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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.
- Development of graphene oxide-based hydrogels for cancer therapyPublication . Costa, Francisco José Palácio; Correia, Ilídio Joaquim Sobreira; Diogo, Duarte Miguel de Melo; Sousa, Ana Rita LimaBreast cancer is a major cause of death of women worldwide. This high mortality rate is a consequence of the limitations of the currently used therapies, such as surgery, chemotherapy and radiotherapy. Such therapies exhibit a poor efficacy and induce several side effects. Therefore, the development of new therapies is imperative. Along the years, researchers have developed several types of nanomaterials (e.g. dendrimers, liposomes, micelles) for application in different anticancer modalities. Recently, the focus has turned towards the photothermal capacity of some nanomaterials. When irradiated with Near Infrared (NIR; 750 – 1000 nm) light, these nanomaterials can absorb its energy, releasing it as heat that induces damage in cancer cells. These light-responsive nanomaterials can also accommodate drugs in their structure, enabling their use in combinatorial therapeutic approaches. However, the nanomaterials are commonly administered by intravenous injection, which is not ideal considering the weak tumor-homing capacity of systemically administered nanomaterials, leading to a subpar outcome. Due to that, new technologies capable of delivering nanoparticles directly into the tumor tissue are under investigation. In particular, hydrogels formed through Thiol-Maleimide Michael type additions display potential to this application owing to their ability to incorporate high doses of nanoparticles into their compact 3D structure, as well as good chemical selectivity, biocompatibility, and simple production. However, such hydrogels have been mostly prepared using synthetic polymers, which are not ideal considering their non-biodegradability. Herein, a novel Thiol-Maleimide crosslinked hydrogel, engineered using natural polymers, was produced for application in the chemo-photothermal therapy of breast cancer cells. To obtain natural polymers compatible with this crosslinking chemistry, Hyaluronic Acid was decorated with Thiol groups and deacetylated Chitosan was grafted with Maleimide groups. Simultaneously, Dopamine-reduced Graphene Oxide was produced and loaded with Doxorubicin (DOX/DOPA-rGO) to create NIR light responsive nanomaterial with chemo-photothermal capabilities. In order to formulate the Thiol-Maleimide crosslinked hydrogels incorporating this therapeutic nano-agent (DOX/DOPA-rGO@TMgel), a simple mixture of Hyaluronic acid-Thiol, deacetylated Chitosan-Maleimide and DOX/DOPA-rGO was performed. In in vitro studies, when breast cancer cells were incubated with DOPA-rGO@TMgel and exposed to NIR ligh (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-phototherapeutic potential.
- 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.
- 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.