RESUMO
BACKGROUND: Early detection and treatment of colorectal cancer (CRC) is crucial for improving patient survival rates. This study aims to identify signature molecules associated with CRC, which can serve as valuable indicators for clinical hematological screening. METHOD: We have systematically searched the Human Protein Atlas database and the relevant literature for blood protein-coding genes. The CRC dataset from TCGA was used to compare the acquired genes and identify differentially expressed molecules (DEMs). Weighted Gene Co-expression Network Analysis (WGCNA) was employed to identify modules of co-expressed molecules and key molecules within the DEMs. Signature molecules of CRC were then identified from the key molecules using machine learning. These findings were further validated in clinical samples. Finally, Logistic regression was used to create a predictive model that calculated the likelihood of CRC in both healthy individuals and CRC patients. We evaluated the model's sensitivity and specificity using the ROC curve. RESULT: By utilizing the CRC dataset, WGCNA analysis, and machine learning, we successfully identified seven signature molecules associated with CRC from 1478 blood protein-coding genes. These markers include S100A11, INHBA, QSOX2, MET, TGFBI, VEGFA and CD44. Analyzing the CRC dataset showed its potential to effectively discriminate between CRC and normal individuals. The up-regulated expression of these markers suggests the existence of an immune evasion mechanism in CRC patients and is strongly correlated with poor prognosis. CONCLUSION: The combined detection of the seven signature molecules in CRC can significantly enhance diagnostic efficiency and serve as a novel index for hematological screening of CRC.
RESUMO
Mild photothermal therapy (mPTT), which circumvents the limitations of conventional photothermal therapy, is emerging and exhibits remarkable potential in clinical applications. Nevertheless, mPTT is not able to efficiently eradicate tumors because its therapeutic efficacy is dramatically diminished by stress-induced heat shock proteins (HSP). Herein, a core-shell structured Au@Pd (AP) bimetallic nanozyme was fabricated for reactive oxygen species (ROS) augmentation-induced mPTT. The nanocatalytic AP nanozymes with photothermal conversion performance harbor multienzymatic (catalase, oxidase, and peroxidase) activities to induce ROS storm formation. The generated ROS could suppress the heat-defense response of tumor cells by cleaving HSP. Overall, our work highlights a ROS-regulating strategy to counteract hyperthermia-associated resistance in mPTT.
Assuntos
Neoplasias , Terapia Fototérmica , Humanos , Espécies Reativas de Oxigênio , Neoplasias/terapia , Peroxidase , Peroxidases , Linhagem Celular Tumoral , Microambiente Tumoral , Peróxido de HidrogênioRESUMO
A core-shell-structured Cu2 O@Mn3 Cu3 O8 (CMCO) nanozyme is constructed to serve as a tumor microenvironment (TME)-activated copper ionophore to achieve safe and efficient cuproptosis. The Mn3 Cu3 O8 shell not only prevents exposure of normal tissues to the Cu2 O core to reduce systemic toxicity but also exhibits enhanced enzyme-mimicking activity owing to the better band continuity near the Fermi surface. The glutathione oxidase (GSHOx)-like activity of CMCO depletes glutathione (GSH), which diminishes the ability to chelate Cu ions, thereby exerting Cu toxicity and inducing cuproptosis in cancer cells. The catalase (CAT)-like activity catalyzes the overexpressed H2 O2 in the TME, thereby generating O2 in the tricarboxylic acid (TCA) cycle to enhance cuproptosis. More importantly, the Fenton-like reaction based on the release of Mn ions and the inactivation of glutathione peroxidase 4 induced by the elimination of GSH results in ferroptosis, accompanied by the accumulation of lipid peroxidation and reactive oxygen species that can cleave stress-induced heat shock proteins to compromise their protective capacity of cancer cells and further sensitize cuproptosis. CMCO nanozymes are partially sulfurized by hydrogen sulfide in the colorectal TME, exhibiting excellent photothermal properties and enzyme-mimicking activity. The mild photothermal effect enhances the enzyme-mimicking activity of the CMCO nanozymes, thus inducing high-efficiency ferroptosis-boosted-cuproptosis.
