RESUMO
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.
Assuntos
Neoplasias da Mama , Grafite , Hipertermia Induzida , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Ácido Hialurônico/química , Terapia Fototérmica , Grafite/química , Doxorrubicina/química , Di-Hidroxifenilalanina , FototerapiaRESUMO
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.
Assuntos
Neoplasias , Fotoquimioterapia , Fármacos Fotossensibilizantes , Di-Hidroxifenilalanina , Fototerapia , Linhagem Celular Tumoral , Neoplasias/terapiaRESUMO
Asymmetric wound dressings have captured researchers' attention due to their ability to reproduce the structural and functional properties of the skin layers. Furthermore, recent studies also report the benefits of using near-infrared (NIR) radiation-activated photothermal therapies in treating infections and chronic wounds. Herein, a chitosan (CS) and reduced graphene oxide (rGO) hydrogel (CS_rGO) was combined with a polycaprolactone (PCL) and cellulose acetate (CA) electrospun membrane (PCL_CA) to create a new NIR-responsive asymmetric wound dressing. The rGO incorporation in the hydrogel increased the NIR absorption capacity and allowed a mild hyperthermy effect, a temperature increase of 12.4 °C when irradiated with a NIR laser. Moreover, the PCL_CA membrane presented a low porosity and hydrophobic nature, whereas the CS_rGO hydrogel showed the ability to provide a moist environment, prevent exudate accumulation and allow gaseous exchanges. Furthermore, the in vitro data demonstrate the capacity of the asymmetric structure to act as a barrier against bacteria penetration as well as mediating a NIR-triggered antibacterial effect. Additionally, human fibroblasts were able to adhere and proliferate in the CS_rGO hydrogel, even under NIR laser irradiation, presenting cellular viabilities superior to 90 %. Altogether, our data support the application of the NIR-responsive asymmetric wound dressings for skin regeneration.
Assuntos
Quitosana , Hipertermia Induzida , Nanofibras , Humanos , Quitosana/química , Hidrogéis/farmacologia , Hidrogéis/química , Nanofibras/química , Antibacterianos/farmacologiaRESUMO
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.
Assuntos
Nanopartículas , Nanoestruturas , Neoplasias , Fotoquimioterapia , Doxorrubicina , Fármacos Fotossensibilizantes , Linhagem Celular TumoralRESUMO
Nano-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, Doxorubicin 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 nanomaterial 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.
Assuntos
Neoplasias da Mama , Quitosana , Grafite , Hipertermia Induzida , Nanoestruturas , Humanos , Feminino , Grafite/química , Terapia Fototérmica , Hidrogéis/química , Compostos de Sulfidrila , Ácido Hialurônico/química , Doxorrubicina , Neoplasias da Mama/tratamento farmacológico , Polímeros/química , Maleimidas , Di-Hidroxifenilalanina , Fototerapia , Linhagem Celular TumoralRESUMO
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.
Assuntos
Nanoestruturas , Neoplasias , Humanos , Fototerapia , Hidrogéis/química , Terapia Fototérmica , Nanoestruturas/química , Neoplasias/tratamento farmacológicoRESUMO
Aims: To address the limitations of IR780 by preparing hydrophilic polymer-IR780 conjugates and to employ these conjugates in the assembly of nanoparticles (NPs) intended for cancer photothermal therapy. Materials & methods: The cyclohexenyl ring of IR780 was conjugated for the first time with thiol-terminated poly(2-ethyl-2-oxazoline) (PEtOx). This novel poly(2-ethyl-2-oxazoline)-IR780 (PEtOx-IR) conjugate was combined with D-α-tocopheryl succinate (TOS), leading to the assembly of mixed NPs (PEtOx-IR/TOS NPs). Results: PEtOx-IR/TOS NPs displayed optimal colloidal stability as well as cytocompatibility in healthy cells at doses within the therapeutic range. In turn, the combination of PEtOx-IR/TOS NPs and near-infrared light reduced heterotypic breast cancer spheroid viability to just 15%. Conclusion: PEtOx-IR/TOS NPs are promising agents for breast cancer photothermal therapy.
Conventional anticancer approaches are often associated with severe side effects. Herein, the authors assembled a novel nanoparticle whose therapeutic effect is triggered by laser light. In in vitro assays, the produced nanomaterial was able to, after interacting with laser light, reduce the viability of classic and advanced cancer models. In these conditions, but in the absence of laser light, no cytotoxicity was observed. In this way, the on-demand effect (triggered by laser light) may contribute to reduced side effects. Moreover, the produced nanoparticle revealed good stability, which is important for its future translation.
Assuntos
Neoplasias da Mama , Nanopartículas , Fotoquimioterapia , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Fototerapia , Nanopartículas/uso terapêutico , alfa-Tocoferol/uso terapêutico , Linhagem Celular TumoralRESUMO
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.
RESUMO
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/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.
Assuntos
Grafite , Neoplasias , Dopamina , Neoplasias/tratamento farmacológico , Fototerapia , Terapia Fototérmica , PoliaminasRESUMO
Chemo-photothermal therapy (chemo-PTT) mediated by nanomaterials holds a great potential for cancer treatment. However, the tumor uptake of the systemically administered nanomaterials was recently found to be below 1%. To address this limitation, the development of injectable tridimensional polymeric matrices capable of delivering nanomaterials directly into the tumor site appears to be a promising approach. In this work, an injectable in situ forming ionotropically crosslinked chitosan-based hydrogel co-incorporating IR780 loaded nanoparticles (IR/BPN) and Doxorubicin (DOX) loaded nanoparticles (DOX/TPN) was developed for application in breast cancer chemo-PTT. The produced hydrogels (IR/BPN@Gel and IR/BPN+DOX/TPN@Gel) displayed suitable physicochemical properties and produced a temperature increase of about 9.1 °C upon exposure to Near Infrared (NIR) light. As importantly, the NIR-light exposure also increased the release of DOX from the hydrogel by 1.7-times. In the in vitro studies, the combination of IR/BPN@Gel with NIR light (photothermal therapy) led to a reduction in the viability of breast cancer cells to 35%. On the other hand, the non-irradiated IR/BPN+DOX/TPN@Gel (chemotherapy) only diminished cancer cells' viability to 85%. In contrast, the combined action of IR/BPN+DOX/TPN@Gel and NIR light reduced cancer cells' viability to about 9%, demonstrating its potential for breast cancer chemo-PTT.
Assuntos
Neoplasias da Mama , Hipertermia Induzida , Nanopartículas , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Doxorrubicina , Feminino , Humanos , Hidrogéis , Fototerapia , Terapia FototérmicaRESUMO
Aim: Enhance the colloidal stability and photothermal capacity of graphene oxide (GO) by functionalizing it with sulfobetaine methacrylate (SBMA)-grafted bovine serum albumin (BSA; i.e., SBMA-g-BSA) and by loading IR780, respectively. Materials & methods: SBMA-g-BSA coating and IR780 loading into GO was achieved through a simple sonication process. Results: SBMA-g-BSA-functionalized GO (SBMA-BSA/GO) presented an adequate size distribution and cytocompatibility. When in contact with biologically relevant media, the size of the SBMA-BSA/GO only increased by 8%. By loading IR780 into SBMA-BSA/GO, its photothermal capacity increased by twofold. The combination of near infrared light with SBMA-BSA/GO did not induce photocytotoxicity on breast cancer cells. In contrast, the interaction of IR780-loaded SBMA-BSA/GO with near infrared light caused the ablation of cancer cells. Conclusion: IR780-loaded SBMA-BSA/GO displayed an improved colloidal stability and phototherapeutic capacity.