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Ludmilla David De ,moura - One of the best experts on this subject based on the ideXlab platform.
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Tratamento de câncer de mama utilizando terapia fotodinâmica com nonoemulsões de Ftalocianina de cloro alumínio
2017Co-Authors: Ludmilla David De ,mouraAbstract:Dissertação (mestrado)—Universidade de Brasília, Instituto de Ciências Biológicas, Pós-Graduação em Nanociência e Nanobiotecnologia, 2017.O câncer é caracterizado por um complexo de alterações que afetam a atividade molecular intracelular e também as comunicações entre as células e tecidos. Dentre todos os tipos de cânceres existentes, o câncer de mama representa 25% do total de neoplasias no mundo, com possibilidade de metástases. Ressalta-se que as terapias atuais, incluindo a cirurgia, a terapia hormonal, quimioterapia e terapia de radiação, são pouco seletivas para a eficácia no tratamento do câncer de mama primário e metastático. Portanto, são necessárias novas terapias que possam ser mais eficazes no tratamento deste tumor, de modo a destruir a propagação de metástases. Um dos tratamentos em ascensão é o uso da terapia fotodinâmica (TFD), a qual envolve três elementos fundamentais, sendo eles: um agente fotossensibilizante ou fotossensibilizador, uma fonte de luz específica e moléculas de oxigênio. Ademais, o uso de nanoestruturas associadas à TFD, tem proporcionado bons resultados aos tratamentos para o câncer, pois aumenta a eficiência dos fármacos, no caso os fotossensibilizadores, utilizados. Assim, o objetivo deste trabalho, foi desenvolver um tratamento para o câncer de mama utilizando a terapia fotodinâmica, com uma nanopartícula contendo o fotossensibilizador cloreto de alumínio - ftalocianina, de forma a promover a mortalidade de células tumorais mamárias primárias e possíveis focos de metástases. Para tal, foram desenvolvidas e caracterizadas três nanoformulações, sendo elas: Nanoemulsão de Fatalocianina de Cloro-Alumínio (NE-ALCLFT), Nanoemulsão de Ftalocianina de Cloro-Alumínio com Ácido Fólico (NE-FO-ALCLFT) e Micela de Ácido Fólico (MIC-FO-ALCLFT). Para a caracterização, foram utilizadas as metodologias: análise de estabilidade, ZetaSizer, FT-IR, RAMAN, Microscopia eletrônica de Transmissão (MET) e de Varredura (MEV), análise por Espectrofluorímetro e o estudo da produção de espécies reativas de oxigênio (ROS). Posteriormente, foi realizado o estudo in vitro para avaliação da viabilidade celular e citotoxicidade, utilizando duas linhagens celulares, sendo uma de adenocarcinoma mamário (4T1) e outra de fibroblastos (NIH/3T3), pela avaliação do método colorimétrico MTT e análise morfológica das células pós-tratamentos por Microscopia de Fluorescência e contraste de fase. Nestes testes também foram avaliados a interferência da potência utilizada pelo LED para a aplicação da TFD, sendo testadas as potências 10mW/cm², 50mW/cm² e 100mW/cm². Por fim, foram realizados os testes in vivo e ex vivo, que incluem o estudo da biodistribuição das três nanoformulações pela via de administração endovenosa, por meio da avaliação de imageamento em tempo real no equipamento IVIS Lumina XR. Posteriormente ao estudo da biodistribuição, foi selecionada uma das nanoformulações (aquela que apresentou melhores resultados) para o tratamento do câncer de mama utilizando a TFD. Nesta última fase do trabalho, foram realizadas três formas de tratamento, sendo elas: sistêmica ( usando a administração do fármaco por via endovenosa e irradiação do LED também sistêmico (corpo todo do animal)), parcialmente sistêmica (com administração do fármaco por via endovenosa e irradiação apenas no local do tumor), e local (utilizando a administração do fármaco por via Intratumoral e irradiação do LED também no local do tumor). Foram avaliados o peso dos camundongos, o volume tumoral, análises bioquímicas, hematológicas, análise por microtomografia computadorizada pelo equipamento PET/SPECT (avaliando o volume pulmonar e ósseo) e análise histopatológica. Os resultados apresentam todos os preparos das nanoformulações e suas respectivas caracterizações, sugerindo relevante estabilidade das nanopartículas. Os ensaios de viabilidade celular mostram que as nanoformulações apresentam citotoxicidade para ambas as linhagens celulares testadas, e que o uso apenas do LED (sem a presença dos nanoformulações) provocam o aumento