurodevelopmental Animal Model of Schizophrenia.

J Pharmacol Exp Ther 2020 10 27;375(1):49-58. Epub 2020 Jul 27.

Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia (F.C., V.E.H., K.J.S., L.B.O., K.P., S.S.G., S.M.K.R., T.D.C.), Centro de Reprodução e Experimentação de Animais de Laboratório, Instituto de Ciências Básicas da Saúde (F.S.M.), and Programa de Pós-Graduação em Farmacologia e Terapêutica, Instituto de Ciências Básicas da Saúde (A.P.H.), Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Pharmacometrics and Systems Pharmacology Research Unit, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain (I.T.); and IdiSNA, Navarra Institute for Health Research, Pamplona, Spain (I.T.)

This study investigated plasma and brain disposition of quetiapine lipid core nanocapsules (QLNC) in naive and schizophrenic (SCZ-like) rats and developed a semimechanistic model to describe changes in both compartments following administration of the drug in solution (FQ) or nanoencapsulated. QLNC (1 mg/ml) presented 166 ± 39 nm, low polydispersity, and high encapsulation (93.0% ± 1.4%). A model was built using experimental data from total and unbound plasma and unbound brain concentrations obtained by microdialysis after administration of single intravenous dose of FQ or QLNC to naive and SCZ-like rats. A two-compartment model was identifiable both in blood and in brain with a bidirectional drug transport across the blood-brain barrier (CL and CL). SCZ-like rats' significant decrease in brain exposure with FQ (decrease in CL) was reverted by QLNC, showing that nanocarriers govern quetiapine tissue distribution. Model simulations allowed exploring the potential of LNC for brain delivery. SIGNIFICANCE STATEMENT: A population approach was used to simultaneously model total and unbound plasma and unbound brain quetiapine concentrations allowing for quantification of the rate and extent of the drug's brain distribution following administration of both free drug in solution or as nanoformulation to naive and SCZ-like rats. The model-based approach is useful to better understand the possibilities and limitations of this nanoformulation for drug delivering to the brain, opening the opportunity to use this approach to improve SCZ-treatment-limited response rates.
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http://dx.doi.org/10.1124/jpet.120.000109DOI Listing
October 2020

(-)-linalool-Loaded Polymeric Nanocapsules Are a Potential Candidate to Fibromyalgia Treatment.

AAPS PharmSciTech 2020 Jul 6;21(5):184. Epub 2020 Jul 6.

Department of Pharmacy, Federal University of Sergipe, Av. Marechal Rondon, Jardim Rosa Elze, São Cristóvão, Sergipe, 49100-000, Brazil.

Fibromyalgia (FM) is a chronic disease that has as main characteristic generalized musculoskeletal pain, which can cause physical and emotional problems to patients. However, pharmacological therapies show side effects that hamper the adhesion to treatment. Given this, (-)-linalool (LIN), a monoterpene with several therapeutic properties already reported in scientific literature as anti-depressive, antinociceptive, anti-inflammatory, and antihyperalgesic also demonstrated therapeutic potential in the treatment of FM. Nevertheless, physicochemical limitations as high volatilization and poor water-solubility make its use difficult. In this perspective, this present research had performed the incorporation of LIN into polymeric nanocapsules (LIN-NC). Size, morphology, encapsulation efficiency, cytotoxicity, and drug release were performed. The antihyperalgesic effect of LIN-NC was evaluated by a chronic non-inflammatory muscle pain model. The results demonstrated that the polymeric nanocapsules showed particle size of 199.1 ± 0.7 nm with a PDI measurement of 0.13 ± 0.01. The drug content and encapsulation efficiency were 13.78 ± 0.05 mg/mL and 80.98 ± 0.003%, respectively. The formulation did not show cytotoxicity on J774 macrophages. The oral treatment with LIN-NC and free-LIN increased the mechanical withdrawal threshold on all days of treatment in comparison with the control group. In conclusion, LIN-NC is a promising proposal in the development of phytotherapy-based nanoformulations for future clinical applications.
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http://dx.doi.org/10.1208/s12249-020-01719-8DOI Listing
July 2020

Spray-dried raloxifene submicron particles for pulmonary delivery: Development and in vivo pharmacokinetic evaluation in rats.

Int J Pharm 2020 Jul 26;585:119429. Epub 2020 May 26.