Assuntos
Apoptose , Neoplasias Colorretais , Ferroptose , Humanos , Cobre , Glutationa , Íons , Microambiente TumoralRESUMO
In photothermal treatments (PTTs), normal tissues around cancerous tumors get injured by excessive heat, whereas damaged cancer cells are easily restored by stress-induced heat shock proteins (HSPs) at low temperatures. Therefore, to achieve a unique tumor microenvironment (TME), it is imperative to increase PTT efficiency and reduce normal tissue injury by adopting appropriate reactive oxygen species (ROS) and lipid peroxides (LPO) cross-linked with HSPs. In the present research, a potential strategy for mild photothermal treatments (mPTTs) was proposed by initiating localized catalytic chemical reactions in TME based on Pd nanozyme-modified hydrogenated TiO2 (H-TiO2@Pd). In vitro and in vivo evaluations demonstrated that H-TiO2@Pd had good peroxidase-like activities (POD), glutathione oxidase-like activities (GSHOx), and photodynamic properties and also satisfactory biocompatibility for 4T1 cells. Localized catalytic chemical reactions in H-TiO2@Pd significantly depleted GSH to downregulate the protein expression of GPX4 and promoted the accumulation of LPO and ROS, which consumed HSP70 or inhibited its function in 4T1 cells. Hence, the as-constructed low-temperature photothermal therapeutic platform based on Pd nanozyme-modified H-TiO2 can be a promising candidate to develop a safe and effective mPTT for cancer treatments.
Assuntos
Peróxidos Lipídicos , Terapia Fototérmica , Espécies Reativas de Oxigênio , Temperatura , CatáliseRESUMO
Upregulation of heat shock proteins (HSPs) drastically compromises the treatment effect of mild photothermal therapy (PTT). Herein, we designed a polyporous Cu single atom nanozyme (Cu SAzyme) loaded with licogliflozin (LIK066) for HSP-silencing induced mild PTT. On one hand, LIK066 inhibits glucose uptake by shutting sodium-dependent glucose transporter (SGLT) "valve", effectively blocking the energy source for adenosine triphosphate (ATP) generation. Without sufficient energy, cancer cells cannot synthesize HSPs. On the other hand, Cu SAzyme presents extraordinary multienzyme activities to induce reactive oxygen species (ROS) storm formation, which can damage the existing HSPs in cancer cells. Through a two-pronged strategy of SGLT inhibitor and ROS storm, LIK066-loaded Cu SAzyme shows high efficiency for comprehensive removal of HSPs to realize mild PTT.
Assuntos
Neoplasias , Terapia Fototérmica , Humanos , Espécies Reativas de Oxigênio/metabolismo , Anidridos , Sorbitol , Proteínas de Choque Térmico/metabolismo , Neoplasias/terapia , Linhagem Celular TumoralRESUMO
The depletion of reactive oxygen species (ROS) by glutathione (GSH) and oxidative stress induced protective autophagy severely impaired the therapeutic effect of chemodynamic therapy (CDT). Therefore, how to construct a CDT treatment nanosystem with high yield and full utilization of ROS in tumor site is the main issue of CDT. Herein, a multifunctional cascade bioreactor based on mesoporous Mo-doped Cu9S5 (m-MCS) nanozymes loaded with L-Arginine (LA), abbreviated as m-MCS@LA, is constructed for realizing enhanced CDT promoted by ultrasound (US) triggered gas therapy. The m-MCS based on the catalytic performance of multivalent metal ions, which were served as nanozymes, exhibit enhanced Fenton-like and glutathione (GSH) peroxidase-like activities in comparison to Cu9S5 nanoparticles without Mo-doping. Once placed in tumor microenvironment (TME), the existence of redox couples (Cu+/Cu2+ and Mo4+/Mo6+) in m-MCS enabled it to react with hydrogen peroxide (H2O2) to generate ·OH for achieving CDT effect via Fenton-like reaction. Meanwhile, m-MCS could consume overexpressed GSH in tumor microenvironment (TME) to alleviate antioxidant capability for enhancing CDT effect. Moreover, m-MCS with mesoporous structure could be employed as the carrier to load natural nitric oxide (NO) donor LA. US as the excitation source with high tissue penetration can trigger m-MCS@LA to produce NO. As the gas transmitter with physiological functions, NO could play dual roles to kill cancer cells through gas therapy directly, and enhance CDT effect by inhibiting protective autophagy simultaneously. As a result, this US-triggered and NO-mediated synergetic cancer chemodynamic/gas therapy based on m-MCS@LA NPs can effectively eliminate primary tumor and achieved tumor-specific treatment, which provide a possible strategy for developing more effective CDT in future practical applications. STATEMENT OF SIGNIFICANCE: The depletion of reactive oxygen species (ROS) by glutathione (GSH) and oxidative stress induced protective autophagy severely impaired the therapeutic effect of chemodynamic therapy (CDT). Herein, a multifunctional cascade bioreactor based on mesoporous Mo-doped Cu9S5 (m-MCS) nanozymes loaded with L-Arginine (m-MCS@LA) is constructed for realizing enhanced CDT promoted by ultrasound (US) triggered gas therapy. The m-MCS with double redox couples presents the enhanced enzyme-like activities to perform cascade reactions for reducing GSH and generating ROS. LA loaded by m-MCS can produce NO triggered by US to inhibit the mitochondria protective autophagy for reactivating mitochondria involved apoptosis pathway. The US-triggered and NO-mediated CDT based on m-MCS@LA can effectively eliminate primary tumor through the high yield and full utilization of ROS.
