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Research Project
Injectable in situ forming graphene-based hydrogels for double immune checkpoint inhibitor photothermal therapy
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IR780 loaded sulfobetaine methacrylate-functionalized albumin nanoparticles aimed for enhanced breast cancer phototherapy
Publication . Alves, Cátia; Diogo, Duarte de Melo; Sousa, Rita Lima; Correia, I.J.
New insights about nanomaterials' biodistribution revealed their ability to achieve tumor accumulation by taking advantage from the dynamic vents occurring in tumor's vasculature. This paradigm-shift emphasizes the importance of extending nanomaterials' blood circulation time to enhance their tumor uptake. The classic strategy to improve nanomaterials' stability during circulation relies on their functionalization with poly(ethylene glycol). However, recent reports have been showing that PEGylated nanomaterials can suffer from the accelerated blood clearance phenomenon, emphasizing the importance of developing novel coatings for functionalizing the nanomaterials. To address this limitation, the modification of natural carriers' surface to enhance their stability appears to be a promising strategy. Herein, sulfobetaine methacrylate (SBMA)-functionalized bovine serum albumin (BSA) was synthesized for the first time to investigate the capacity of this modification to improve the resulting nanoparticles' physicochemical properties, colloidal stability and in vitro performance. This novel polymer was then employed in the formulation of nanoparticles loaded with IR780 for application in breast cancer phototherapy (IR/SBMA-BSA NPs). When compared to their non-functionalized equivalents, the IR/SBMA-BSA NPs presented a neutral surface charge and a higher stability in biologically relevant media. Due to these features, the IR/SBMA-BSA NPs could achieve a 1.9-fold greater uptake by breast cancer cells than IR/BSA NPs. Furthermore, the IR/SBMA-BSA NPs were cytocompatible towards normal cells and reduced breast cancer cells' viability up to 42%. The phototherapy mediated by IR/SBMA-BSA NPs could further decrease cancer cells' viability to about 12%. Overall, the IR/SBMA-BSA NPs have enhanced features that propel their application in breast cancer phototherapy.
Heptamethine Cyanine-Loaded Nanomaterials for Cancer Immuno-Photothermal/Photodynamic Therapy: A Review
Publication . Alves, Cátia; Sousa, Ana Rita Lima; Melo, Bruna L.; Moreira, André F.; Correia, I.J.; Diogo, Duarte de Melo
The development of strategies capable of eliminating metastasized cancer cells and preventing tumor recurrence is an exciting and extremely important area of research. In this regard, therapeutic approaches that explore the synergies between nanomaterial-mediated phototherapies and immunostimulants/immune checkpoint inhibitors have been yielding remarkable results in pre-clinical cancer models. These nanomaterials can accumulate in tumors and trigger, after irradiation of the primary tumor with near infrared light, a localized temperature increase and/or reactive oxygen species. These effects caused damage in cancer cells at the primary site and can also (i) relieve tumor hypoxia, (ii) release tumor-associated antigens and danger-associated molecular patterns, and (iii) induced a pro-inflammatory response. Such events will then synergize with the activity of immunostimulants and immune checkpoint inhibitors, paving the way for strong T cell responses against metastasized cancer cells and the creation of immune memory. Among the different nanomaterials aimed for cancer immuno-phototherapy, those incorporating near infrared-absorbing heptamethine cyanines (Indocyanine Green, IR775, IR780, IR797, IR820) have been showing promising results due to their multifunctionality, safety, and straightforward formulation. In this review, combined approaches based on phototherapies mediated by heptamethine cyanine-loaded nanomaterials and immunostimulants/immune checkpoint inhibitor actions are analyzed, focusing on their ability to modulate the action of the different immune system cells, eliminate metastasized cancer cells, and prevent tumor recurrence.