Pharmaceutical Sciences Graduate Program, Faculty of Pharmacy, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. Electronic address:

Raloxifene hydrochloride (RH) is a selective oestrogen receptor modulator used for the treatment of osteoporosis. Even though 60% of an oral dose is quickly absorbed via the gastrointestinal tract, the absolute bioavailability of RH is only 2-3% in humans due to extensive first-pass metabolism. Various approaches to improve RH bioavailability have been reported over the past few years; however, none have focused on the development of products for pulmonary administration. Therefore, in this study, submicron particles containing RH were produced for pulmonary administration with the aim to limit first-pass metabolism. Powders were produced by vibrational atomisation spray drying with a high process yield (>80%). The drug content was between 440 and 890 mg·g, and powders had a high encapsulation efficiency (>95%), mean particle size of 400-700 nm, low residual moisture (<2%) and spherical shape. These powders showed an improved drug dissolution rate compared to the raw RH material. Moreover, they presented high dose uniformity (95-100%), a high in vitro respirable fraction (>55%) and adequate mass median aerodynamic diameter for pulmonary delivery (<5 μm). The pharmacokinetic study in male Wistar rats demonstrated an absolute bioavailability of 47.20% after pulmonary administration of the particles. Therefore, these submicron-sized powders are promising for pulmonary RH delivery as a dry powder medicine.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119429DOI Listing
July 2020

Chitosan-Coated Lipid-Core Nanocapsules Functionalized with Gold-III and Bevacizumab Induced In Vitro Cytotoxicity against C6 Cell Line and In Vivo Potent Antiangiogenic Activity.

Pharm Res 2020 May 8;37(6):91. Epub 2020 May 8.

Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Av. Ipiranga, 2752, Porto Alegre, RS, 90610-000, Brazil.

Purpose: Bevacizumab (BCZ) is a recombinant monoclonal antibody that inhibits the biological activity of the vascular endothelial growth factor, which has an important role in angiogenesis for tumoral growth and progression. In this way, our objective was to develop chitosan-coated lipid-core nanocapsules functionalized with BCZ by an organometallic complex using gold-III.

Methods: The formulation was produced and characterized in relation to physicochemical characteristics. Furthermore, the antitumoral and antiangiogenic activities were evaluated against C6 glioma cell line and chicken embryo chorioallantoic membrane (CAM), respectively.

Results: Final formulation showed nanometric size, narrow polydispersity, positive zeta potential and gold clusters size lower than 2 nm. BCZ in aqueous solution (0.01-0.10 μmol L) did not show cytotoxic activity in vitro against C6 glioma cell line; although, MLNC-Au-BCZ showed cytotoxicity with a median inhibition concentration of 30 nmol L of BCZ. Moreover, MLNC-Au-BCZ demonstrated cellular internalization dependent on incubation time and BCZ concentration. BCZ solution did not induce significant apoptosis as compared to MLNC-Au-BCZ within 24 h of treatment. CAM assay evidenced potent antiangiogenic activity for MLNC-Au-BCZ, representing a decrease of 5.6 times in BCZ dose comparing to BCZ solution.

Conclusion: MLNC-Au-BCZ is a promising product for the treatment of solid tumors.
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http://dx.doi.org/10.1007/s11095-020-02804-0DOI Listing
May 2020

Simultaneous nanoencapsulation of lipoic acid and resveratrol with improved antioxidant properties for the skin.

Colloids Surf B Biointerfaces 2020 Apr 12;192:111023. Epub 2020 Apr 12.

Programa de Pós Graduação em Ciências farmacêuticas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Programa de Pós Graduação em Nanotecnologia Farmacêutica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.

Cutaneous aging is intimately related to redox imbalance, which is mainly caused by ultraviolet radiation exposure. The aim of the present investigation was to develop lipid-core nanocapsules for the co-nanoencapsulation of resveratrol and lipoic acid aiming to improve the chemical stability and photostability of the compounds, as well as their antioxidant properties. Lipid-core nanocapsules were developed and characterized according to their mean size, size distribution, zeta potential, pH value, drug content, encapsulation efficiency, release profile, stability under storage, photostability and skin permeation profile. In vitro antioxidant activity was analyzed by lipid peroxidation method and the in vitro cytotoxicity by MTT assay and cellular count, using BALB/c-3T3 fibroblasts. It was possible to co-nanoencapsulate resveratrol and lipoic acid into particles of average diameter close to 200 nm, low polydispersity index and encapsulation efficiencies around 90 %. Nanoencapsulation increased the substances stability under storage and photostability under UVA light exposure, besides controlling substances release. The actives were able to permeate a skin model membrane when nanoencapsulated, with a faster permeation of lipoic acid. The antioxidant activity was potentiated by the co-nanoencapsulation of resveratrol and lipoic acid, without signs of cytotoxicity to fibroblasts. Therefore, the co-nanoencapsulation of resveratrol and lipoic acid is promising for application in topical formulations aiming antioxidant effects.
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http://dx.doi.org/10.1016/j.colsurfb.2020.111023DOI Listing
April 2020

Phenytoin-loaded lipid-core nanocapsules improve the technological properties and in vivo performance of fluidised bed granules.

