Browsing by Author "Sousa, Rita Lima"
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- Assessing the Combinatorial Chemo‐Photothermal Therapy Mediated by Sulfobetaine Methacrylate‐Functionalized Nanoparticles in 2D and 3D In Vitro Cancer ModelsPublication . Mó, Inês; Alves, Cátia; Diogo, Duarte de Melo; Sousa, Rita Lima; Correia, I.J.Combinatorial cancer therapies mediated by nanomaterials can potentially overcome the limitations of conventional treatments. These therapies are generally investigated using 2D in vitro cancer models, leading to an inaccurate screening. Recently, 3D in vitro spheroids have emerged in the pre-clinical testing stage of nanomedicines due to their ability to mimic key features of the in vivo solid tumors.
- Chitosan-based injectable in situ forming hydrogels containing dopamine-reduced graphene oxide and resveratrol for breast cancer chemo-photothermal therapyPublication . Melo, Bruna L.; Sousa, Rita Lima; Alves, Cátia; Moreira, André F.; Correia, I.J.; Diogo, Duarte de MeloStrategies combining nanomaterials’ chemotherapy and photothermal therapy hold an enormous potential for improving cancer treatment. Still, the translation of this modality has been hindered by the immunogenicity triggered by some of the polymers used for coating nanomaterials as well as by the nanostructures’ poor tumor uptake after systemic administration. To address this bottleneck, the formulation of injectable polymeric matrices capable of delivering/confining chemotherapeutics and nanomaterials into the tumor site has been gathering a great interest. In this work, ionotropically crosslinked chitosan-based injectable in situ forming hydrogels co-incorporating Dopamine-reduced graphene oxide (DOPA-rGO; photothermal nano-agent) and Resveratrol (RES; chemotherapeutic drug), were prepared for the first time, to be applied in cancer chemo- photothermal therapy. The formulated hydrogels displayed injectability and in situ gelation as well as suitable physicochemical properties and good cytocompatibility. In vitro, the hydrogels’ photothermal therapy (DOPA- rGO@Gel +NIR light) only diminished the breast cancer cells’ viability to 72%. Moreover, cancer cells exposed to the hydrogels’ chemotherapy (RES+DOPA-rGO@Gel) still displayed a viability of 75%. In stark contrast, the hydrogels’ chemo-photothermal therapy (RES+DOPA-rGO@Gel +NIR light) was capable of decreasing cancer cells’ viability to just 31%. Overall, RES+DOPA-rGO@Gel presents an enormous potential for the chemo- photothermal therapy of breast cancer cells.
- 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.
- Development of Thiol-Maleimide hydrogels incorporating graphene-based nanomaterials for cancer chemo-photothermal therapyPublication . Costa, Francisco J. P.; Nave, Micaela; Sousa, Rita Lima; Alves, Cátia; Melo, Bruna L.; Correia, I.J.; Diogo, Duarte de MeloNano-sized materials have been widely explored in the biomedicine field, especially due to their ability to encapsulate drugs intended to be delivered to cancer cells. However, systemically administered nanomaterials face several barriers that can hinder their tumor-homing capacity. In this way, researchers are now focusing their efforts in developing technologies that can deliver the nanoparticles directly into the tumor tissue. Particularly, hydrogels assembled using Thiol-Maleimide Michael type additions are emerging for this purpose due to their capacity to incorporate high nanoparticles’ doses in a compact 3D structure as well as good chemical selectivity, biocompatibility, and straightforward preparation. Nevertheless, such hydrogels have been mostly prepared using synthetic polymers, which is not ideal due to their poor biodegradability. In this work, a novel natural polymer-based Thiol-Maleimide hydrogel was produced for application in breast cancer chemo-photothermal therapy. To obtain natural polymers compatible with this crosslinking chemistry, Hyaluronic acid was endowed with Thiol groups and deacetylated Chitosan was grafted with Maleimide groups. Parallelly, Doxoru- bicin loaded Dopamine-reduced graphene oxide (DOX/DOPA-rGO) was prepared for attaining Near Infrared (NIR) light responsive chemo-photothermal nanoagents. By simply mixing Hyaluronic Acid-Thiol, deacetylated Chitosan-Maleimide and DOX/DOPA-rGO, Thiol-Maleimide crosslinked hydrogels incorporating this nano- material could be assembled (DOX/DOPA-rGO@TMgel). When breast cancer cells were incubated with DOPA- rGO@TMgel and exposed to NIR light (photothermal therapy), their viability was reduced to about 59 %. On the other hand, DOX/DOPA-rGO@TMgel (chemotherapy) reduced cancer cells’ viability to 50 %. In stark contrast, the combined action of DOX/DOPA-rGO@TMgel and NIR light decreased breast cancer cells’ viability to just 21 %, highlighting its chemo-photothermal potential.
