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- Thermo- and pH-responsive nano-in-micro particles for combinatorial drug delivery to cancer cellsPublication . Moreira, André; Dias, Diana Rodrigues; Costa, Elisabete C.; Correia, Ilídio Joaquim SobreiraDrug combinatorial therapy has been gaining the scientific community attention as a suitable approach to increase treatments efficacy and promote cancer eradication. In this study, a new pH- and thermo- responsive carrier was developed by combining doxorubicin-loaded gold-core silica shell nanorods with salicylic acid loaded poly (lactic-co-glycolic acid) based microparticles (NIMPS). The obtained results showed that the drugs and nanorods release could be triggered by the near-infrared (NIR) laser irradiation or by the exposition to an acidic environment. The in vitro 2D cell studies showed that the NIMPS are biocompatible and easily uptaken by HeLa cells. In addition, 3D cell culture models revealed that the NIMPS administration, combined with the NIR laser irradiation, was capable of reducing the size of the HeLa spheroids up to 48%. Overall, the attained data support the application of the nano-in-micro spheres as a dual stimuli responsive drug carrier system for the local administration of combined therapies to cervical cancer cells.
- Microneedle-based delivery devices for cancer therapy: a reviewPublication . Moreira, André; Rodrigues, Ana Carolina Félix; Jacinto, Telma A.; Miguel, Sónia; Costa, Elisabete; Correia, I.J.Macroscale delivery systems that can be locally implanted on the tumor tissue as well as avoid all the complications associated to the systemic delivery of therapeutics have captured researchers' attention, in recent years. Particularly, the microneedle-based devices can be used to efficiently deliver both small and macro-molecules, like chemotherapeutics, proteins, and genetic material, along with nanoparticle-based anticancer therapies. Such capacity prompted the application of microneedle devices for the development of new anticancer vaccines that can permeate the tumor tissue and simultaneously improve the effectiveness of therapeutic agents. Based on the promising results demonstrated by the microneedle systems in the local administration of anticancer therapeutics, this review summarizes the different microneedle formulations developed up to now aimed for application on cancer therapy (mphasizing those produced with polymers). Additionally, the microneedles' general properties, type of therapeutic approach and its main advantages are also highlighted.
- Reduced graphene oxide–reinforced tricalcium phosphate/gelatin/chitosan light-responsive scaffolds for application in bone regenerationPublication . Cabral, Cátia S. D.; Melo-Diogo, Duarte de; Ferreira, Paula; Moreira, André F.; Correia, I.J.Bone is a mineralized tissue with the intrinsic capacity for constant remodeling. Rapid prototyping techniques, using biomaterials that mimic the bone native matrix, have been used to develop osteoinductive and osteogenic personalized 3D structures, which can be further combined with drug delivery and phototherapy. Herein, a Fab@Home 3D Plotter printer was used to promote the layer-by-layer deposition of a composite mixture of gelatin, chitosan, tricalcium phosphate, and reduced graphene oxide (rGO). The phototherapeutic potential of the new NIR-responsive 3D_rGO scaffolds was assessed by comparing scaffolds with different rGO concentrations (1, 2, and 4 mg/mL). The data obtained show that the rGO incorporation confers to the scaffolds the capacity to interact with NIR light and induce a hyperthermy effect, with a maximum temperature increase of 16.7 °C after under NIR irradiation (10 min). Also, the increase in the rGO content improved the hydrophilicity and mechanical resistance of the scaffolds, particularly in the 3D_rGO4. Furthermore, the rGO could confer an NIR-triggered antibacterial effect to the 3D scaffolds, without compromising the osteoblasts' proliferation and viability. In general, the obtained data support the development of 3D_rGO for being applied as temporary scaffolds supporting the new bone tissue formation and avoiding the establishment of bacterial infections.
- 3D tumor spheroids: an overview on the tools and techniques used for their analysisPublication . Costa, Elisabete C.; Moreira, André; Diogo, Duarte Miguel de Melo; Gaspar, V. M.; Carvalho, Marco António Paulo de; Correia, I.J.In comparison with 2D cell culture models, 3D spheroids are able to accurately mimic some features of solid tumors, such as their spatial architecture, physiological responses, secretion of soluble mediators, gene expression patterns and drug resistance mechanisms. These unique characteristics highlight the potential of 3D cellular aggregates to be used as in vitro models for screening new anticancer therapeutics, both at a small and large scale. Nevertheless, few reports have focused on describing the tools and techniques currently available to extract significant biological data from these models. Such information will be fundamental to drug and therapeutic discovery process using 3D cell culture models. The present review provides an overview of the techniques that can be employed to characterize and evaluate the efficacy of anticancer therapeutics in 3D tumor spheroids.