Mater Sci Eng C Mater Biol Appl 2020 Jun 19;111:110753. Epub 2020 Feb 19.

Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. Electronic address:

Lipid-core nanocapsules (LNCs) were recently reported by our group as a suitable binder system to produce fluidised bed granules. However, there is still a lack of knowledge about the influence of using these nanocarriers loaded with a drug on the properties of the granules and their in vivo performance. Therefore, this study was designed to produce innovative fluidised bed granules containing phenytoin-loaded LNCs (LNC) as a strategy to evaluate the influence of the presence of the drug-loaded nanocarriers on their in vitro and in vivo properties. Granules were produced using a mixture of maltodextrin and phenytoin (1:0.004 w/w) as substrate. They were prepared by fluid bed granulation using water or LNC as the liquid binder, affording good yields (73-82%) of granules with low moisture content (<5%). Granules prepared with LNC had larger mean size (122 μm) compared to maltodextrin primary particles (50 μm) due to the formation of solid bridges. Moreover, the use of LNC as the liquid binder improved their powder flow properties. The nanocarriers were recovered after aqueous dispersion (3.00 mg.mL of PHT) with a redispersibility close to 90%. After reconstitution in water, granules containing LNC showed an improved dissolution behaviour compared to those prepared without them. In addition, they showed a higher mucoadhesive effect due to a combined effect of the LNC and maltodextrin in the interactions with porcine intestinal mucosa. Regarding the in vivo studies, granules containing the combination of non-encapsulated PHT and PHT-loaded lipid-core nanocapsules increased the latency to seizures compared to placebo granules, showing effective anticonvulsant effect in mice. In conclusion, the use of drug-loaded nanocapsules as binder is an encouraging approach to produce fluidised bed mucoadhesive granules with improved technological properties and in vivo performance.
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http://dx.doi.org/10.1016/j.msec.2020.110753DOI Listing
June 2020

Characterization and antiproliferative activity of glioma-derived extracellular vesicles.

Nanomedicine (Lond) 2020 04 6;15(10):1001-1018. Epub 2020 Apr 6.

Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, 90035-003, Brazil.

To characterize a method to isolate glioma-derived extracellular vesicles (GEVs) and understand their role in immune system modulation and glioma progression. GEVs were isolated by differential centrifugation from C6 cell supernatant and characterized by size and expression of CD9, HSP70, CD39 and CD73. The glioma model was performed by injecting C6 glioma cells into the right striatum of Wistar rats in the following groups: controls (C6 cells alone), coinjection (C6 cells + GEVs) and GEVs by intranasal administration followed by immune cells, tumor size and cells proliferation analyses. GEVs presented uniform size (175 nm), expressed CD9, HSP70, CD39, CD73 and produced adenosine. , we observed a reduction in tumor size, in cell proliferation (Ki-67) and in a regulatory cell marker (FoxP3). GEVs, administered before or at tumor challenge, have antiproliferative properties and reduce regulatory cells in the glioma microenvironment.
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http://dx.doi.org/10.2217/nnm-2019-0431DOI Listing
April 2020

Addition of norbixin microcapsules obtained by spray drying in an isotonic tangerine soft drink as a natural dye.

J Food Sci Technol 2020 Mar 22;57(3):1021-1031. Epub 2019 Oct 22.

1Department of Food Science, Institute of Food Science and Technology, Universidade Federal de Rio Grande do Sul (UFRGS), Porto Alegre, 91501-970 Brazil.