- 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
- Injectable in situ forming thermo-responsive graphene based hydrogels for cancer chemo-photothermal therapy and NIR light-enhanced antibacterial applicationsPublication . Sousa, Rita Lima; Diogo, Duarte de Melo; Alves, Cátia; Cabral, Cátia S. D.; Miguel, Sónia P.; Mendonça, António; Correia, I.J.Functionalized graphene oxide (GO) and reduced GO (rGO) based nanomaterials hold a great potential for cancer photothermal therapy. However, their systemic administration has been associated with an accelerated blood clearance and/or with suboptimal tumor uptake. To address these limitations, the local delivery of GO/rGO to the tumor site by 3D matrices arises as a promising strategy. In this work, injectable chitosan-agarose in situ forming thermo-responsive hydrogels incorporating GO (thermogel-GO) or rGO (thermogel-rGO) were prepared for the first time. The hydrogels displayed suitable injectability and gelation time, as well as good physicochemical properties and cytocompatibility. When irradiated with near infrared (NIR) light, the thermogel-rGO produced a 3.8-times higher temperature increase than thermogel-GO, thus decreasing breast cancer cells' viability to 60%. By incorporating an optimized molar ratio of the Doxorubicin:Ibuprofen combination on thermogel-rGO, this formulation mediated a chemo-photothermal effect that further diminished cancer cells' viability to 34%. In addition, the hydrogels' antibacterial activity was further enhanced upon NIR laser irradiation, which is an important feature considering the possible risk of infection at the site of administration. Overall, thermogel-rGO is a promising injectable in situ forming hydrogel for combinatorial chemo-photothermal therapy of breast cancer cells and NIR light enhanced antibacterial applications.
- IR780 loaded sulfobetaine methacrylate-functionalized albumin nanoparticles aimed for enhanced breast cancer phototherapyPublication . Alves, Cátia; Diogo, Duarte de Melo; Sousa, Rita Lima; Correia, I.J.New insights about nanomaterials' biodistribution revealed their ability to achieve tumor accumulation by taking advantage from the dynamic vents occurring in tumor's vasculature. This paradigm-shift emphasizes the importance of extending nanomaterials' blood circulation time to enhance their tumor uptake. The classic strategy to improve nanomaterials' stability during circulation relies on their functionalization with poly(ethylene glycol). However, recent reports have been showing that PEGylated nanomaterials can suffer from the accelerated blood clearance phenomenon, emphasizing the importance of developing novel coatings for functionalizing the nanomaterials. To address this limitation, the modification of natural carriers' surface to enhance their stability appears to be a promising strategy. Herein, sulfobetaine methacrylate (SBMA)-functionalized bovine serum albumin (BSA) was synthesized for the first time to investigate the capacity of this modification to improve the resulting nanoparticles' physicochemical properties, colloidal stability and in vitro performance. This novel polymer was then employed in the formulation of nanoparticles loaded with IR780 for application in breast cancer phototherapy (IR/SBMA-BSA NPs). When compared to their non-functionalized equivalents, the IR/SBMA-BSA NPs presented a neutral surface charge and a higher stability in biologically relevant media. Due to these features, the IR/SBMA-BSA NPs could achieve a 1.9-fold greater uptake by breast cancer cells than IR/BSA NPs. Furthermore, the IR/SBMA-BSA NPs were cytocompatible towards normal cells and reduced breast cancer cells' viability up to 42%. The phototherapy mediated by IR/SBMA-BSA NPs could further decrease cancer cells' viability to about 12%. Overall, the IR/SBMA-BSA NPs have enhanced features that propel their application in breast cancer phototherapy.