Assuntos
Peróxido de Hidrogênio , Neoplasias , Antioxidantes/farmacologia , Arginina/farmacologia , Autofagia , Linhagem Celular Tumoral , Glutationa/farmacologia , Humanos , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/farmacologia , Mitocôndrias/metabolismo , Neoplasias/tratamento farmacológico , Óxido Nítrico/farmacologia , Peroxidases/farmacologia , Peroxidases/uso terapêutico , Espécies Reativas de Oxigênio , Microambiente TumoralRESUMO
Development of nanotheranostic agents with near-infrared (NIR) absorption offers an effective tool for fighting malignant diseases. Lanthanide ion neodymium (Nd3+)-based nanomaterials, due to the maximum absorption at around 800 nm and unique optical properties, have caught great attention as potential agents for simultaneous cancer diagnosis and therapy. Herein, we employed an active nanoplatform based on gadolinium-ion-doped NdVO4 nanoplates (NdVO4:Gd3+ NPs) for multiple-imaging-assisted photothermal therapy. These NPs exhibited enhanced NIR absorption and excellent biocompatibility after being grafted with polydopamine (pDA) and bovine serum albumin (BSA) layers on their surface. Upon expose to an 808 nm laser, these resulting NPs were able to trigger hyperthermia rapidly and cause photo-destruction of cancer cells. In a xenograft tumor model, tumor growth was also significantly inhibited by these photothermal agents under NIR laser irradiation. Owing to the multicomponent nanostructures, we demonstrated these nanoagents as being novel contrast agents for in vivo magnetic resonance (MR) imaging, X-ray computed tomography (CT), photoacoustic (PA) imaging, and second biological window fluorescent imaging of tumor models. Thus, we believe that this new kind of nanotherapeutic will benefit the development of emerging nanosystems for biological imaging and cancer therapy.
RESUMO
Single-atom nanozymes (SAzymes) with specific response to the unique tumor microenvironment (TME) feature providing 100 % metal atoms utilization for high-efficient enzyme-catalyzed therapy and accurate template for the study of therapeutic mechanisms. In this review, we first introduce the various synthetic strategies of SAzymes, and the TME-responsive SAzymes activities. Next, the TME-responsive enhanced antitumor therapeutic approaches based on the enzymatic activities of SAzymes are summarized, and the corresponding therapy mechanisms are elaborated. Subsequently, a concise but concentrated summary, and the challenges and opportunities for the future design and engineering of SAzyme are outlined. As a new discipline, SAzymes have vast space for development in enhanced antitumor therapy. This timely review provides guidance and constructive suggestions for the future of SAzymes.
Assuntos
Microambiente Tumoral , CatáliseRESUMO
At present, some progress has been made in the field of cancer theranostics based on nanocatalysts (NCs), but achieving precise theranostics in response to the specific tumor microenvironment (TME) remains a major challenge. Herein, a TME-responsive upconversion nanoparticles (UCNPs)-based smart UCNPs@Cu-Cys-GOx (UCCG) nanosystem is engineered, which combines natural enzymes and nanozymes so as to amplify reactive oxygen species (ROS) generation in situ for cancer starvation/chemodynamic/immunotherapy. One of the biggest merits of this material is that it can be preserved inert (off) in normal tissues, and only in the TME can it be specifically activated (on) through a series of enzymatic cascades to boost ROS production via a strategy of open source (H2 O2 self-supplying ability) and reduce expenditure (glutathione (GSH) consuming ability). More importantly, the enhanced oxidative stress by UCCG NCs reverses the immunosuppressive TME, and facilitates antitumor immune responses. Meanwhile, the starvation/chemodynamic synergistic therapy triggered by UCCG combined with PD-L1 antibody effectively inhibits the growth of primary tumors and cancer metastasis. In addition, the UCNPs in UCCG present upconversion luminescence enhancement, which can be exploited to visualize the reinforced ROS generation in real time. Collectively, this work provides an original method for the devising and exploitation of UCNPs-based catalytic immunotherapy.