Annatto seeds ( L.) are a natural source of norbixin, a carotenoid with antioxidant activity and an intense yellow-orange color which is a commonly used food and beverage colorant. However, it is susceptible to environmental factors such as light, oxygen, and temperature. Microencapsulation presents an alternative for improving the bioactive compound's stability. In this study, norbixin microcapsules (MCN) were added to isotonic tangerine soft drinks in a quantity not exceeding food additive regulations. The final concentration was 2.86 ± 0.02 µg norbixin/mL, and according to the CIELab system, the beverage acquired the expected orange tonality. The addition of MCN favorably affects beverage stability during storage under accelerated conditions (heat and light), and the half-life time was more significant (29.71 days) than when non-encapsulated norbixin was used (393.39 min). In conclusion, MCN should be considered as an additive with potential use in processed beverage industries instead of synthetic dyes.
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http://dx.doi.org/10.1007/s13197-019-04135-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026349PMC
March 2020

Quetiapine lipid core nanocapsules restore prepulse inhibition deficits in a neurodevelopmental model of schizophrenia in male and female rats.

Schizophr Res 2020 04 21;218:173-179. Epub 2020 Jan 21.

Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Av. Ipiranga, 2759, 90610-000 Porto Alegre, RS, Brazil.

Lipid core nanocapsules (LNC) have been extensively studied as a new treatment strategy to improve therapeutic effects of antipsychotic drugs. We investigated the efficacy of quetiapine LNCs (QLNCs) on the poly(i:c) model of schizophrenia in both male and female rats using the pre-pulse inhibition of startle response (PPI) test paradigm after evaluating the outcomes of three different poly(i:c) doses administered to pregnant damns at GD15 on neurodevelopmental outcomes of maternal immune activation (MIA) in adult offspring. QTP solution was not capable of producing a reversal in the sensorimotor gating-disruptive effect caused by the prenatal poly(i:c) exposure. The same dose of QTP given as QLNCs significantly improved PPI-impairment. This is the first study reporting the restoration of the PPI deficits in a neurodevelopmental model of SCZ using LNCs. This is a promising delivery system strategy to improve antipsychotic effects contributing to the development of better SCZ pharmacological treatments.
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http://dx.doi.org/10.1016/j.schres.2020.01.007DOI Listing
April 2020

Nasal Drug Delivery of Anticancer Drugs for the Treatment of Glioblastoma: Preclinical and Clinical Trials.

Molecules 2019 Nov 26;24(23). Epub 2019 Nov 26.

Food and Drug Department, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy.

Glioblastoma (GBM) is the most lethal form of brain tumor, being characterized by the rapid growth and invasion of the surrounding tissue. The current standard treatment for glioblastoma is surgery, followed by radiotherapy and concurrent chemotherapy, typically with temozolomide. Although extensive research has been carried out over the past years to develop a more effective therapeutic strategy for the treatment of GBM, efforts have not provided major improvements in terms of the overall survival of patients. Consequently, new therapeutic approaches are urgently needed. Overcoming the blood-brain barrier (BBB) is a major challenge in the development of therapies for central nervous system (CNS) disorders. In this context, the intranasal route of drug administration has been proposed as a non-invasive alternative route for directly targeting the CNS. This route of drug administration bypasses the BBB and reduces the systemic side effects. Recently, several formulations have been developed for further enhancing nose-to-brain transport, mainly with the use of nano-sized and nanostructured drug delivery systems. The focus of this review is to provide an overview of the strategies that have been developed for delivering anticancer compounds for the treatment of GBM while using nasal administration. In particular, the specific properties of nanomedicines proposed for nose-to-brain delivery will be critically evaluated. The preclinical and clinical data considered supporting the idea that nasal delivery of anticancer drugs may represent a breakthrough advancement in the fight against GBM.
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http://dx.doi.org/10.3390/molecules24234312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930669PMC
November 2019

Encapsulation in lipid-core nanocapsules improves topical treatment with the potent antileishmanial compound CH8.

Nanomedicine 2020 02 28;24:102121. Epub 2019 Oct 28.

Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, RJ, Brazil. Electronic address:

Cutaneous leishmaniasis (CL) is a neglected parasitic disease conventionally treated by multiple injections with systemically toxic drugs. Aiming at a more acceptable therapy, we developed lipid-core nanocapsules (LNCs) entrapping the potent antileishmanial chalcone (CH8) for topical application. Rhodamine-labeled LNC (Rho-LNC-CH8) was produced for imaging studies. LNC-CH8 and Rho-LNC-CH8 had narrow size distributions (polydispersity index <0.10), with similar mean sizes (~180 nm) by dynamic light scattering. In vitro, Rho-LNC-CH8 was rapidly internalized by extracellular Leishmania amazonensis parasites macrophages in less than 15 min. LNC-CH8 activated macrophage oxidative mechanisms more efficiently than CH8, and was more selectively toxic against the intracellular parasites. In vivo, topically applied Rho-LNC-CH8 efficiently permeated mouse skin. In L. amazonensis-infected mice, LNC-CH8 reduced the parasite load by 86% after three weeks of daily topical treatment, while free CH8 was ineffective. In conclusion, LNC-CH8 has strong potential as a novel topical formulation for CL treatment.
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http://dx.doi.org/10.1016/j.nano.2019.102121DOI Listing
February 2020

Larvae as an Model to Evaluate the Toxicity of Polymeric Nanocapsules.

