Browsing by Author "Sousa, Ana Rita Lima"
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- Breast cancer targeted photothermal therapy mediated by hyaluronic acid functionalized reduced graphene oxidePublication . Sousa, Ana Rita Lima; Diogo, Duarte de Melo; Alves, Cátia Gomes; Costa, Elisabete; Louro, Ricardo; Mendonça, António G.; Correia, I.J.The use of graphene-based nanomaterials in cancer photothermal therapy (PTT) is an emerging alternative to the currently available cancer treatments. In this regard, reduced graphene oxide (rGO) has been widely explored for cancer PTT due to its excellent photothermal capacity. However, rGO has some limitations, such as low colloidal stability and water insolubility, as well as absence of targeting capacity towards cancer cells. Herein, rGO produced by an environmentally- friendly method was functionalized with an amphiphilic polymer based on hyaluronic acid (HA-rGO) through hydrophobic-hydrophobic interactions for application in targeted breast cancer PTT. The functionalization improved rGO colloidal stability and cytocompatibility towards normal and breast cancer cells, as well as conferred targeting capacity towards CD44 overexpressing breast cancer cells. In addition, the photothermal effect mediated by HA-rGO upon laser irradiation reduced breast cancer cells’ viability. Overall, HA-rGO demonstrated a great potential for being used on-demand and selective treatment of breast cancer cells.
- Environmentally-friendly reduced graphene oxide functionalized with hyaluronic acid for targeted cancer photothermal therapyPublication . Sousa, Ana Rita Lima; Diogo, Duarte de Melo; Alves, Cátia; Costa, Elisabete; Ferreira, Paula; Louro, Ricardo; Mendonça, António; Correia, I.J.Reduced Graphene Oxide (rGO) is one of the most promising nanomaterials for cancer photothermal therapy (PTT) due to its high near infrared (NIR) absorption. However, the rGO producing methods uses dangerous reducing agents, resulting in poor biocompatibility. Additionally, rGO also displays poor colloidal stability and is unable to target cancer cells. These limitations can be improved by using environmentally-friendly reduction methods and by functionalizing this nanomaterial with amphiphilic polymers. In this work, the production of reduced Graphene Oxide (rGO) rGO was performed by using an environmentally-friendly method (reduction with L-ascorbic Acid (LAA)). Then, the obtained rGO was functionalized with an amphiphilic polymer based on hyaluronic acid (HA-g-PMAO) for application in CD44-targeted breast cancer PTT
- Functionalization of graphene family nanomaterials for application in cancer therapyPublication . Diogo, Duarte Miguel de Melo; Sousa, Ana Rita Lima; Alves, Cátia; Costa, Elisabete C.; Louro, Ricardo; Correia, Ilídio Joaquim SobreiraGraphene 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.
- Graphene family nanomaterials for application in cancer combination photothermal therapyPublication . Diogo, Duarte de Melo; Sousa, Ana Rita Lima; Alves, Cátia; Correia, I.J.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.
- Heptamethine Cyanine-Loaded Nanomaterials for Cancer Immuno-Photothermal/Photodynamic Therapy: A ReviewPublication . Alves, Cátia; Sousa, Ana Rita Lima; Melo, Bruna L.; Moreira, André F.; Correia, I.J.; Diogo, Duarte de MeloThe 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.
- Hyaluronic acid functionalized green reduced graphene oxide for targeted cancer photothermal therapyPublication . Sousa, Ana Rita Lima; Diogo, Duarte Miguel de Melo; Alves, Cátia; Costa, Elisabete C.; Ferreira, Paula; Louro, Ricardo; Correia, Ilídio Joaquim SobreiraReduced 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.
- Hyaluronic acid functionalized nanoparticles loaded with IR780 and DOX for cancer chemo-photothermal therapyPublication . Alves, Cátia; Diogo, Duarte Miguel De Melo; Sousa, Ana Rita Lima; Costa, Elisabete; Correia, IlidioIR780 is a near infrared (NIR) dye with a huge potential to be applied in cancer phototherapy and imaging. However, IR780 poor water solubility and acute cytotoxicity limit its direct use in cancer theragnostic. Herein, a novel Hyaluronic acid (HA)-based amphiphilic polymer was used, for the first time, in the preparation of polymeric nanoparticles (HPN) encapsulating IR780 aimed to be applied in breast cancer therapy. Furthermore, HPN co-encapsulating IR780 and Doxorubicin (DOX) were also produced in order to further enhance the therapeutic effectiveness of this nanoformulation. The results revealed that HPN were able to successfully encapsulate IR780 (IR-HPN) and the IR780-DOX combination (IR/DOX-HPN). Furthermore, the encapsulation of IR780 in HPN improved its absorption at 808 nm by about 2.2-fold, thereby enhancing its photothermal potential, as well as its cytocompatibility. The 2D in vitro cell uptake studies demonstrated that the nanostructures displayed a higher internalization by breast cancer cells than by normal cells. In addition, the assays performed in 3D in vitro models of breast cancer revealed that HPN can penetrate into spheroids. Furthermore, the 3D in vitro studies also demonstrated that the combined application of IR-HPN and NIR light was unable to induce cytotoxicity on spheroids. In contrast, IR/DOX-HPN produced a decrease on spheroids cells' viability, and their combination with NIR light induced an even stronger therapeutic effect, thus revealing the potential of these nanoparticles for cancer chemo-phototherapy.
- IR780 based nanomaterials for cancer imaging and photothermal, photodynamic and combinatorial therapiesPublication . Alves, Cátia; Sousa, Ana Rita Lima; Diogo, Duarte Miguel de Melo; Correia, Ilídio Joaquim SobreiraIR780, 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.
- Poly(2-ethyl-2-oxazoline) functionalized reduced graphene oxide: Optimization of the reduction process using dopamine and application in cancer photothermal therapyPublication . Sousa, Ana Rita Lima; Alves, Cátia; Melo, Bruna L.; Moreira, André; Mendonça, António; Correia, I.J.; Diogo, Duarte de MeloThe 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/cm2, 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.
- POxylated graphene oxide nanomaterials for combination chemo-phototherapy of breast cancer cellsPublication . Diogo, Duarte Miguel de Melo; Costa, Elisabete C.; Alves, Cátia; Sousa, Ana Rita Lima; Ferreira, Paula; Louro, Ricardo; Correia, Ilídio Joaquim SobreiraPEGylated graphene oxide (GO) nanomaterials have been showing promising results in cancer therapy, due to their drug loading and photothermal capacities. However, the recent reports regarding the immunogenicity of poly(ethylene glycol) based coatings highlight the importance of investigating alternative materials to functionalize GO. Herein, GO derivatives were functionalized for the first time with an amphiphilic polymer based on poly(2-ethyl-2-oxazoline) and were co-loaded with doxorubicin (DOX) and D-α-Tocopherol succinate (TOS) to be applied in chemo-phototherapy of breast cancer cells. The results revealed that POxylated GO displays the required properties for application in cancer therapy. Moreover, the screening of different DOX:TOS combination ratios showed that the 1:3 DOX:TOS molar ratio produces an optimal synergistic therapeutic effect towards breast cancer cells. Furthermore, this drug ratio had a lower impact on normal cells. POxylated GO was then loaded with this drug combination in order to assess its chemo-phototherapeutic potential. The delivery of DOX:TOS by POxylated GO to cancer cells induced a stronger therapeutic effect than that attained with the free drug combination. Furthermore, an even greater cytotoxicity towards cancer cells was achieved by exposing DOX:TOS loaded POxylated GO to near infrared radiation. Overall, POxylated GO is a promising drug delivery and phototherapeutic agent.