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Nanomaterials 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Progress 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.

Near 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 chemo-photodynamic/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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The 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/cm 2 , 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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Combinatorial cancer therapies mediated by nanomaterials can potentially overcome the limitations of conventional treatments. These therapies are generally investigated using 2D in vitro cancer models, leading to an inaccurate screening. Recently, 3D in vitro spheroids have emerged in the preclinical testing stage of nanomedicines due to their ability to mimic key features of the in vivo solid tumors. Investigate the chemo-photothermal therapy mediated by Doxorubicin and IR780 loaded sulfobetaine methacrylate functionalized nanoparticles, for the first time, using monolayers of cancer cells and spheroids. In the 2D cancer models, the nanomaterials' mediated photothermal therapy, chemotherapy, and chemo-photothermal therapy reduced cancer cells' viability to about 58%, 29%, and 1%, respectively. Interestingly, when the nanomaterials' mediated photothermal therapy is tested on 3D spheroids, no cytotoxic effect is noticed. In contrast, the nanostructures' induced chemotherapy decreased spheroids' viability to 42%. On the other hand, nanomaterials' mediated chemo-photothermal therapy diminished spheroids' viability to 16%, being the most promising therapeutic modality. These results demonstrate the importance of using 3D spheroids during the in vitro screening of single/combinatorial therapies mediated by nanomaterials., (© 2020 Wiley-VCH GmbH.)

Functionalized graphene oxide (GO) and reduced GO (rGO) based nanomaterials hold a great potential for cancer photothermal therapy. However, their systemic administration has been associated with an accelerated blood clearance and/or with suboptimal tumor uptake. To address these limitations, the local delivery of GO/rGO to the tumor site by 3D matrices arises as a promising strategy. In this work, injectable chitosan-agarose in situ forming thermo-responsive hydrogels incorporating GO (thermogel-GO) or rGO (thermogel-rGO) were prepared for the first time. The hydrogels displayed suitable injectability and gelation time, as well as good physicochemical properties and cytocompatibility. When irradiated with near infrared (NIR) light, the thermogel-rGO produced a 3.8-times higher temperature increase than thermogel-GO, thus decreasing breast cancer cells' viability to 60%. By incorporating an optimized molar ratio of the Doxorubicin:Ibuprofen combination on thermogel-rGO, this formulation mediated a chemo-photothermal effect that further diminished cancer cells' viability to 34%. In addition, the hydrogels' antibacterial activity was further enhanced upon NIR laser irradiation, which is an important feature considering the possible risk of infection at the site of administration. Overall, thermogel-rGO is a promising injectable in situ forming hydrogel for combinatorial chemo-photothermal therapy of breast cancer cells and NIR light enhanced antibacterial applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The use of nanomedicines for cancer treatment holds a great potential due to their improved efficacy and safety. During the nanomedicine preclinical in vitro evaluation stage, these are mainly tested on cell culture monolayers. However, these 2D models are an unrealistic representation of the in vivo tumors, leading to an inaccurate screening of the candidate formulations. To address this problem, spheroids are emerging as an additional tool to validate the efficacy of new therapeutics due to the ability of these 3D in vitro cancer models to mimic the key features displayed by in vivo solid tumors. In this review, the application of spheroids for the evaluation of nanomedicines' physicochemical properties and therapeutic efficacy is discussed.

Developing technologies that allow the simultaneous diagnosis and treatment of cancer (theragnostic) has been the quest of numerous interdisciplinary research teams. In this context, nanomaterials incorporating prototypic near infrared (NIR)-light responsive heptamethine cyanines have been showing very promising results for cancer theragnostic. The precisely engineered features of these nanomaterials endow them with the ability to achieve a high tumor accumulation, enabling a tumor's visualization by NIR fluorescence and photoacoustic imaging modalities. Upon interaction with NIR light, the tumor-homed heptamethine cyanine-incorporating nanomaterials can also produce a photothermal/photodynamic effect with a high spatio-temporal resolution and minimal side effects, leading to an improved therapeutic outcome. This progress report analyses the application of nanomaterials incorporating prototypic NIR-light responsive heptamethine cyanines (IR775, IR780, IR783, IR797, IR806, IR808, IR820, IR825, IRDye 800CW, and Cypate) for cancer photothermal therapy, photodynamic therapy, and imaging. Overall, the continuous development of nanomaterials incorporating the prototypic NIR absorbing heptamethine cyanines will cement their phototheragnostic capabilities., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Combining hyperthermia with other therapies holds a great potential for improving cancer treatment. In this approach, the increase in the body temperature can exert a therapeutic effect on cells and/or enhance the effectiveness of anticancer agents. However, the conventional methodologies available to induce hyperthermia cannot confine a high temperature increase to the tumor-site while maintaining healthy tissues unexposed and ensuring minimal invasiveness. To overcome these limitations, combination photothermal therapy (PTT) mediated by graphene family nanomaterials (GFN) has been showing promising results. Such is owed to the ability of GFN to accumulate at the tumor site and convert near infrared light into heat, enabling a hyperthermia with a high spatial-temporal resolution. Furthermore, GFN can also incorporate different therapeutic agents on their structure for delivery purposes to cancer cells. In this way, the combination PTT mediated by GFN can result in an improved therapeutic effect. In this review, the combination of GFN mediated PTT with chemo-, photodynamic-, gene-, radio-, and immuno-therapies is examined. Furthermore, the main parameters that influence these types of combination approaches are also analyzed, with emphasis on the photothermal potential of GFN and on the vascular and cellular effects produced by the temperature increase mediated by GFN.

Reduced graphene oxide (rGO) nanomaterials display promising properties for application in cancer photothermal therapy (PTT). rGO is usually obtained by treating graphene oxide (GO) with hydrazine hydrate. However, this reducing agent contributes for the low cytocompatibility exhibited by rGO. Furthermore, rGO has a low water stability and does not show selectivity towards cancer cells. Herein, rGO attained using an environmentally-friendly method was functionalized with a novel hyaluronic acid (HA)-based amphiphilic polymer to be used in targeted cancer PTT. Initially, the green-reduction of GO with L-Ascorbic acid was optimized considering the near infrared absorption and the size distribution of the nanomaterials. Then, rGO was functionalized with the HA-based amphiphile. The functionalization of rGO improved its stability, cytocompatibility and internalization by CD44 overexpressing cells, which indicates the targeting capacity of this nanoformulation. Furthermore, the on-demand PTT mediated by HA-functionalized rGO induced cancer cells' ablation, thereby confirming its potential for targeted cancer therapy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Graphene 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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

IR780, 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., (Copyright © 2018 Elsevier B.V. All rights reserved.)