J Nanosci Nanotechnol 2020 03;20(3):1486-1494

Programa de Pós-GraduaÇão em Ciências Farmacêuticas, Faculdade de Farmácia and Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Av. Ipiranga, 2752, Porto Alegre, 90610-000, Brazil.

larvae is an invertebrate that has been extensively used as experimental model in the investigation of microbial virulence and efficacy of antimicrobial agents and can be used to provide faster and cheaper data than traditional test systems. Our objective was to propose the use of larvae as an model to evaluate the toxicity of lipid-core nanocapsule (LNC) formulations having different surface coatings. Blank LNC formulations were coated with polysorbate 80 (LNC-1), lecithin and polysorbate 80 (LNC-2), and lecithin, chitosan and polysorbate 80 (LNC-3). Subsequently, the formulations were systemically administered to larvae at doses of 3.75×10, 3.75×10, 3.75×10, 3.75×10 and 3.75×10 mols of LNC per kg of larvae. The results demonstrated that those nanocapsules having neutral (LNC-1), negative (LNC-2) or positive (LNC-3) surface did not show acute toxicity effects in larvae. larvae is a viable and promising alternative for nanotoxicological studies. We conclude that larvae can be used as an alternative model for the screening of the toxicity of polymeric nanocapsules functionalized with (i) polysorbate 80, (ii) lecithin and polysorbate 80, and (iii) lecithin, chitosan and polysorbate 80. Future studies can be now developed in order to evaluate their toxicity when loaded or functionalized with drugs.
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http://dx.doi.org/10.1166/jnn.2020.17170DOI Listing
March 2020

Redispersible Spray-Dried Powder Containing Nanoencapsulated Curcumin: the Drying Process Does Not Affect Neuroprotection In vitro.

AAPS PharmSciTech 2019 Aug 12;20(7):283. Epub 2019 Aug 12.

Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

A redispersible spray-dried formulation containing curcumin-loaded, lipid-core nanocapsules (LNC-C) was developed for oral administration. The neuroprotective activity of curcumin after the spray-drying process was evaluated in vitro. The spray-dried powder (SD-LNC-C) was produced using a drying adjuvant composed of a blend of maltodextrin and L-leucine (90:10 w/w). Acceptable process yield (~ 70%) and drug content (6.5 ± 0.2 mg g) were obtained. SD-LNC-C was formed by smooth, spherical-shaped particles, and confocal Raman analysis indicated the distribution of the LNC-C on the surface of the leucine/maltodextrin agglomerates. The surface of the agglomerates was formed by a combination of LNC-C and adjuvants, and laser diffraction showed that SD-LNC-C had adequate aqueous redispersion, with no loss of controlled drug release behaviour of LNC-C. The in vitro curcumin activity against the lipopolysaccharide (LPS)-induced proinflammatory response in organotypic hippocampal slice cultures was evaluated. Both formulations (LNC-C and SD-LNC-C) reduced TNF-α to similar levels. Therefore, neuroprotection of curcumin in vitro may be improved by nanoencapsulation followed by spray-drying, with no loss of this superior performance. Hence, the redispersible spray-dried powder proposed here represents a suitable approach for the development of innovative nanomedicines containing curcumin for the prevention/treatment of neurodegenerative diseases.
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http://dx.doi.org/10.1208/s12249-019-1501-1DOI Listing
August 2019

Incorporation of zeaxanthin nanoparticles in yogurt: Influence on physicochemical properties, carotenoid stability and sensory analysis.

Food Chem 2019 Dec 23;301:125230. Epub 2019 Jul 23.

