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- Estudo da influência do ácido retinóico no acidente vascular cerebralPublication . Pouso, Manuel António do Rosário; Oliveira, Maria Elisa Cairrão RodriguesO acidente vascular cerebral constitui uma das principais causas de morte e de invalidez em todo o mundo. A artéria cerebral média deriva da artéria carótida interna e é responsável pela irrigação de diversas áreas do cérebro, estando associada à maioria dos quadros clínicos de acidente vascular cerebral. Embora represente apenas 2% da massa corporal, o cérebro humano utiliza cerca de 20% da energia gerada pelo organismo. Desta forma, é de extrema importância manter os níveis de perfusão adequados, uma vez que é através do fluxo sanguíneo que o cérebro recebe os níveis corretos de oxigénio e nutrientes para o desempenho das suas funções. As células musculares lisas são os principais componentes celulares das artérias sendo responsáveis pela alteração do diâmetro das mesmas, através de mecanismos de contração e relaxamento, possibilitando a regulação do fluxo sanguíneo em função das necessidades energéticas do cérebro. Assim, o principal objetivo deste trabalho é analisar o efeito do ácido retinóico, um derivado da vitamina A com propriedades vasoativas e anti-inflamatórias, na regulação da função vascular mediada por neurónios e astrócitos após um evento isquémico. Foram isolados explantes da artéria cerebral média de ratos Wistar e aderidos a placas de culturas revestidas com colagénio. A partir dessas artérias foram obtidas células do músculo liso tendo estas sido expostas a meios condicionados por co-culturas de neurónios e astrócitos, previamente incubadas com diferentes concentrações de ácido retinóico e submetidas a isquemia. Através da técnica de Planar Cell Surface Area, foi analisada a resposta das células do músculo liso ao agente contráctil, noradrenalina, e ao agente relaxante, nitroprussiato de sódio. A utilização deste derivado da vitamina A modulou o secretoma de neurónios e astrócitos submetidos a ambiente isquémico. A concentração de 5 µL de ácido retinóico apresenta os resultados mais promissores, promovendo o relaxamento das células musculares lisas quando expostas ao agente contráctil utilizado, mantendo o mesmo perfil após a adição do agente vasodilatador. Assim, estes dados indicam que a utilização de ácido retinóico apresenta benefícios terapêuticos, após um acidente vascular cerebral, promovendo o relaxamento das células do músculo liso e aumentando, assim, os níveis suprimento sanguíneo.
- Development of dual-crosslinked Pluronic F127/Chitosan injectable hydrogels incorporating graphene nanosystems for breast cancer photothermal therapy and antibacterial applicationsPublication . Pouso, Manuel António do Rosário; Melo, Bruna L.; Gonçalves, Joaquim; Mendonça, António; Correia, I.J.; Diogo, Duarte de MeloNanomaterials with responsiveness to near-infrared light can mediate the photoablation of cancer cells with an exceptional spatio-temporal resolution. However, the therapeutic outcome of this modality is limited by the nanostructures’ poor tumor uptake. To address this bottleneck, it is appealing to develop injectable in situ forming hydrogels due to their capacity to perform a tumor-confined delivery of the nanomaterials with minimal off-target leakage. In particular, injectable in situ forming hydrogels based on Pluronic F127 have been emerging due to their FDA-approval status, biocompatibility, and thermosensitive sol–gel transition. Nevertheless, the application of Pluronic F127 hydrogels has been limited due to their fast dissociation in aqueous media. Such limitation may be addressed by combining the thermoresponsive sol–gel transition of Pluronic F127 with other polymers with crosslinking capabilities. In this work, a novel dual-crosslinked injectable in situ forming hydrogel based on Pluronic F127 (thermosensitive gelation) and Chitosan (ionotropic gelation in the presence of NaHCO3), loaded with Dopamine-reduced graphene oxide (DOPA-rGO; photothermal nanoagent), was developed for application in breast cancer photothermal therapy. The dual-crosslinked hydrogel incorporating DOPA-rGO showed a good injectability (through 21 G needles), in situ gelation capacity and cytocompatibility (viability > 73 %). As importantly, the dual-crosslinking improved the hydrogel’s porosity and prevented its premature degradation. After irradiation with near-infrared light, the dual-crosslinked hydrogel incorporating DOPA-rGO produced a photothermal heating (ΔT ≈ 22 °C) that reduced the breast cancer cells’ viability to just 32 %. In addition, this formulation also demonstrated a good antibacterial activity by reducing the viability of S. aureus and E. coli to 24 and 33 %, respectively. Overall, the dual-crosslinked hydrogel incorporating DOPA-rGO is a promising macroscale technology for breast cancer photothermal therapy and antimicrobial applications.
