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- Thiol-Maleimide and Ionic dual-crosslinked hydrogels incorporating graphene-based nanomaterials for cancer Chemo-Photothermal TherapyPublication . Marques, Pedro Henrique Infante; Diogo, Duarte Miguel de Melo; Correia, Ilídio Joaquim Sobreira; Melo, Bruna Daniela LopesBreast cancer is one of the leading causes of death among women worldwide. The high mortality rate of this type of cancer is associated with the shortcomings of the therapies currently available in the clinic, that comprise surgery, radiotherapy and chemotherapy. Such therapies have associated several side effects and low efficacy. Throughout the years, the scientific community has undertaken extensive research efforts to attain a cure for this disease, namely through the use of nanotechnological approaches. In particular, nanomaterials with photothermal capacity are emerging as an auspicious venue for cancer treatment. Upon Near Infrared (NIR; 750-1000 nm) light irradiation, these nanomaterials absorb the radiation and convert it into heat, inducing hyperthermia-driven damage in cancer cells. Furthermore, these nanomaterials can also be loaded with other therapeutic agents, such as chemotherapeutic drugs, paving the way for combinatorial anticancer therapies. However, the classic intravenous administration route of these nanomaterials is inefficient, since there are several biological barriers that reduce their accumulation in the tumor microenvironment, thus decreasing their therapeutic efficacy. Therefore, the development of novel therapeutical strategies that allow a local delivery of nanomaterials into the tumor site is crucial. In this regard, injectable hydrogels are macroscale delivery systems that are emerging as a technological approach to confine nanomaterials/drugs into the tumor site. Besides controlling the delivery of therapeutic agents, the injectable hydrogels also have a high drug loading capacity and a high water content. These formulations are injected in a liquified form, achieving in situ gelation on the tumor by exploiting different chemical and/or physical cues. In the present Master dissertation, a novel injectable in situ forming hydrogel was developed via Thiol-Maleimide “Click chemistry” and Ionic dual-crosslinkings, and it was subsequently explored for combinatorial Chemo-Photothermal Therapy of breast cancer cells. To accomplish that, Alginate, a natural and biocompatible polysaccharide, was firstly functionalized with thiol groups stemming from cysteine, yielding Thiolated Alginate. Then, the Thiolated Alginate was allowed to react with the synthetic and biocompatible 4arm-PEG-Maleimide (via Thiol-Maleimide “Click chemistry”) and with divalent calcium ions (via ionic interactions), yielding a dual-crosslinked hydrogel. In addition to this, the photothermal agent Dopamine reduced Graphene Oxide (DOPA-rGO) was synthesized and co-loaded in the hydrogel, alongside with the chemotherapeutic drug Doxorubicin (DOX). The obtained results showed that the developed formulations displayed injectability and capacity of gelling in situ through dual-crosslinking. By introducing DOPA-rGO into the dual-crosslinked hydrogels, their degradation and swelling profiles were modulated. The dual-crosslinked hydrogels also generated a local temperature variation upon NIR laser irradiation, which could speedup the DOX release profile by ˜ 1.4 – 1.6-fold. In in vitro studies, the DOPA-rGO loaded dual-crosslinked hydrogel presented cytocompatible profile towards both normal and breast cancer cells. Moreover, the dual-crosslinked hydrogel co-loading DOX and DOPA-rGO only reduced the breast cancer cells’ viability to ˜ 80%, showcasing an outstanding ability to retain the drug within the hydrogel matrix. On the other hand, upon NIR irradiation, the dual-crosslinked hydrogel co-loading DOX and DOPA-rGO was able to decrease the breast cancer cells’ viability to just ˜ 33%. Such ˜ 2.42-times enhanced therapeutic outcome highlighted the capacity of the dual-crosslinked hydrogel co-loading DOX and DOPA-rGO for the Chemo-Photothermal Therapy of breast cancer cells.