- Combining Photothermal‐Photodynamic Therapy Mediated by Nanomaterials with Immune Checkpoint Blockade for Metastatic Cancer Treatment and Creation of Immune MemoryPublication . Sousa, Rita Lima; Melo, Bruna L.; Alves, Cátia; Moreira, André; Mendonça, António; Correia, I.J.; Diogo, Duarte de MeloThe pursuit of effective treatments for metastatic cancer is still one of the most intensive areas of research in the biomedical field. In a not-so-distant past, the scientific community has witnessed the rise of immunotherapy based on immune checkpoint inhibitors (ICIs). This therapeutic modality intends to abolish immunosuppressive interactions, re-establishing T cell responses against metastasized cancer cells. Despite the initial enthusiasm, the ICIs were later found to be associated with low clinical therapeutic outcomes and immune-related side effects. To address these limitations, researchers are exploring the combination of ICIs with nanomaterial-mediated phototherapies. These nanomaterials can accumulate within the tumor and produce, upon interaction with light, a temperature increase (photothermal therapy) and/or reactive oxygen species (photodynamic therapy), causing damage to cancer cells. Importantly, these photothermal-photodynamic effects can pave the way for an enhanced ICI-based immunotherapy by inducing the release of tumor-associated antigens and danger-associated molecular patterns, as well as by relieving tumor hypoxia and triggering a pro-inflammatory response. This progress report analyses the potential of nanomaterial-mediated photothermal-photodynamic therapy in combination with ICIs, focusing on their ability to modulate T cell populations leading to an anti-metastatic abscopal effect and on their capacity to generate immune memory that prevents tumor recurrence.
- Injectable in situ forming hydrogels incorporating dual-nanoparticles for chemo- photothermal therapy of breast cancer cellsPublication . Sabino, Ivo; Sousa, Rita Lima; Alves, Cátia; Melo, Bruna L.; Moreira, André F.; Correia, I.J.; Diogo, Duarte de MeloChemo-photothermal therapy (chemo-PTT) mediated by nanomaterials holds a great potential for cancer treatment. However, the tumor uptake of the systemically administered nanomaterials was recently found to be below 1 %. To address this limitation, the development of injectable tridimensional polymeric matrices capable of delivering nanomaterials directly into the tumor site appears to be a promising approach. In this work, an injectable in situ forming ionotropically crosslinked chitosan-based hydrogel co-incorporating IR780 loaded nanoparticles (IR/BPN) and Doxorubicin (DOX) loaded nanoparticles (DOX/TPN) was developed for application in breast cancer chemo-PTT. The produced hydrogels (IR/BPN@Gel and IR/BPN+DOX/TPN@Gel) displayed suitable physicochemical properties and produced a temperature increase of about 9.1 °C upon exposure to Near Infrared (NIR) light. As importantly, the NIR-light exposure also increased the release of DOX from the hydrogel by 1.7-times. In the in vitro studies, the combination of IR/BPN@Gel with NIR light (photothermal therapy) led to a reduction in the viability of breast cancer cells to 35 %. On the other hand, the non-irradiated IR/BPN+DOX/TPN@Gel (chemotherapy) only diminished cancer cells' viability to 85 %. In contrast, the combined action of IR/BPN+DOX/TPN@Gel and NIR light reduced cancer cells' viability to about 9 %, demonstrating its potential for breast cancer chemo-PTT
- Optical clearing methods: An overview of the techniques used for the imaging of 3D spheroidsPublication . Costa, Elisabete C; Silva, Daniel N.; Moreira, André; Correia, I.J.Spheroids have emerged as in vitro models that reproduce in a great extent the architectural microenvironment found in human tissues. However, the imaging of 3D cell cultures is highly challenging due to its high thickness, which results in a light-scattering phenomenon that limits light penetration. Therefore, several optical clearing methods, widely used in the imaging of animal tissues, have been recently explored to render spheroids with enhanced transparency. These methods are aimed to homogenize the microtissue refractive index (RI) and can be grouped into four different categories, namely (a) simple immersion in an aqueous solution with high RI; (b) delipidation and dehydration followed by RI matching; (c) delipidation and hyperhydration followed by RI matching; and (d) hydrogel embedding followed by delipidation and RI matching. In this review, the main optical clearing methods, their mechanism of action, advantages, and disadvantages are described. Furthermore, the practical examples of the optical clearing methods application for the imaging of 3D spheroids are highlighted.
