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- Injectable hydrogels for the delivery of nanomaterials for cancer combinatorial photothermal therapyPublication . Lima-Sousa, Rita; Alves, Cátia; Melo, Bruna L.; Costa, Francisco J. P.; Nave, Micaela; Moreira, André F.; Mendonça, António; Correia, I.J.; de Melo-Diogo, DuarteProgress in the nanotechnology field has led to the development of a new class of materials capable of producing a temperature increase triggered by near infrared light. These photothermal nanostructures have been extensively explored in the ablation of cancer cells. Nevertheless, the available data in the literature have exposed that systemically administered nanomaterials have a poor tumor-homing capacity, hindering their full therapeutic potential. This paradigm shift has propelled the development of new injectable hydrogels for the local delivery of nanomaterials aimed at cancer photothermal therapy. These hydrogels can be assembled at the tumor site after injection (in situ forming) or can undergo a gel–sol–gel transition during injection (shear-thinning/self-healing). Besides incorporating photothermal nanostructures, these injectable hydrogels can also incorporate or be combined with other agents, paving the way for an improved therapeutic outcome. This review analyses the application of injectable hydrogels for the local delivery of nanomaterials aimed at cancer photothermal therapy as well as their combination with photodynamic-, chemo-, immuno- and radio-therapies.
- 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.
- Development of multifunctional graphene oxide based nanomaterials for cancer therapyPublication . Melo, Bruna Daniela Lopes; Diogo, Duarte Miguel de Melo; Correia, Ilídio Joaquim Sobreira; Sousa, Ana Rita LimaBreast cancer remains as one of the deadliest diseases affecting the worldwide population. The high mortality rate exhibited by this disease can be attributed to the limitations of the treatments currently in use in the clinic (e.g. radiotherapy, chemotherapy), which display a low therapeutic efficacy and induce adverse side effects in patients. Therefore, there is an urgent demand for innovative therapeutic approaches that can enhance breast cancer survival rates. Recently, nanomaterials’ mediated Photothermal Therapy (PTT) has been showing promising results for cancer treatment. This therapeutic modality employs nanostructures that, due to their specific set of physicochemical characteristics, can accumulate at the tumor site. Afterwards, this zone is irradiated with Near Infrared (NIR) light and the tumor-homed nanomaterials induce a local temperature increase (hyperthermia) that can induce damage to cancer cells. Among the several nanomaterials with potential for cancer PTT, Graphene Oxide (GO) has been extensively investigated due to its absorption in the NIR. After interacting with this radiation, GO produces a temperature increase that can cause damage to cancer cells. In addition, this nanomaterial has an aromatic matrix that can be used to encapsulate a wide variety of compounds, thus having a great versatility. However, the direct application of GO in cancer PTT is limited by two factors: i) the low colloidal stability of GO, which causes its precipitation in biological fluids, and ii) the poor photothermal capacity of GO, which leads to the use of high doses/intense radiation in order to achieve an adequate therapeutic effect. In this MSc research work, GO was functionalized with an albumin based amphiphilic coating containing Sulfobetaine Methacrylate (SBMA) brushes (SBMA-g-BSA) and was loaded with IR780, with the intent to improve its colloidal stability and photothermal capacity, respectively. The results revealed that GO functionalized with SBMA-g-BSA (SBMA-BSA/GO) presents an adequate size distribution and cytocompatibility for cancer-related applications. When in contact with biologically relevant media, the size of the SBMA-functionalized GO derivatives only increased by 8 % after 48 h. In the same condition and period, the non-SBMA functionalized GO (BSA coated GO) suffered a 31 % increase in its size. By loading IR780 into SBMA-BSA/GO (IR/SBMA-BSA/GO), the nanomaterials’ NIR absorption increased by 5.6-fold. In this way, the IR/SBMA-BSA/GO could produce a up to 2-times higher photoinduced heat than SBMA-BSA/GO. In in vitro cell studies, the combination of NIR light with SBMA-BSA/GO did not induce photocytotoxicity on breast cancer cells. In stark contrast, the interaction of IR/SBMA-BSA/GO with NIR light caused the ablation of cancer cells (cell viability < 2 %). Overall, IR/SBMA-BSA/GO displays a greatly improved colloidal stability and phototherapeutic capacity, being a promising hybrid nanomaterial for application in the PTT of breast cancer cells.
- 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.
- Poly(2-ethyl-2-oxazoline)–IR780 conjugate nanoparticles for breast cancer phototherapyPublication . Alves, Cátia; Lima-Sousa, Rita; Melo, Bruna L.; Ferreira, Paula; Moreira, André; Correia, I.J.; de Melo-Diogo, DuarteConventional anticancer approaches are often associated with severe side effects. Herein, the authors assembled a novel nanoparticle whose therapeutic effect is triggered by laser light. In in vitro assays, the produced nanomaterial was able to, after interacting with laser light, reduce the viability of classic and advanced cancer models. In these conditions, but in the absence of laser light, no cytotoxicity was observed. In this way, the on-demand effect (triggered by laser light) may contribute to reduced side effects. Moreover, the produced nanoparticle revealed good stability, which is important for its future translation.
- Poly(2-ethyl-2-oxazoline) functionalized reduced graphene oxide: Optimization of the reduction process using dopamine and application in cancer photothermal therapyPublication . Sousa, Ana Rita Lima; Alves, Cátia; Melo, Bruna L.; Moreira, André; Mendonça, António; Correia, I.J.; Diogo, Duarte de MeloThe high near infrared (NIR) absorption displayed by reduced graphene oxide (rGO) nanostructures renders them a great potential for application in cancer photothermal therapy. However, the production of this material often relies on the use of hydrazine as a reductant, leading to poor biocompatibility and environmental-related issues. In addition, to improve rGO colloidal stability, this material has been functionalized with poly(ethylene glycol). However, recent studies have reported the immunogenicity of poly(ethylene glycol)-based coatings. In this work, the production of rGO, by using dopamine as the reducing agent, was optimized considering the size distribution and NIR absorption of the attained materials. The obtained results unveiled that the rGO produced by using a 1:5 graphene oxide:dopamine weight ratio and a reaction time of 4 h (termed as DOPA-rGO) displayed the highest NIR absorption while retaining its nanometric size distribution. Subsequently, the DOPA-rGO was functionalized with thiol-terminated poly(2-ethyl-2-oxazoline) (P-DOPA-rGO), revealing suitable physicochemical features, colloidal stability and cytocompatibility. When irradiated with NIR light, the P-DOPA-rGO could produce a temperature increase (ΔT) of 36 ◦C (75 μg/mL; 808 nm, 1.7 W/cm2, 5 min). The photothermal therapy mediated by P-DOPA-rGO was capable of ablating breast cancer cells monolayers (viability < 3%) and could reduce heterotypic breast cancer spheroids' viability to just 30%. Overall, P-DOPA-rGO holds a great potential for application in breast cancer photothermal therapy.