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- Development of injectable hydrogels incorporating graphene-based nanoparticles for breast cancer chemo-photothermal therapyPublication . Gonçalves, Joaquim José Figueiredo; Diogo, Duarte Miguel de Melo; Correia, Ilídio Joaquim Sobreira; Melo, Bruna Daniela LopesBreast cancer is a complex and challenging disease that is responsible for a high number of deaths worldwide. The high mortality rate exhibited by this disease is associated with the limitations of the therapies currently employed in the clinic, which include surgery, radiotherapy, immunotherapy, and chemotherapy. All of these treatment modalities have a low efficacy and induce different side effects. Therefore, it is of utmost importance to develop innovative treatments that can contribute to reduce the mortality rates associated with breast cancer. In the last decade, approaches based on nanomaterials’ chemo-photothermal therapy have been demonstrating remarkable results for cancer treatment. These nanomaterials have a distinct set of physicochemical properties that grant them capacity to encapsulate drugs as well as the ability to become accumulated at the tumor site. Furthermore, the optical properties of these nanomaterials grant them the capacity to interact with Near-infrared light (NIR light). In this way, when the tumor area is exposed to NIR light, it is absorbed by the nanomaterials which converted it into heat, causing damage to the cancer cells. Simultaneously, the nanostructures’ photoinduced heat can promote the release of the loaded chemotherapeutic agents and/or sensitize the cancer cells to the action of chemotherapeutic agents, thus promoting a therapeutic synergetic effect. Nevertheless, the nanomaterials have been demonstrating a poor tumor-targeting capacity after systemic administration, which has hindered the full potential of this therapeutic modality. To overcome this issue, injectable in situ forming hydrogels have been emerging due to their capacity to perform the direct delivery of therapeutics (e.g., nanomaterials, drugs) into the tumor site with minimal off-target leakage. In particular, physical crosslinked injectable in situ forming hydrogels are appealing due to their straightforward preparation that exploits the native properties of specific polymers/materials. Additionally, this class of hydrogels generally does not require the use of initiators or catalysts, further improving their intrinsic biocompatibility. However, the features of these hydrogels (e.g., injectability, degradation, swelling) are strongly pre-determined by the physical interactions occurring in the selected polymers/materials, which can occasionally produce undesired outcomes. Hence, the combination of multiple physical crosslinking cues may allow the preparation of injectable in situ forming hydrogels with enhanced properties. In this MSc dissertation, a novel dual physically crosslinked injectable in situ forming hydrogel was engineered by combining Pluronic F127/a-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 being applied in cancer chemo-photothermal therapy. When compared to the single-crosslinked hydrogels, the dual-crosslinking contributed to the assembly of formulations with suitable injectability and improved degradation and swelling behaviors. Moreover, the dual-crosslinked hydrogels presented a good photothermal capacity, leading to an enhanced Doxorubicin release. The data obtained in the in vitro studies highlighted the good cytocompatibility of the developed hydrogels. In addition, the dual-crosslinked hydrogels mediated a chemo-photothermal effect that was able to diminish the cancer cells’ viability to just 23%. Overall, the dual-crosslinked injectable in situ forming hydrogels incorporating Doxorubicin and Dopamine-reduced Graphene Oxide developed in this MSc dissertation work plan are macroscale systems that presented promising results for their application in breast cancer chemo-photothermal therapy. Besides this, the injectable hydrogels developed in this MSc dissertation may also be explored in the delivery of other therapeutic agents, allowing their usage in other anticancer (e.g., skin or colon cancers) and/0r biomedical (e.g., bone repair, antimicrobial applications, or 3D culture) applications.
- 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.