da viabilidade celular na linhagem de fibroblastos. O ensaio de biodistribuição ressalta os principais órgãos atingidos pelas nanoformulações, sendo especialmente o fígado, baço e rins. Além disso, concluiu-se que a nanoformulação NE-ALCLFT, foi a que apresentou melhor biodistribuição para a região tumoral. Por fim, os tratamentos in vivo com o uso da TFD, apontam efeitos de necrose tumoral e infiltrados inflamatórios. Além disso, foi possível concluir que a melhor forma de tratamento, dentre as analisadas, foi utilizar a nanoformulação por administração endovenosa, e a irradiação do LED no local da região do tumor, onde apresentou 80% de eficiência do tratamento, com 4 camundongos apresentando todos tecidos normais (n=5). Portanto, com este trabalho, foi possível desenvolver um método eficiente para o tratamento do câncer de mama, utilizando a TFD com uma nanoemulsão de ftalocianina de cloro alumínio, por administração endovenosa.Cancer is characterized by a complex of alterations that affect intracellular molecular activity as well as communications between cells and tissues. Among all types of cancer, breast cancer represents 25% of the total number of neoplasms worldwide, with the possibility of metastases. It is noteworthy that current therapies, including surgery, hormone therapy, chemotherapy and radiation therapy, are not completely selective for efficacy in the treatment of primary and metastatic breast cancer. Therefore, new therapies are needed that may be more effective in treating this tumor, in order to destroy the spread of metastases. One of the rising treatments is the use of Photodynamic Therapy (PDT), which involves three fundamental elements: a photosensitizing or photosensitizing agent, a specific light source and oxygen molecules. In addition, the use of nanostructures associated with PDT has provided good results for cancer treatments, since it increases the efficiency of the Drugs, in this case the photosensitizers, used. Thus, the objective of this work was to develop a treatment for breast cancer using photodynamic therapy with a nanoparticle containing the photosensitizer Chloro-Aluminum Phthalocyanine in order to promote the mortality of primary mammary tumor cells and possible foci of metastases . To that end, three nanoformulations were developed and characterized: Nanoemulsion of Fatalocyanine Chlorine-Aluminum (NE-ALCLFT), Folic Acid Chlorine-Aluminum Phthalocyanine Nanoemulsion (NE-FO-ALCLFT) and Folic Acid Micelle -FO-ALCLFT). For the characterization, the methodologies were used: stability analysis, ZetaSizer, FT-IR, RAMAN, Transmission Electron Microscopy (SEM) and Scanning (SEM), Spectrofluorimeter analysis and the study of the production of reactive oxygen species ). The in vitro study was carried out to evaluate cell viability and cytotoxicity, using two cell lines, one of the squamous cell carcinoma (4T1) and the other of fibroblasts (NIH / 3T3), by the evaluation of the MTT colorimetric method and the morphological analysis of the Post-treatment cells by Fluorescence Microscopy and phase contrast. These tests also evaluated the interference of the power used by the LED for the application of the PDT, being tested the powers 10mW / cm², 50mW / cm² and 100mW / cm². Finally, the in vivo and ex vivo tests were carried out, including the study of the biodistribution of the three nanoformulations through intravenous Administration, by means of real time imaging evaluation in the Lumina XR IVIS equipment. After the biodistribution study, one of the nanoformulations (the one that presented the best results) was selected for the treatment of breast cancer using PDT. In this last phase of the study, three forms of treatment were performed: systemic (using intravenous Drug Administration and systemic LED irradiation (whole body of the animal)), partially systemic (with intravenous Administration of the Drug And irradiation only at the tumor site), and local (using Intratumoral Drug Administration and LED irradiation also at the tumor site). The weight of the mice, tumor volume, biochemical and hematological analyzes, PET / SPECT (evaluating lung and bone volume) and histopathological analysis were analyzed by microtomography. The results show all the syntheses of the nanoformulations and their respective characterizations, suggesting the relevant stability of the nanoparticles. The cell viability assays show that