- Reduced graphene oxide-enriched chitosan hydrogel/cellulose acetate-based nanofibers application in mild hyperthermia and skin regenerationPublication . Graça, Mariana F. P.; Melo, Bruna L.; Sousa, Rita Lima; Ferreira, Paula; Moreira, André; Correia, I.J.Asymmetric wound dressings have captured researchers' attention due to their ability to reproduce the structural and functional properties of the skin layers. Furthermore, recent studies also report the benefits of using near infrared (NIR) radiation-activated photothermal therapies in treating infections and chronic wounds. Herein, a chitosan (CS) and reduced graphene oxide (rGO) hydrogel (CS_rGO) was combined with a polycaprolactone (PCL) and cellulose acetate (CA) electrospun membrane (PCL_CA) to create a new NIR-responsive asymmetric wound dressing. The rGO incorporation in the hydrogel increased the NIR absorption capacity and allowed a mild hyperthermy effect, a temperature increase of 12.4 ◦C when irradiated with a NIR laser. Moreover, the PCL_CA membrane presented a low porosity and hydrophobic nature, whereas the CS_rGO hydrogel showed the ability to provide a moist environment, prevent exudate accumulation and allow gaseous exchanges. Furthermore, the in vitro data demonstrate the capacity of the asymmetric structure to act as a barrier against bacteria penetration as well as mediating a NIR-triggered antibacterial effect. Additionally, human fibroblasts were able to adhere and proliferate in the CS_rGO hydrogel, even under NIR laser irradiation, presenting cellular viabilities superior to 90 %. Altogether, our data support the application of the NIR-responsive asymmetric wound dressings for skin regeneration.
- Optimization of the GSH-Mediated Formation of Mesoporous Silica-Coated Gold Nanoclusters for NIR Light-Triggered Photothermal ApplicationsPublication . Fernandes, Natanael; Rodrigues, Ana Carolina Félix; Diogo, Duarte de Melo; Correia, I.J.; Moreira, AndréCancer light-triggered hyperthermia mediated by nanomaterials aims to eliminate cancer cells by inducing localized temperature increases to values superior to 42 C, upon irradiation with a laser. Among the different nanomaterials with photothermal capacity, the gold-based nanoparticles have been widely studied due to their structural plasticity and advantageous physicochemical properties. Herein, a novel and straightforward methodology was developed to produce gold nanoclusters coated with mesoporous silica (AuMSS), using glutathione (GSH) to mediate the formation of the gold clusters. The obtained results revealed that GSH is capable of triggering and control the aggregation of gold nanospheres, which enhanced the absorption of radiation in the NIR region of the spectra. Moreover, the produced AuMSS nanoclusters mediated a maximum temperature increase of 20 C and were able to encapsulate a drug model (acridine orange). In addition, these AuMSS nanoclusters were also biocompatible with both healthy (fibroblasts) and carcinogenic (cervical cancer) cells, at a maximum tested concentration of 200 g/mL. Nevertheless, the AuMSS nanoclusters’ NIR light-triggered heat generation successfully reduced the viability of cervical cancer cells by about 80%. This confirms the potential of the AuMSS nanoclusters to be applied in cancer therapy, namely as theragnostic agents.
- Desenvolvimento de novos micro- e nano-sistemas responsivos para entrega de drogas anti-tumoraisPublication . Moreira, André Ferreira; Correia, Ilídio Joaquim Sobreira; Gaspar, Vítor Manuel AbreuCancer is a major health care problem with growing incidence, not only at a national level but also worldwide. Due to this urgency in reducing cancer prevalence, the scientific community has put forward a great attention in the search for novel anti-cancer treatments, particularly, in the development of nanocarriers capable to control and promote drug delivery to target cells. These drug delivery systems are capable to overcome the limitations presented by the conventional chemotherapeutic treatments. Among the various types of nanocarriers developed so far, mesoporous silica nanoparticles (MSNs) possess unique structural properties that make them highly suitable to encapsulate and deliver drugs to cancer cells. However, for these specialized nanocarriers to be applied in cancer therapies it is still of critical importance to control the time frame of drug release at the tumor microenvironment or inside cancer cells, in order to maximize the therapeutic effect and reduce unspecific cytotoxicity. One alternative to control drug release is to endow the nanocarriers with a pH responsive drug release that takes advantage of the naturally acidic tumor microenvironment and also of the acidic pH of lysosomes. In this thesis the development of dual drug loaded pH-responsive mesoporous silica nanoparticles (MSNs) with a calcium carbonate-based coating is presented as an effective alternative to deliver drugs to prostate cancer cells. This approach allowed the simultaneous co-encapsulation of a non-steroidal anti-inflammatory drug (Ibuprofen) and Doxorubicin (an anti-tumoral drug), with high efficiency. Furthermore, the idealized calcium carbonate coating successfully promoted a pH sensitive drug release from the MSNs matrix. The delivery systems proved to be capable of maintaining the drugs inside their mesoporous structure under physiological pH, and to prompt its release in acidic environments. The resulting dual loaded MSNs coated with calcium carbonate have spherical morphology and a mean size of 167 nm, presenting therefore, good characteristics to be applied as nanocarriers. Such, is supported by the cytotoxicity studies where the idealized MSNs produced a 93% higher anti-proliferative effect than the non-coated silica nanoparticles, being even more effective than the dual free drug administration, as well. Overall, the carbonate coating of MSNs showed to be a simple and cost-effective approach for cancer therapy, in particular for a pH-triggered drug delivery. Moreover, the versatile nature of these nanocarriers allows surface modifications that can improve the selectivity to target cells, allow imaging or even a combination of them both.