4 research outputs found

    Desenvolvimento de nanomateriais para a terapia fototermal do cancro

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    Breast cancer is one of the most prevalent and one of the leading causes of cancer-related deaths among women worldwide. In the specific case of the Portuguese population, breast cancer incidence and mortality rates increased in the past years. This scenario is mostly owed to the ineffectiveness of the currently available treatments (surgery, radiotherapy and small molecule-based therapies), whose therapeutic success is hindered by safety issues, non-specific toxicity and resistance mechanisms displayed by cancer cells to drugs. Such emphasizes the demand for a plethora of novel therapeutic approaches. In the past decades, light-induced therapies have started to be investigated as alternative strategies to combat cancer. These treatment modalities comprise photodynamic therapy (PDT) and photothermal therapy (PTT). Both therapeutic approaches depend on the external irradiation of the tumor region with near-infrared (NIR) light for activating photosensitizers or photothermal agents, that lead to the generation of reactive oxygen species (ROS; in PDT) or to a temperature increase (in PTT), which have a cytotoxic effect on cancer cells. Yet, such treatments still need to be further improved in what concerns their efficacy and selectivity towards the tumor region. Recently, the entrapment of NIR photoabsorbers in nanoparticles surpassed problems like the poor solubility of these molecules in biological fluids. Moreover, nanoparticles due to their physicochemical properties can display a preferential tumor accumulation, which is crucial for increasing the loaded NIR photoabsorbers bioavailability and ultimately the efficacy and selectivity of this therapeutic approach. Herein, a novel nanovehicle loaded with a NIR dye aimed for breast cancer phototherapy was developed. To accomplish that, two vitamin E derivatives, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and D-α-tocopheryl succinate (TOS), were used to assemble amphiphilic micelles with a core-shell structure. TPGS and TOS were selected due to their intrinsic anticancer activity (e.g. through the generation of ROS) and ability to encapsulate poorly water-soluble molecules. 2-[2-[2-Chloro-3-[(1,3-dihydro-3,3-dimethyl-1-propyl-2H-indol-2-ylidene)ethylidene]-1-cyclohexen-1-yl]ethenyl]-3,3-dimethyl-1-propylindolium iodide (IR780) was chosen due to its versatile nature as a NIR light-responsive compound (photothermal agent, photosensitizer and NIR imaging dye). IR780-loaded TPGS-TOS micelles (IR780-TTM) with suitable sizes were obtained by using specific TPGS and TOS weight feed ratios during micelles formulation and these were able to encapsulate IR780 with high efficiency. In in vitro assays, the IR780-TTM induced a cytotoxic effect in cancer cells upon exposure to NIR irradiation through the generation of reactive oxygen species (PDT). This effective ablation of cancer cells was achieved using an ultra-low IR780 concentration. Moreover, IR780-TTM also demonstrated the ability to act as photothermal and imaging agents. Overall, the novel micellar nanoplatforms developed in this study possess a huge potential for breast cancer PDT. Moreover, IR780-TTM also demonstrate promising results to act as photothermal and imaging agents, which widens their applicability for the treatment and diagnosis of cancer.O cancro da mama é um dos mais prevalentes e uma das principais causas de morte das mulheres em todo o mundo. No caso específico da população Portuguesa, as taxas de incidência e mortalidade associadas ao cancro da mama têm vindo a aumentar nos últimos anos. Este cenário deve-se maioritariamente à ineficácia dos tratamentos atualmente disponíveis (cirurgia, radioterapia e terapias baseadas em pequenas moléculas), cuja eficácia terapêutica é reduzida devido a problemas de segurança, toxicidade não específica e ainda devido aos mecanismos de resistência a fármacos que as células cancerígenas apresentam. Estes factos evidenciam a necessidade de desenvolver novas abordagens terapêuticas. Nas últimas décadas, as fototerapias têm sido investigadas como estratégias alternativas para combater as células cancerígenas. Estas modalidades terapêuticas incluem a terapia fotodinâmica e a fototérmica. Ambos os tratamentos dependem da irradiação da região tumoral com radiação com um comprimento de onda próximo do infravermelho (near-infrared (NIR)) que ativa moléculas fotoresponsivas, as quais induzem a produção de espécies reativas de oxigénio (terapia fotodinâmica) ou um aumento de temperatura (terapia fototérmica), que têm um efeito citotóxico nas células cancerígenas. Porém, estes tratamentos ainda têm que ser otimizados para incrementar a sua eficácia e seletividade para o tumor. A nanotecnologia tem permitido ultrapassar algumas das principais limitações da aplicação das fototerapias no tratamento do cancro, através da encapsulação de agentes fotoresponsivos em nanopartículas. A encapsulação de moléculas fotoresponsivas à luz NIR em nanoveículos é crucial para reverter a baixa solubilidade destas moléculas em fluidos biológicos. Para além disso, estes nanotransportadores acumulam-se preferencialmente no tumor devido às suas propriedades físico-químicas, o que permite aumentar a biodisponibilidade das moléculas fotoresponsivas encapsuladas nestes, melhorando assim a eficácia e seletividade destas abordagens terapêuticas. Na presente tese é descrito o desenvolvimento de um nanoveículo com capacidade de encapsular um agente fotoresponsivo à luz NIR, para aplicação na fototerapia do cancro da mama. Para tal, foram utilizados dois derivados de vitamina E, succinato de D-α-tocoferil polietilenoglicol 1000 (TPGS) e succinato de D-α-tocoferil (TOS), para formular micelas anfifílicas com uma estrutura tipo “núcleo-concha”. O TPGS e o TOS foram selecionados por apresentarem atividade anticancerígena intrínseca (por exemplo, através da produção de espécies reativas de oxigénio) e pela sua capacidade para encapsular moléculas pouco solúveis em água. O iodeto de 2-[2-[2-cloro-3-[(1,3-dihidro-3,3-dimetil-1-propil-2H-indol-2-ilideno) etilideno]-1-ciclohexeno-1-il]etenil]-3,3-dimetil-1-propilindólio (IR780) foi escolhido devido à sua versatilidade como molécula fotoresponsiva, uma vez que possui características que permitem a sua aplicação como agente fototerapêutico (terapia fotodinâmica e fototermal) e de diagnóstico. No presente estudo foram obtidas micelas de TPGS-TOS contendo IR780 (IR780-TTM) com características físico-químicas adequadas, utilizando proporções de TPGS e TOS específicas aquando da sua formulação. As micelas produzidas permitiram a encapsulação do IR780 com elevada eficiência. Nos ensaios in vitro realizados verificou-se que as IR780-TTM medeiam um efeito citotóxico nas células cancerígenas após irradiação com luz NIR, através da produção de espécies reativas de oxigénio (terapia fotodinâmica). Esta eficiente ablação das células cancerígenas foi alcançada usando uma concentração de IR780 mais baixa do que a que foi descrita até agora na literatura. Aliado a isto, constatou-se que as IR780-TTM demonstram potencial para serem utilizadas como agentes de fototermia e imagiologia. Em suma, os nanoveículos desenvolvidos na presente tese apresentam um enorme potencial para a terapia fotodinâmica do cancro da mama. Por outro lado, as propriedades fototérmicas e imagiológicas que as IR780-TTM apresentam aumentam a aplicabilidade destas micelas no tratamento e diagnóstico do cancro