the nanoformulations have cytotoxicity for both cell lines tested, and that the use of LEDs alone (without the presence of nanoformulations) provokes an increase in cell viability in the fibroblast lineage. The biodistribution test highlights the main organs affected by nanoformulations, especially the liver, spleen and kidneys. In addition, it was concluded that the NE-ALCLFT nanoformulation presented the best biodistribution to the tumor region. Finally, in vivo treatments with the use of PDT, point to effects of tumor necrosis and inflammatory infiltrates. In addition, it was possible to conclude that the best form of treatment, among those analyzed, was to use nanoformulation by intravenous Administration, and LED irradiation at the site of the tumor region, where it presented 80% of treatment efficiency, with 4 mice presenting all normal tissues (n = 5). Therefore, with this work, it was possible to develop an efficient method for the treatment of breast cancer, using PDT with a chlorthal aluminum phthalocyanine nanoemulsion, by intravenous Administration
Nipan Israsena - One of the best experts on this subject based on the ideXlab platform.
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Antitumor efficacy and Intratumoral distribution of SN-38 from polymeric depots in brain tumor model.
Experimental biology and medicine (Maywood N.J.), 2015Co-Authors: Ketpat Vejjasilpa, Norased Nasongkla, Chawan Manaspon, Noppadol Larbcharoensub, Atthaporn Boongird, Suradej Hongeng, Nipan IsrasenaAbstract:We investigate antitumor efficacy and 2D and 3D Intratumoral distribution of 7-ethyl-10-hydroxycamptothecin (SN-38) from polymeric depots inside U-87MG xenograft tumor model in nude mice. Results showed that polymeric depots could be used to administer and controlled release of a large amount of SN-38 directly to the brain tumor model. SN-38 released from depots suppressed tumor growth, where the extent of suppression greatly depended on doses and the number of depot injections. Tumor suppression of SN-38 from depots was three-fold higher in animals which received double injections of depots at high dose (9.7 mg of SN-38) compared to single injection (2.2 mg). H&E staining of tumor sections showed that the area of tumor cell death/survival of the former group was two-fold higher than those of the latter group. Fluorescence imaging based on self-fluorescent property of SN-38 was used to evaluate the Intratumoral distribution of this Drug compared to histological results. The linear correlation between fluorescence intensity and the amount of SN-38 allowed quantitative determination of SN-38 in tumor tissues. Results clearly showed direct correlation between the amount of SN-38 in tumor sections and cancer cell death. Moreover, 3D reconstruction representing the distribution of SN-38 in tumors was obtained. Results from this study suggest the rationale for Intratumoral Drug Administration and release of Drugs inside tumor, which is necessary to design Drug delivery systems with efficient antitumor activity.
Shirley Lehnert - One of the best experts on this subject based on the ideXlab platform.
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Sensitization to radiation from an implanted 125I source by sustained Intratumoral release of chemotherapeutic Drugs.
Radiation research, 2004Co-Authors: Mohammed Berrada, Zhi Yang, Shirley LehnertAbstract:Abstract Berrada, M., Yang, Z. and Lehnert, S. M. Sensitization to Radiation from an Implanted 125I Source by Sustained Intratumoral Release of Chemotherapeutic Drugs. Radiat. Res. 162, 64–70 (2004). We have investigated tumor response to low-dose-rate irradiation from an implanted 125I source alone or in conjunction with Intratumoral Drug Administration. The Drug (cis-DDP or 5-FU) was incorporated homogeneously into the co-polymer CPP-SA, 20:80, and the polymer/Drug rods were implanted in the RIF-1 fibrosarcomas growing subcutaneously in C3H mice. Twenty-four hours later, the tumor was implanted with an 125I seed. Tumor growth time was the end point in these experiments. For implanted 125I sources of different dose rates and implant times giving a range of total doses, a consistent dose–response relationship was shown between tumor growth time and total dose. In other experiments, 125I sources of different specific activities were implanted for periods of time adjusted so that the total dose to the tumor...