- Mitoxantrone-loaded lipid nanoparticles for breast cancer therapy – quality-by-design approach and efficacy assessment in 2D and 3D in vitro cancer modelsPublication . Granja, Andreia; Sousa, Rita Lima; Alves, Cátia; Diogo, Duarte de Melo; Pinheiro, Marina; Sousa, Célia T.; Correia, I.J.; Reis, SaletteBreast cancer is the leading cause of cancer-related deaths among women worldwide. The conventional chemotherapeutic regimens used in the treatment of this disease often lead to severe side-effects and reduced efficacy. In this study, a novel drug delivery system for the chemotherapeutic drug mitoxantrone (Mito) was developed using solid lipid nanoparticles (SLN). The production of the SLN was carried out using an organic-solvent-free, low-cost method and optimized using a Box-Behnken design. SLN presented adequate size for cancer-related applications, more than 90% of EE% and remained stable for at least 6 months. A much higher drug release was obtained at acidic pH (mimicking the endosomal compartment) than plasmatic pH, highlighting the potential of the nanosystem for tumor drug delivery. Additionally, SLN were non-hemolytic and cytocompatible, even at high concentrations of lipid. A significantly higher anti-cancer efficacy was obtained for Mito-loaded SLN comparing to the free drug at different concentrations in MCF-7 2D models. Finally, the nanoformulation was evaluated in heterotypic breast cancer spheroids showing capacity to penetrate the tridimensional structure and ability to induce a high anti-tumoral effect, similarly to the free drug. Overall, these results support that the developed SLN are effective Mito nanocarriers for the treatment of breast cancer.
- 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.
- Simple preparation of POxylated nanomaterials for cancer chemo-PDT/PTTPublication . Nave, Micaela; Costa, Francisco J. P.; Alves, Cátia; Sousa, Rita Lima; Melo, Bruna L.; Correia, I.J.; Diogo, Duarte de MeloNear infrared (NIR) light-responsive nanomaterials hold potential to mediate combinatorial therapies targeting several cancer hallmarks. When irradiated, these nanomaterials produce reactive oxygen species (photodynamic therapy) and/or a temperature increase (photothermal therapy). These events can damage cancer cells and trigger the release of drugs from the nanomaterials’ core. However, engineering nanomaterials for cancer chemophotodynamic/photothermal therapy is a complex process. First, nanomaterials with photothermal capacity are synthesized, being then loaded with photosensitizers plus chemotherapeutics, and, finally functionalized with polymers for achieving suitable biological properties. To overcome this limitation, in this work, a novel straightforward approach to attain NIR light-responsive nanosystems for cancer chemo-photodynamic/ photothermal therapy was established. Such was accomplished by synthesizing poly(2-ethyl-2-oxazoline)- IR780 amphiphilic conjugates, which can be assembled into nanoparticles with photodynamic/photothermal capabilities that simultaneously encapsulate Doxorubicin (DOX/PEtOx-IR NPs). The DOX/PEtOx-IR NPs presented a suitable size and surface charge for cancer-related applications. When irradiated with NIR light, the DOX/PEtOx-IR NPs produced singlet oxygen as well as a smaller thermic effect that boosted the release of DOX by 1.7-times. In the in vitro studies, the combination of DOX/PEtOx-IR NPs and NIR light could completely ablate breast cancer cells (viability ≈ 4 %), demonstrating the enhanced outcome arising from the nanomaterials' chemo-photodynamic/photothermal therapy.