    IR780-loaded TPGS-TOS micelles for breast cancer photodynamic therapy

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    IR780 iodide is a near-infrared (NIR) dye with a huge potential for cancer imaging and phototherapy. However, its biomedical application is strongly impaired by its lipophilic character. Herein, amphiphilic micelles based on d-α-tocopheryl polyethylene glycol succinate (TPGS) and d-α-tocopheryl succinate (TOS), two vitamin E derivatives with intrinsic anticancer activity, are explored to load IR780. IR780-loaded micelles with suitable sizes are obtained by using specific TPGS and TOS weight feed ratios during micelles formulation and these are able to encapsulate IR780 with high efficiency. In in vitro assays, the IR780-loaded micelles induce a cytotoxic effect in cancer cells upon exposure to NIR irradiation through the generation of reactive oxygen species (photodynamic therapy). This effective ablation of cancer cells is achieved using an ultra-low IR780 concentration. Moreover, IR780-loaded micelles also have the ability to act as photothermal and imaging agents, which widens their therapeutic and diagnostic potential. Overall, TPGS-TOS micelles are promising nanoplatforms for IR780-mediated cancer phototherapy and imaging.info:eu-repo/semantics/publishedVersio

    D-α-tocopheryl polyethylene glycol 1000 succinate functionalized nanographene oxide for cancer therapy

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    Aim: To evaluate the therapeutic capacity of D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS)-functionalized nanographene oxide (nGO) in breast cancer cells. Methods: TPGS-functionalized nGO-based materials were obtained through two different approaches: a simple sonication method and a one-pot hydrothermal treatment. Results: TPGS coating successfully improved the stability of the nGO-based materials. The nanomaterials that underwent the hydrothermal procedure generated a 1.4- to 1.6-fold higher temperature variation under near infrared laser irradiation than those prepared only by sonication. In vitro, the TPGS/nGO derivatives reduced breast cancer cells’ viability and had an insignificant effect on healthy cells. Furthermore, the combined application of TPGS/nGO derivatives and near infrared light generated an improved therapeutic effect. Conclusion: TPGS/nGO derivatives are promising materials for breast cancer phototherapy.info:eu-repo/semantics/publishedVersio

    Strategies to Improve Cancer Photothermal Therapy Mediated by Nanomaterials

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    The deployment of hyperthermia‐based treatments for cancer therapy has captured the attention of different researchers worldwide. In particular, the application of light‐responsive nanomaterials to mediate hyperthermia has revealed promising results in several pre‐clinical assays. Unlike conventional therapies, these nanostructures can display a preferential tumor accumulation and thus mediate, upon irradiation with near‐infrared light, a selective hyperthermic effect with temporal resolution. Different types of nanomaterials such as those based on gold, carbon, copper, molybdenum, tungsten, iron, palladium and conjugated polymers have been used for this photothermal modality. This progress report summarizes the different strategies that have been applied so far for increasing the efficacy of the photothermal therapeutic effect mediated by nanomaterials, namely those that improve the accumulation of nanomaterials in tumors (e.g. by changing the corona composition or through the functionalization with targeting ligands), increase nanomaterials' intrinsic capacity to generate photoinduced heat (e.g. by synthesizing new nanomaterials or assembling nanostructures) or by optimizing the parameters related to the laser light used in the irradiation process (e.g. by modulating the radiation wavelength). Overall, the development of new strategies or the optimization and combination of the existing ones will surely give a major contribution for the application of nanomaterials in cancer PTT.info:eu-repo/semantics/publishedVersio
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