Doutorado em Nanotecnologia Farmacêutica em Rede (FF)
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Item Obtenção, caracterização e avaliação pré-clínica da segurança de nanopartículas lipídicas e poliméricas contendo o antiangiogênico sunitinibe para aplicação tópica ocular: um estudo comparativo(Universidade Federal de Goiás, 2014-06-27) Souza, Leonardo Gomes; Lima, Eliana Martins; http://lattes.cnpq.br/7248774319455970; Lima, Eliana Martins; Gremião, Maria Palmira Daflon; Cunha Júnior, Armando da Silva; Isaac, David Leonardo Cruvinel; Marreto, Ricardo NevesCorneal vascularization (CV) is a common cause of visual impairment and blindness. Sunitinib (SUB) is an antiangiogenic agent that has demonstrated a significant reduction of VC in rabbits. Incorporation of SUB in nanosystems can increase your corneal retention and decrease P-glycoprotein resistance and it conversion to inactive isomer E (trans) when the drug is exposed to light. In this work, liposomes (LIPO), polymeric nanospheres (NE) and solid lipid nanoparticles (SLN) containing SUB was developed. Systems presented particle size between 70 and 200 nm and PdI below 0.3 and a high encapsulation efficiency. NE had a greater capacity to incorporate sunitinib when compared to liposomes and SLN. This system had drug loading of 4.3% while LIPO and SLN showed 2.87% and 1.66%, respectively. Release profile of sunitinib was different in three developed systems. Liposomes sustained drug release greater than that observed for the polymer nanospheres and solid lipid nanoparticles in the same period. SLN showed higher corneal retention of SUB when compared to other systems. Within thirty minutes corneal retention of SUB from SLN (15 µg/cm2) was more than twice that observed for liposomes (6.8 µg/cm2). NE also showed corneal retention of SUB (12.7 µg/cm2) superior to liposomes. Spectroscopic studies of electron paramagnetic resonance (EPR) comparing liposomes and SLN demonstrated that SLN are more flexible than liposomes. These studies also indicated that sub is located in the lipid bilayer of liposomes near the phospholipid-water interface, leading to increased rigidity. In SLN the drug is also probably located near the lipid-water interface, altering the crstaline organiation of the lipids and increased fluidity. These results justify the faster release profile observed for SUB from SLN and higher corneal retention of drug from these nanosystems. Employing alternative methods to the use of animals for determining the safety of the formulations, all three formulations developed showed no potential for ocular irritation in tests of bovine corneal opacity and permeability test method (BCOP), in the evaluation of hemolytic potential and in the test in chorioallantoic membrane of chicken egg (HET-CAM). Among the systems developed in this work containing SUB, SLN seems to present a greatest potential for clinical application in the treatment of VC.Item Dispositivo de liberação intravítrea para tratamento de degeneração macular relacionada à idade(Universidade Federal de Goiás, 2023-04-04) Guerra, Maria Carolina Andrade; Fialho, Sílvia Ligório; http://lattes.cnpq.br/6277013725246341; Cunha Júnior, Armando da Silva; http://lattes.cnpq.br/8278273904187275; Cunha Júnior, Armando da Silva; Lima, Eliana Martins; Dias, Marina França; Dourado, Lays Fernanda Nunes; Fialho, Silvia LigórioAge-related macular degeneration, AMD, is a chronic eye disease which damages the macular area. It is the main cause of adult blindness worldwide. The pharmacological treatment of choice for the neovascular form of AMD consists of intravitreal injections of anti-VEGF agents that, occasionally, might be combined with corticosteroids. Intravitreal injections are the preferred route for drug delivery to the posterior segment of the eye but have limited therapeutic success due to the quick elimination of substances, requiring frequent injections that bring complications to the patient and low adherence to treatment. Intravitreal implants are capable to maintain therapeutic levels of drugs for a long period. Biodegradable nanofibers can modulate drug release in addition to allowing the incorporation of fragile bioactive substances. The present work aimed the development of biodegradable intravitreal implants containing dexamethasone coated with polymeric nanofibers containing bevacizumab as a therapeutic proposal for the treatment of AMD. Nanocoated implants were successfully developed. The characterization of the system, the study of degradation and efficiency of the coating process were evaluated by scanning electron microscopy. The drug release profile was determined by high performance liquid cromatography and the Bradford method. The antiangiogenic activity was determined by the chicken embryo chorioallantoic membrane model. The safety of the formulation was evaluated in rabbit eyes. So far, the system was successfully developed. The study degradation study confirmed the presence of nanofibers on the implant surface for up to 35 days. The degradation study demonstrated the presence of nanofibers on the surface of the implant for up to 35 days. The release profile showed that 68% of dexamethasone was released within 35 days and 90% of bevacizumab within 48 hours. The formulation presented activity in reducing