Multifunctional targeted solid lipid nanoparticles for combined photothermal therapy and chemotherapy of breast cancer
Publication . Granja, Andreia; Lima-Sousa, Rita; Alves, Cátia; de Melo-Diogo, Duarte; Nunes, Cláudia; Sousa, Célia T.; Correia, I.J.; Reis, Salette
Photothermal therapy has emerged as a new promising strategy for the management of cancer, either alone or
combined with other therapeutics, such as chemotherapy. The use of nanoparticles for multimodal therapy can
improve treatment performance and reduce drug doses and associated side effects. Here we propose the development of a novel multifunctional nanosystem based on solid lipid nanoparticles co-loaded with gold
nanorods and mitoxantrone and functionalized with folic acid for dual photothermal therapy and chemotherapy
of breast cancer. Nanoparticles were produced using an economically affordable method and presented suitable physicochemical properties for tumor passive accumulation. Upon Near-Infrared irradiation (808 nm, 1.7 W cm -2, 5 min), nanoparticles could effectively mediate a temperature increase of >20 ◦C. Moreover, exposure to light resulted in an enhanced release of Mitoxantrone. Furthermore, nanoparticles were non-hemolytic and well tolerated by healthy cells even at high concentrations. The active targeting strategy was found to be successful, as shown by the greater accumulation of the functionalized nanoparticles in MCF-7 cells. Finally, the combined effects of chemotherapy, light-induced drug release and photothermal therapy significantly enhanced breast cancer cell death. Overall, these results demonstrate that the developed lipid nanosystem is an efficient vehicle for breast cancer multimodal therapy.
Hyaluronic acid-functionalized graphene-based nanohybrids for targeted breast cancer chemo-photothermal therapy
Publication . Lima-Sousa, Rita; Melo, Bruna L.; Mendonça, António; Correia, I.J.; Melo-Diogo, Duarte de
Nanomaterials’ application in cancer therapy has been driven by their ability to encapsulate chemotherapeutic drugs as well as to reach the tumor site. Nevertheless, nanomedicines’ translation has been limited due to their lack of specificity towards cancer cells. Although the nanomaterials’ surface can be coated with targeting ligands, such has been mostly achieved through non-covalent functionalization strategies that are prone to premature detachment. Notwithstanding, cancer cells often establish resistance mechanisms that impair the effect of the loaded drugs. This bottleneck may be addressed by using near-infrared (NIR)-light responsive nanomaterials. The NIR-light triggered hyperthermic effect generated by these nanomaterials can cause irreversible damage to cancer cells or sensitize them to chemotherapeutics’ action. Herein, a novel covalently functionalized targeted NIR-absorbing nanomaterial for cancer chemo-photothermal therapy was developed. For such, dopamine-reduced graphene oxide nanomaterials were covalently bonded with hyaluronic acid, and then loaded with doxorubicin (DOX/HA-DOPA-rGO). The produced nanomaterials showed suitable physicochemical properties, high encapsulation efficiency, and photothermal capacity. The in vitro studies revealed that the nanomaterials are cytocompatible and that display an improved uptake by the CD44-overexpressing breast cancer cells. Importantly, the combination of DOX/HA-DOPA-rGO with NIR light reduced breast cancer cells’ viability to just 23 %, showcasing their potential chemo-photothermal therapy.
Sulfobetaine methacrylate-functionalized graphene oxide-IR780 nanohybrids aimed at improving breast cancer phototherapy
Publication . Leitão, Miguel; Alves, Cátia; Diogo, Duarte de Melo; Sousa, Rita Lima; Moreira, André F.; Correia, I.J.
The application of Graphene Oxide (GO) in cancer photothermal therapy is hindered by its lack of colloidal stability in biologically relevant media and modest Near Infrared (NIR) absorption. In this regard, the colloidal stability of GO has been improved by functionalizing its surface with poly(ethylene glycol) (PEG), which may not be optimal due to the recent reports on PEG immunogenicity. On the other hand, the chemical reduction of GO using hydrazine hydrate has been applied to enhance its photothermal capacity, despite decreasing its cytocompatibility. In this work GO was functionalized with an amphiphilic polymer containing [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SBMA) brushes and was loaded with IR780, for the first time, aiming to improve its colloidal stability and phototherapeutic capacity. The attained results revealed that the SBMA-functionalized GO displays a suitable size distribution, neutral surface charge and adequate cytocompatibility. Furthermore, the SBMA-functionalized GO exhibited an improved colloidal stability in biologically relevant media, while its non-SBMA functionalized equivalent promptly precipitated under the same conditions. By loading IR780 into the SBMA-functionalized GO, its NIR absorption increased by 2.7-fold, leading to a 1.2 times higher photothermal heating. In in vitro cell studies, the combination of SBMA-functionalized GO with NIR light only reduced breast cancer cells' viability to 73%. In stark contrast, by combining IR780 loaded SBMA-functionalized GO and NIR radiation, the cancer cells' viability decreased to 20%, hence confirming the potential of this nanomaterial for cancer photothermal therapy.
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Funding agency
Fundação para a Ciência e a Tecnologia
Funding programme
POR_CENTRO
Funding Award Number
SFRH/BD/144922/2019