- Injectable and implantable hydrogels for localized delivery of drugs and nanomaterials for cancer chemotherapy: A reviewPublication . Pouso, Manuel António do Rosário ; Melo, Bruna Daniela Lopes ; Gonçalves, Joaquim; Louro, Ricardo; Mendonça, António; Correia, Ilídio Joaquim Sobreira ; de Melo-Diogo, DuarteMultiple chemotherapeutic strategies have been developed to tackle the complexity of cancer. Still, the outcome of chemotherapeutic regimens remains impaired by the drugs’ weak solubility, unspecific biodistribution and poor tumor accumulation after systemic administration. Such constraints triggered the development of nanomaterials to encapsulate and deliver anticancer drugs. In fact, the loading of drugs into nanoparticles can overcome most of the solubility concerns. However, the ability of systemically administered drug-loaded nanomaterials to reach the tumor site has been vastly overestimated, limiting their clinical translation. The drugs’ and drug-loaded nanomaterials’ systemic administration issues have propelled the development of hydrogels capable of performing their direct/local delivery into the tumor site. The use of these macroscale systems to mediate a tumor-confined delivery of the drugs/drugs-loaded nanomaterials grants an improved therapeutic efficacy and, simultaneously, a reduction of the side effects. The manufacture of these hydrogels requires the careful selection and tailoring of specific polymers/materials as well as the choice of appropriate physical and/or chemical crosslinking interactions. Depending on their administration route and assembling process, these matrices can be classified as injectable in situ forming hydrogels, injectable shear-thinning/selfhealing hydrogels, and implantable hydrogels, each type bringing a plethora of advantages for the intended biomedical application. This review provides the reader with an insight into the application of injectable and implantable hydrogels for performing the tumor-confined delivery of drugs and drug-loaded nanomaterials.
- Dual-crosslinked injectable in situ forming Alginate/CaCl2/Pluronic F127/ α-Cyclodextrin hydrogels incorporating Doxorubicin and graphene-based nanomaterials for cancer chemo-photothermal therapyPublication . Gonçalves, Joaquim; Melo, Bruna Daniela Lopes ; Pouso, Manuel António do Rosário ; Correia, Ilídio Joaquim Sobreira ; de Melo-Diogo, DuarteInjectable in situ forming hydrogels have been emerging due to their capacity to perform the direct delivery of therapeutics into the tumor site with minimal off-target leakage. Particularly, physical crosslinked injectable in situ forming hydrogels are appealing due to their straightforward preparation that exploits the native jointing capabilities of specific polymers/materials. However, the features of these hydrogels (e.g., injectability, degradation, swelling) are strongly pre-determined by the physical interactions available on the selected polymers/ materials, occasionally yielding undesired outcomes. Thus, the combination of multiple physical crosslinking cues may allow the preparation of hydrogels with enhanced properties. In this work, a dual-crosslinked injectable in situ forming hydrogel was engineered by combining Pluronic F127/α-Cyclodextrin and Alginate/CaCl2 (i.e., combination of host-guest and electrostatic interactions), being loaded with Doxorubicin (chemotherapeutic drug) and Dopamine-reduced Graphene Oxide (photothermal nano-agent) for application in cancer chemophotothermal therapy. When compared to the single-crosslinked hydrogels, the dual-crosslinking contributed to the assembly of formulations with suitable injectability and improved degradation and water absorption behaviors. Moreover, the dual-crosslinked hydrogels presented a good photothermal capacity (ΔT ≈ 14 ◦C), leading to a 1.18-times enhanced Doxorubicin release. In in vitro cell-based studies, the dual-crosslinked hydrogels exhibited an excellent cytocompatibility towards healthy (normal human dermal fibroblasts) and breast cancer (MCF-7) cells. As importantly, the dual-crosslinked hydrogels were able to mediate a chemophotothermal effect that diminished the cancer cells’ viability to just 23 %. Overall, the developed dualcrosslinked injectable in situ forming hydrogels incorporating Doxorubicin and Dopamine-reduced Graphene Oxide are a promising macroscale system for breast cancer chemo-photothermal therapy.