vessels and was safe for the rabbits’ retina. No clinical or histopathological changes were observed, neither alteration in retinal thickness by optical coherence tomography during the 28 days. The developed implants, therefore, may be considered as a new alternative for the treatment of AMD.Item Liberação controlada por magnetohipertermia de doxorrubicina em magnetolipossomas direcionados ao receptor de superfície celular folato(Universidade Federal de Goiás, 2018-10-08) Cintra, Emilio Ramos; Lima, Eliana Martins; http://lattes.cnpq.br/7248774319455970; Lima, Eliana Martins; Senna, Elenara Mara Teixeira Lemos; Bakuzis, Andris Figueiroa; Mendanha Neto, Sebastião Antônio; Souza, Ana Luiza Ribeiro deDoxorubicin is one of the most commonly used antineoplastic agents in the treatment of solid tumors, such as soft tissue tumors and osteosarcomas. However, the high occurrence of cardiotoxic side effects due to its prolonged use causes damages to adherence and therapeutic efficacy. In order to diminish the side effects, during the present research magnetoliposomes with magnetic nanoparticles coencapsulating doxorubicin were developed in their aqueous interior vectors for the folate receptor aiming controlled release by magnetohypertermia. This work was divided in four stages: optimization and validation of analytical methodology to quantify doxorubicin; synthesis of magnetic fluids with different layers of coverage; development of magnetoliposomes coencapsulating doxorubicin with and without vectorization in order to compare if the effectiveness of the vectorization and in vitro studies for the chemotherapy effectiveness of the liposomal formulation against the B16F10 cell was verified. The magnetoliposomes were prepared by the lipid film hydration method followed by extrusion and the physical-chemical and morphological results showed that the liposomal formulations have an average size close to 150 nm. The magnetic particles have an average size of 13 nm, high saturation magnetization, superparamagnetic behavior and are composed by manganese ferrite with different layers of coverings. The magnetoliposomes were able to generate heat through magnetohyperthermia with alternating magnetic field. The liposomal formulation of magnetoliposome with vectorized doxorubicin to the folate receptor showed higher antitumor activity when compared to formulation without vectorization. When compared to hyperthermia test, it showed that the increase in temperature is linked to a better effect with the drug for a greater cytotoxic effect. These results suggest, therefore, that the obtaining of a liposomal formulation towards the antitumor activity represents a promising alternative associated to the codelivery chemotherapeutic and magnetic nanoparticles directed at the tumor tissue.Item Desenvolvimento e avaliação da atividade quimiopreventiva de nanopartículas contendo imiquimode em modelo murino de câncer de pele(Universidade Federal de Goiás, 2018-04-11) Dias, Marina França; Silva Júnior, Armando da Cunha; http://lattes.cnpq.br/8278273904187275; Lima, Eliana Martins; Serakides, Rogéria; Barros, André Luís Branco de; Pereira, Bruno GonçalvesSkin cancer has the highest incidence among all types of neoplasms and the tendency is the increasing number of new cases in next decades, wich makes necessary new modalities and treatment options. Chemotherapeutic agent imiquimod is used in treatment of disease, but the high occurrence of local and systemic adverse effects associated with its use as well as its low skin permeation impair adherence and therapeutical effectiveness, respectively. The aim of the present work was evaluate the antitumor activity of nanocapsules imiquimod-loaded compared to its commercial product in murine model of skin cancer. Polymeric nanocapsules containing imiquimod, in the absence and presence of chitosan coating, were obtained by the precipitation of preformed polymer technique and characterized by encapsulation efficiency, size, zeta potential, pH, morphology (transmission electron microscopy and scanning), optical scanning spectrophotometry and in vitro release through dialysis membrane in pH 5.6 buffer. Presence of chemical interactions between formulation components was evaluated by thermogravimetric analysis and infrared spectroscopy. Detection of crystalline structures was performed by X-ray diffractometry. The nanocapsules and commercial imiquimod formulation antiagiogenic activity was determined in a chicken embryo chorioallantoic membrane model. Cutaneous permeation of nanocapsules imiquimod-loaded and commercial imiquimod was determined in Swiss albino mice. The chemopreventive activity of colloidal dispersions and the commercial imiquimod was evaluated through the tumoral inhibition promoted by these treatments in a multi- stage model of chemical carcinogenesis in Swiss mice. Encapsulation efficiency, mean diameter, zeta potential and pH of uncoated nanocapsules imiquimod-loaded were 92.5% ± 0.4; 249 ± 22.4 nm; -40.1 mV ± 3.7 and 5.4 ± 0.01 respectively, whereas for nanocapsules with cationic coating the parameters found were: 88.6 ± 2.3%; 287.0 ± 12.6 nm; + 11.3 ± 0.5 mV and 3.7 ± 0.0, respectively. The formulations morphology obtained by scanning and transmission electron microscopy images confirmed the presence