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- IR780 based nanomaterials for cancer imaging and photothermal, photodynamic and combinatorial therapiesPublication . Alves, Cátia; Sousa, Ana Rita Lima; Diogo, Duarte Miguel de Melo; Correia, Ilídio Joaquim SobreiraIR780, a molecule with a strong optical absorption and emission in the near infrared (NIR) region, is receiving an increasing attention from researchers working in the area of cancer treatment and imaging. Upon irradiation with NIR light, IR780 can produce reactive oxygen species as well as increase the body temperature, thus being a promising agent for application in cancer photodynamic and photothermal therapy. However, IR780’s poor water solubility, fast clearance, acute toxicity and low tumor uptake may limit its use. To overcome such issues, several types of nanomaterials have been used to encapsulate and deliver IR780 to tumor cells. This mini-review is focused on the application of IR780 based nanostructures for cancer imaging, and photothermal, photodynamic and combinatorial therapies.
- 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.
- Breast cancer targeted photothermal therapy mediated by hyaluronic acid functionalized reduced graphene oxidePublication . Sousa, Ana Rita Lima; Diogo, Duarte de Melo; Alves, Cátia Gomes; Costa, Elisabete; Louro, Ricardo; Mendonça, António G.; Correia, I.J.The use of graphene-based nanomaterials in cancer photothermal therapy (PTT) is an emerging alternative to the currently available cancer treatments. In this regard, reduced graphene oxide (rGO) has been widely explored for cancer PTT due to its excellent photothermal capacity. However, rGO has some limitations, such as low colloidal stability and water insolubility, as well as absence of targeting capacity towards cancer cells. Herein, rGO produced by an environmentally- friendly method was functionalized with an amphiphilic polymer based on hyaluronic acid (HA-rGO) through hydrophobic-hydrophobic interactions for application in targeted breast cancer PTT. The functionalization improved rGO colloidal stability and cytocompatibility towards normal and breast cancer cells, as well as conferred targeting capacity towards CD44 overexpressing breast cancer cells. In addition, the photothermal effect mediated by HA-rGO upon laser irradiation reduced breast cancer cells’ viability. Overall, HA-rGO demonstrated a great potential for being used on-demand and selective treatment 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.
- 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
- Sulfobetaine methacrylate-coated reduced graphene oxide-IR780 hybrid nanosystems for effective cancer photothermal-photodynamic therapyPublication . Melo, Bruna L.; Lima-Sousa, Rita; Alves, Cátia; Correia, I.J.; de Melo-Diogo, DuarteNanomaterials with near infrared light absorption can mediate an antitumoral photothermal-photodynamic response that is weakly affected by cancer cells’ resistance mechanisms. Such nanosystems are commonly prepared by loading photosensitizers into nanomaterials displaying photothermal capacity, followed by functionalization to achieve biological compatibility. However, the translation of these multifunctional nanomaterials has been limited by the fact that many of the photosensitizers are not responsive to near infrared light. Furthermore, the reliance on poly(ethylene glycol) for functionalizing the nanomaterials is also not ideal due to some immunogenicity reports. Herein, a novel photoeffective near infrared light-responsive nanosystem for cancer photothermal-photodynamic therapy was assembled. For such, dopamine-reduced graphene oxide was, for the first time, functionalized with sulfobetaine methacrylate-brushes, and then loaded with IR780 (IR780/SB/DOPA-rGO). This hybrid system revealed a nanometric size distribution, optimal surface charge and colloidal stability. The interaction of IR780/SB/DOPA-rGO with near infrared light prompted a temperature increase (photothermal effect) and production of singlet oxygen (photodynamic effect). In in vitro studies, the IR780/SB/DOPA-rGO per se did not elicit cytotoxicity (viability > 78 %). In contrast, the combination of IR780/SB/DOPA-rGO with near infrared light decreased breast cancer cells’ viability to just 21 %, at a very low nanomaterial dose, highlighting its potential for cancer photothermal-photodynamic therapy.
