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Development of dissolving microneedles for delivery of cancer cells membrane antigens
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O melanoma é uma das neoplasias da pele mais fatais devido à sua elevada predisposição para invasão tecidular. No entanto, o tratamento atual é pouco eficaz aquando da presença de metástases e está associado, no caso da quimioterapia, a numerosos efeitos adversos, diminuindo a qualidade de vida dos doentes. Deste modo, soluções são necessárias. A imunoterapia revela-se promissora, uma vez que é seletiva, para as células cancerígenas e não proporciona o aparecimento de efeitos adversos significativos. As microagulhas demonstraram ser ideais para a administração de biomoléculas imunológicas às células apresentadoras de antigénio de uma forma não invasiva. Estes dispositivos, por penetrarem apenas a epiderme, estão associados a uma maior facilidade de administração, reduzindo a necessidade de recorrer a profissionais de saúde qualificados. As microagulhas solúveis são ideias para administração de agentes terapêuticos, dissolvendo-se completamente após inserção na pele, sem deixar resíduos. O presente estudo foca-se na preparação destas, através de micromolding, um processo prático e com um custo-efetividade favorável, utilizando poli(metil vinil éter-co-anidrido maleico) e ácido hialurónico. Ao longo deste projeto estudou-se a incorporação de membrana celular proveniente de uma linha do melanoma, marcada com florescência e visualizada ao microscópio confocal com varrimento a laser. Foram também estudadas as propriedades mecânicas e as características de dissolução das microagulhas. Desenvolveram-se dois tipos: (a) revestidas com membrana celular e (b) com membrana celular incorporada na matriz polimérica. As primeiras evidenciaram uma camada uniforme de membrana celular em torno de toda a microagulha, com uma maior acumulação na extremidade. Um resultado semelhante foi obtido após análise das segundas, resultados estes influenciados pela técnica de fabrico e secagem utilizadas. A aplicação, de ambos os polímeros, demonstrou uma eficiente formação de microagulhas contendo membrana celular. As compostas por ácido hialurónico manifestaram melhores propriedades mecânicas, viscoelasticidade, e uma mais rápida dissolução após penetração na pele de porco quando comparadas com as formadas por poli(metil vinil éter- co-anidrido maleico). Ambas atingiram uma profundidade de 508μm, suficiente para penetrar a epiderme e ativar o sistema imunitário.
Malignant melanoma is considered the most dangerous skin neoplasia for its potential to invade distant tissues, associated with high mortality. However, current treatments still have low effectiveness in metastasized cancers and show numerous adverse effects that impair life quality and productivity of the patients. Thus, development of new therapies to fight cancer is needed. Cancer immunotherapies promise a much more targeted approach towards malignant cells and do not have as many adverse effects, improving the patient's overall survival and quality of life. Furthermore, microneedles have been ideal candidates for delivering immunological biomolecules to the dermal antigen-presenting cells in the skin, with minimal invasiveness. The devices only penetrate the non-innervated skin, with a low occurrence of side effects and ease of administration, reducing the need for skilled health care professionals. Dissolving microneedles are a promising type of microneedles to deliver therapeutics through skin and dissolve after penetration leaving no hazardous waste behind. The present study focused on the preparation of dissolving microneedles by micromolding, using poly(methyl vinyl ether-co-maleic anhydride) (PMVE/MA) in comparison to hyaluronic acid (HA). During this project, we have studied the loading of microneedles by cell membrane (CM) from a melanoma cell line. Additionally, the mechanical properties and dissolution characteristics of the microneedles were also evaluated. Two microneedles were produced: (a) microneedles coated with CM and (b) CM loaded within the polymeric matrix. Fluorescently labeled CM was utilized for the microneedles preparation and visualized using confocal laser scanning microscopy. HA-coated microneedles showed a uniform layer of CM surrounding the polymeric microneedles with a higher accumulation in the tip, making the approach viable. The loaded microneedles showed similar results when compared to coated microneedles, revealing a non-viable technique. Efficient loading of CM was obtained using both polymers. HA microneedles showed better mechanical properties, higher viscoelasticity, and faster dissolution after insertion in porcine skin than PMVE/MA. Both systems reached a penetration depth of 508μm, which is enough to penetrate the epidermis, activate the dendritic cells and stimulate the immune system.
Malignant melanoma is considered the most dangerous skin neoplasia for its potential to invade distant tissues, associated with high mortality. However, current treatments still have low effectiveness in metastasized cancers and show numerous adverse effects that impair life quality and productivity of the patients. Thus, development of new therapies to fight cancer is needed. Cancer immunotherapies promise a much more targeted approach towards malignant cells and do not have as many adverse effects, improving the patient's overall survival and quality of life. Furthermore, microneedles have been ideal candidates for delivering immunological biomolecules to the dermal antigen-presenting cells in the skin, with minimal invasiveness. The devices only penetrate the non-innervated skin, with a low occurrence of side effects and ease of administration, reducing the need for skilled health care professionals. Dissolving microneedles are a promising type of microneedles to deliver therapeutics through skin and dissolve after penetration leaving no hazardous waste behind. The present study focused on the preparation of dissolving microneedles by micromolding, using poly(methyl vinyl ether-co-maleic anhydride) (PMVE/MA) in comparison to hyaluronic acid (HA). During this project, we have studied the loading of microneedles by cell membrane (CM) from a melanoma cell line. Additionally, the mechanical properties and dissolution characteristics of the microneedles were also evaluated. Two microneedles were produced: (a) microneedles coated with CM and (b) CM loaded within the polymeric matrix. Fluorescently labeled CM was utilized for the microneedles preparation and visualized using confocal laser scanning microscopy. HA-coated microneedles showed a uniform layer of CM surrounding the polymeric microneedles with a higher accumulation in the tip, making the approach viable. The loaded microneedles showed similar results when compared to coated microneedles, revealing a non-viable technique. Efficient loading of CM was obtained using both polymers. HA microneedles showed better mechanical properties, higher viscoelasticity, and faster dissolution after insertion in porcine skin than PMVE/MA. Both systems reached a penetration depth of 508μm, which is enough to penetrate the epidermis, activate the dendritic cells and stimulate the immune system.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2021, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Cell membrane Dissolving microneedles Hyaluronic acid Immunotherapy Micromolding Mestrado integrado - 2021