of nanocapsules. In the stability analysis by optical scanning spectrophotometry (Turbiscan), all dispersions obtained a backscattering variation less than 2% over 5 weeks and were considered stable. In the in vitro release assay, imiquimod-loaded nanoparticles obtained slower release of the drug compared to free and commercial imiquimod. There were chemical interactions between chitosan and other formulation components evaluated by thermogravimetric and infrared studies. No crystalline structure was detected by the X-ray diffraction technique for the coated and uncoated imiquimod formulation. The dispersion of nanocapsules containing imiquimod presented antiangiogenic activity superior than commercial formulation in chicken embryo chorioallantoic membrane model. Nanocapsules containing imiquimod both uncoated and coated with chitosan presented cutaneous permeation in deep layers of the skin and inhibition in the chemically induced carcinogenicity process superior than tumor control group and groups treated with placebo nanoparticles while the commercial formulation presented retention of the drug in superficial layers of the skin and did not obtain a statistically significant reduction in the number of papillomas formed compared to the carcinogenic control. These results allow to conclude, therefore, that stable nanocarreadores were obtained and the chemopreventive activity and the antiangiogenic effect of these systems represent a promising alternative for the treatment of cutaneous neoplasias.Item Desenvolvimento de lipossomas vetorizados ao receptor folato contendo paclitaxel e imatinibe coencapsulados: avaliação da atividade antiproliferativa e da expressão gênica do VEGF em células tumorais(Universidade Federal de Goiás, 2014-04-30) Peres Filho, Marco Júnio; Lima, Eliana Martins; http://lattes.cnpq.br/7248774319455970; Lima, Eliana Martins; http://lattes.cnpq.br/7248774319455970; Oliveira, Anselmo Gomes; Magalhães, Nereide Stela Santos; Batista, Aline Carvalho; Rocha, Matheus lavorentiThe impact of Nanotechnology is constantly raising in different areas of science, with the development of new products that bring benefits in comparison with the alternatives available in the market. When encapsulated in nanoparticles, anticancer drugs can achieve several advantages, most importantly the possibility of reducing the amount of drug administered through targeting strategies, which are not accomplished by conventional medication. Passive targeting is related to leaky vasculature in pathological sites, and active targeting comprehends the attachment of specific ligands, anchored in nanoparticles surface, to recognize and bind receptors overexpressed in cancer cells. Coencapsulation of anticancer drugs in the same pharmaceutical carrier can coordinate pharmacokinetics of encapsulated drugs. In the present work, liposomal formulations targeted to folate receptor with paclitaxel (PTX) and imatinib (IB) coencapsulated were obtained, aiming to combine cytotoxic and antiangiogenic effects of the drugs, respectively. New analytical method was developed and validated for simultaneous quantification of IB and PTX. Soy phosphatidylcholine liposomes were prepared, with cholesterol and DSPEmPEG( 2000), to obtain long circulation particles. DSPE-PEG(2000)-FA was obtained by an unpublished method of synthesis, and this product was further used in the formulation by post-insertion technique. Cytotoxic effect and VEGF gene suppression were studied in vitro in two different cell lines, MCF7 (breast adenocarcnioma) and PC3 (prostatic adenocarcinoma), after treatment with liposomal vesicles. Analytical procedures were developed with isocratic elution, 6,5 minutes runs, with linearity, specificity, precision and accuracy. Quantification limit was 750 Ng/mL and 1000 Ng/mL for IB and PTX, respectively. After extrusion, liposomes had mean diameter close to 100 nm and low polidispersion index. Post-insertion of folic acid attached to lipid anchor procedure increased polidispersion, because the procedure lasted 24h. Drug to lipid ratios were 1:26 and 1:27 (IB and PTX respectively). Lyophilized formulations containing trehalose remained stable after 60 days of storage in terms of %EE. Synthesis of DSPE-PEG(2000)-FA was confirmed by RMN, FT-IR and ESIMS techniques. Liposomal PTX was more cytotoxic (p<0,05) than free drug in MCF7 cell line, after both 24h and 48h of exposion, for all tested concentrations. Targeted formulation containing folic acid ligand, had more impact on cell viability reduction (p<0,05) than non targeted liposomes (LPIP), also after 24h. On PC3 cell line cell viability reduction was greater (p<0,01) when the cells were exposed to targeted vesicles loaded with 1 and 10 Ng/mL of IB and PTX, after 24 and 48h. VEGF gene expression was reduced in MCF7 and PC3 (p<0,05), and once more targeted vesicles showed better results than non-targeted liposomes. It is, thus, plausible to conclude, through in vitro experiments results, that the attachment of folic acid to liposomal formulations, resulting in multi-functional liposomes, is an interesting strategy to achieve enhanced internalization and accumulation of drugs in targeted cells. This was observed by the enhancement of cytotoxic and antiangiogenic effects in breast and prostate cell lines.