Harry Bartelink - One of the best experts on this subject based on the ideXlab platform.
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Improvement of combined modality therapy with cisplatin and radiation using Intratumoral Drug Administration in murine tumors
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 1994Co-Authors: Adrian C. Begg, M. J. M. Deurloo, W. Kop, Harry BartelinkAbstract:Abstract The aim of these studies was to increase the therapeutic ratio by achieving higher tumor concentrations of cisplatin during the course of a fractionated irradiation treatment. Specific goals were to test, firstly, whether multiple Drug injections could be replaced by a single slow release implant of cisplatin, and secondly, whether the therapeutic potential of the combined treatment could be increased by administering the Drug Intratumorally. Drug Administration routes tested were intraperitoneal (i.p.) of Drug in solution, Intratumoral (i.t.) of Drug in solution, and Intratumoral of Drug in a slow release formulation. The latter consisted of a hydrogel polymer formulated into rods which were implanted into the center of subcutaneous tumors. For Drug alone, both i.t. routes (solution or polymer) produced higher therapeutic gains than i.p. Administration, as judged by tumor growth delay for a given weight loss. When combined with radiation, dose response curves were always shifted to lower doses and were steeper than for radiation or Drug alone, although isobologram analysis indicated additivity. In a first series, Drug enhancement ratios ranged from 1.6 to 2.6, and were highest for the i.t. groups. In a second series, X-ray enhancement ratios ranged from 1.1 to 1.7, with overlap between results from the different routes. Therapeutic ratios, however, were highest for the i.t. groups in both series. Slow release rods produced the highest therapeutic gains in the first series, while i.t. Administration of Drug in solution was approximately as effective in the second series. It is concluded that i.t. Administration of cisplatin in a slow release vehicle is a relatively simple and effective way of providing high tumor Drug levels during a fractionated radiation scheme which can lead to significant therapeutic improvements compared with administering the Drug systemically.
David J. Waxman - One of the best experts on this subject based on the ideXlab platform.
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Antiangiogenesis Enhances Intratumoral Drug Retention
Cancer research, 2011Co-Authors: Chong-sheng Chen, Todd Blute, David J. WaxmanAbstract:The tumor vasculature delivers nutrients, oxygen, and therapeutic agents to tumor cells. Unfortunately, the delivery of anticancer Drugs through tumor blood vessels is often inefficient and can constitute an important barrier for cancer treatment. This barrier can sometimes be circumvented by antiangiogenesis-induced normalization of tumor vasculature. However, such normalizing effects are transient; moreover, they are not always achieved, as shown here, when 9L gliosarcoma xenografts were treated over a range of doses with the VEGF receptor-selective tyrosine kinase inhibitors axitinib and AG-028262. The suppression of tumor blood perfusion by antiangiogenesis agents can be turned to therapeutic advantage, however, through their effects on tumor Drug retention. In 9L tumors expressing the cyclophosphamide-activating enzyme P450 2B11, neoadjuvant axitinib treatment combined with Intratumoral cyclophosphamide Administration significantly increased tumor retention of cyclophosphamide and its active metabolite, 4-hydroxycyclophosphamide. Similar increases were achieved using other angiogenesis inhibitors, indicating that increased Drug retention is a general response to antiangiogenesis. This approach can be extended to include systemic delivery of an anticancer proDrug that is activated Intratumorally, where antiangiogenesis-enhanced retention of the therapeutic metabolite counterbalances the decrease in Drug uptake from systemic circulation, as exemplified for cyclophosphamide. Importantly, the increase in Intratumoral Drug retention induced by neoadjuvant antiangiogenic Drug treatment is shown to increase tumor cell killing and substantially enhance therapeutic activity in vivo. Thus, antiangiogenic agents can be used to increase tumor Drug exposure and improve therapeutic activity following Intratumoral Drug Administration, or following systemic Drug Administration in the case of a therapeutic agent that is activated Intratumorally.