Instituto de Ciência e Tecnologia de Alimentos, Universidade Federal do Rio Grande do Sul (UFRGS), Av. Bento Gonçalves, n. 9500, CEP 91501-970 Porto Alegre, RS, Brazil. Electronic address:

Zeaxanthin nanoparticles (Zea-NP) and zeaxanthin nanoemulsion (Zea-NE) were incorporated in yogurt. Control yogurt (CY), yogurt added of nanoparticles (Y-NP) and yogurt added of nanoemulsion (Y-NE) were evaluated weekly regarding pH, titratable acidity, color, textural parameters, viscosity and syneresis during 28 days. Zeaxanthin retention in Y-NP and Y-NE was also determined over storage. Sensory attributes and morphology were evaluated in all yogurt samples, and zeaxanthin bioaccessibility after in vitro digestion was analyzed in Y-NP and Y-NE after preparation. At the end of storage time, zeaxanthin retention was higher in Y-NP (22.31 ± 2.53%) than in Y-NE (16.84 ± 0.53%). Despite the lower firmness and viscosity observed in Y-NP, these changes were not sensory perceived. The bioaccessibility after in vitro digestion suggested that nanoencapsulation provided a controlled release of the carotenoid. Zea-NP can be incorporated in yogurt, allowing the dispersion of a hydrophobic compound in a hydrophilic matrix, providing stability.
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http://dx.doi.org/10.1016/j.foodchem.2019.125230DOI Listing
December 2019

Orally delivered resveratrol-loaded lipid-core nanocapsules ameliorate LPS-induced acute lung injury via the ERK and PI3K/Akt pathways.

Int J Nanomedicine 2019 12;14:5215-5228. Epub 2019 Jul 12.

Laboratory of Inflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.

Background: Resveratrol (RSV) has attracted interest as an alternative drug for the treatment of acute lung injury (ALI) and other pulmonary diseases, but its poor oral bioavailability is a limitation. In this study, we employed drug delivery nanotechnology to improve the stability, lung localization and efficacy of orally administered resveratrol to control lung damage leading to ALI.

Methods And Materials: RSV-loaded lipid-core nanocapsules (RSV-LNCs), prepared by interfacial deposition of biodegradable polymers, were given orally to A/J mice prior to lipopolysaccharide (LPS) intranasal instillation. Inflammatory changes, oxidative stress and lung tissue elastance were assessed 24 h after LPS challenge.

Results: RSV-LNCs (5 mg/kg), given 1, 4, 6 or 12 h but not 24 h before provocation, inhibited LPS-induced leukocyte accumulation in the bronchoalveolar fluid (BALF), whereas unloaded nanocapsules (ULNCs) or free RSV (5 mg/kg) were ineffective. RSV-LNCs (2.5-10 mg/kg) but not ULNCs or RSV improved lung function and prevented total leukocyte and neutrophil accumulation equally in both BALF and lung tissue when given 4 h before LPS challenge. Similar findings were seen concerning the generation of a range of pro-inflammatory cytokines such as IL-6, KC, MIP-1α, MIP-2, MCP-1 and RANTES in lung tissue. In addition, only RSV-LNCs inhibited MDA levels and SOD activity in parallel with blockade of the ERK and PI3K/Akt pathways following LPS provocation.

Conclusion: Nanoformulation of RSV in biodegradable oil-core polymers is an effective strategy to improve the anti-ALI activity of RSV, suggesting that the modified-release formulation of this plant polyphenol may be of great value in clinical conditions associated with ALI and respiratory failure.
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http://dx.doi.org/10.2147/IJN.S200666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636190PMC
October 2019

Direct effects of poly(ε-caprolactone) lipid-core nanocapsules on human immune cells.

Nanomedicine (Lond) 2019 06 6;14(11):1429-1442. Epub 2019 Jun 6.

Department of Clinical & Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, Brazil.

Poly(ε-caprolactone) lipid-core nanocapsules (LNCs) are efficient drug carriers and drug-free LNCs display therapeutic effects, inhibiting tumor growth and neutrophil activities. Herein, we investigated the direct actions of LNCs on human immune cells, to guide their therapeutic application. LNC's uptake, cytokine release, cell migration, proliferation and intracellular pathways under inflammatory stimulation were investigated. LNCs quickly penetrated leukocytes without cytotoxicity; inhibited mitogen-induced lymphocyte proliferation, cytokine release and leukocyte migration under inflammatory stimulation, which were associated with inhibition of the MAP kinase pathway and intracellular calcium influx. Hence, we showed LNCs as a down-regulatory agent on immune cells, suggesting that either the particles themselves or their application as a drug carrier can halt non-desired inflammatory processes.
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http://dx.doi.org/10.2217/nnm-2018-0484DOI Listing
June 2019