- 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.
- Sulfobetaine methacrylate-albumin-coated graphene oxide incorporating IR780 for enhanced breast cancer phototherapyPublication . Melo, Bruna L.; Sousa, Rita Lima; Alves, Cátia; Ferreira, Paula; Moreira, André; Correia, I.J.; Diogo, Duarte de MeloAim: Enhance the colloidal stability and photothermal capacity of graphene oxide (GO) by functionalizing it with sulfobetaine methacrylate (SBMA)-grafted bovine serum albumin (BSA; i.e., SBMA-g-BSA) and by loading IR780, respectively. Materials & methods: SBMA-g-BSA coating and IR780 loading into GO was achieved through a simple sonication process. Results: SBMA-g-BSA-functionalized GO (SBMA-BSA/GO) presented an adequate size distribution and cytocompatibility. When in contact with biologically relevant media, the size of the SBMA-BSA/GO only increased by 8%. By loading IR780 into SBMA-BSA/GO, its photothermal capacity increased by twofold. The combination of near infrared light with SBMA-BSA/GO did not induce photocytotoxicity on breast cancer cells. In contrast, the interaction of IR780-loaded SBMA-BSA/GO with near infrared light caused the ablation of cancer cells. Conclusion: IR780-loaded SBMA-BSA/GO displayed an improved colloidal stability and phototherapeutic capacity.
- Functionalization of graphene family nanomaterials for application in cancer therapyPublication . Diogo, Duarte Miguel de Melo; Sousa, Ana Rita Lima; Alves, Cátia; Costa, Elisabete C.; Louro, Ricardo; Correia, Ilídio Joaquim SobreiraGraphene family nanomaterials’ (GFN) ability to interact with near-infrared light has propelled their application in cancer photothermal therapy. Furthermore, the graphitic lattice of GFN can adsorb different types of molecules, which has motivated their use in cancer drug delivery. However, the direct application of GFN in cancer therapy is severely hindered by their poor colloidal stability, sub-optimal safety, inefficient tumor uptake and non-selectivity towards cancer cells. To overcome these limitations, GFN have been functionalized with different types of materials. This review is focused on the different functionalizations used in the design of GFN aimed for application in cancer therapy, disclosing their role on surpassing the critical issues related to GFN-based therapies.
- Multifunctional targeted solid lipid nanoparticles for combined photothermal therapy and chemotherapy of breast cancerPublication . Granja, Andreia; Lima-Sousa, Rita; Alves, Cátia; de Melo-Diogo, Duarte; Nunes, Cláudia; Sousa, Célia T.; Correia, I.J.; Reis, SalettePhotothermal therapy has emerged as a new promising strategy for the management of cancer, either alone or combined with other therapeutics, such as chemotherapy. The use of nanoparticles for multimodal therapy can improve treatment performance and reduce drug doses and associated side effects. Here we propose the development of a novel multifunctional nanosystem based on solid lipid nanoparticles co-loaded with gold nanorods and mitoxantrone and functionalized with folic acid for dual photothermal therapy and chemotherapy of breast cancer. Nanoparticles were produced using an economically affordable method and presented suitable physicochemical properties for tumor passive accumulation. Upon Near-Infrared irradiation (808 nm, 1.7 W cm -2, 5 min), nanoparticles could effectively mediate a temperature increase of >20 ◦C. Moreover, exposure to light resulted in an enhanced release of Mitoxantrone. Furthermore, nanoparticles were non-hemolytic and well tolerated by healthy cells even at high concentrations. The active targeting strategy was found to be successful, as shown by the greater accumulation of the functionalized nanoparticles in MCF-7 cells. Finally, the combined effects of chemotherapy, light-induced drug release and photothermal therapy significantly enhanced breast cancer cell death. Overall, these results demonstrate that the developed lipid nanosystem is an efficient vehicle for breast cancer multimodal therapy.