Assuntos
Nanopartículas , Neoplasias , Catálise , Linhagem Celular Tumoral , Humanos , Imunoterapia/métodos , Neoplasias/terapia , Espécies Reativas de Oxigênio , Microambiente TumoralRESUMO
Photothermal therapy (PTT) is an extremely promising tumor therapeutic modality. However, excessive heat inevitably injures normal tissues near tumors, and the damage to cancer cells caused by mild hyperthermia is easily repaired by stress-induced heat shock proteins (HSPs). Thus, maximizing the PTT efficiency and minimizing the damage to healthy tissues simultaneously by adopting appropriate therapeutic temperatures is imperative. Herein, an innovative strategy is reported: ferroptosis-boosted mild PTT based on a single-atom nanozyme (SAzyme). The Pd SAzyme with atom-economical utilization of catalytic centers exhibits peroxidase (POD) and glutathione oxidase (GSHOx) mimicking activities, and photothermal conversion performance, which can result in ferroptosis featuring the up-regulation of lipid peroxides (LPO) and reactive oxygen species (ROS). The accumulation of LPO and ROS provides a powerful approach for cleaving HSPs, which enables Pd SAzyme-mediated mild-temperature PTT.
Assuntos
Nanopartículas/química , Paládio/química , Terapia Fototérmica , Temperatura , Animais , Catálise , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ferroptose , Peróxidos Lipídicos/metabolismo , Camundongos , Oxirredutases/química , Oxirredutases/metabolismo , Paládio/metabolismo , Paládio/farmacologia , Tamanho da Partícula , Espécies Reativas de Oxigênio/metabolismoRESUMO
In order to achieve better antitumor therapeutic efficacy and inhibit tumor metastasis, a multifunctional nanovaccine based on L-arginine (LA)-loaded black mesoporous titania (BMT) is fabricated. In this system, LA is utilized as the exogenous NO supplementation for gas therapy, and BMT is served as acoustic sensitizer for sonodynamic therapy. The ultrasound (US) as the exogenous stimulus can simultaneously trigger BMT and LA to produce singlet oxygen (1 O2 ) and NO gas at tumor sites, respectively. Interestingly, 1 O2 from US-excited BMT can promote the oxidation of LA to produce more NO. The high concentration of 1 O2 and NO in cancer cell can cause intracellular strong oxidative stress level and DNA double-strand breaks to induce cancer cell apoptosis ultimately. The US-triggered BMT@LA "nanovaccine" combining with immune checkpoint inhibitor PD-L1 antibody (αPD-L1) can induce strong antitumor immune response thus effectively killing primary tumors and further inhibiting metastatic tumors. Hence, BMT@LA-based "nanovaccine" combining with αPD-L1 checkpoint blockade treatment can realize synergetic sonodynamic/gas/immunotherapy with enhanced antitumor therapeutic effects.
Assuntos
Neoplasias , Arginina , Humanos , Imunoterapia , Neoplasias/terapia , TitânioRESUMO
The past decades have witnessed hyperthermia therapy (HTT) as an emerging strategy against malignant tumors. Nanomaterial-based photothermal therapy (PTT) and magnetic hyperthermia (MHT), as highly effective and noninvasive treatment models, offer advantages over other strategies in the treatment of different types of tumors. However, both PTT and MHT cannot completely cure cancer due to recurrence and distal metastasis. In recent years, cancer immunotherapy has attracted widespread attention owing to its capability to activate the body's own natural defense to identify, attack, and eradicate cancer cells. Significant efforts have been devoted to studying the activated immune responses caused by hyperthermia-ablated tumors. In this article, the synergistic mechanism of HTT in immunotherapy, including immunogenic cell death and reversal of the immunosuppressive tumor microenvironment is discussed. The reports of the combination of HTT or HTT-based multimodal therapy with immunotherapy, including immunoadjuvant exploitation, immune checkpoint blockade therapy, and adoptive cellular immunotherapy are summarized. As highlighted, these strategies could achieve synergistically enhanced therapeutic outcomes against both primary tumors and metastatic lesions, prevent cancer recurrence, and prolong the survival period. Finally, current challenges and prospective developments in HTT-synergized immunotherapy are also reviewed.
Assuntos
Hipertermia Induzida/métodos , Imunoterapia/métodos , Animais , Humanos , Neoplasias/terapiaRESUMO
Rational design of tumor microenvironment (TME)-activated nanocomposites provides an innovative strategy to construct responsive oncotherapy. In colorectal cancer (CRC), the specific physiological features are the overexpressed endogenous H2 S and slightly acidic microenvironment. Here, a core-shell Cu2 O@CaCO3 nanostructure for CRC "turn-on" therapy is reported. With CaCO3 responsive to pH decomposition and Cu2 O responsive to H2 S sulfuration, Cu2 O@CaCO3 can be triggered "on" into the therapeutic mode by the colorectal TME. When the CaCO3 shell decomposes and releases calcium in acidic colorectal TME, the loss of protection from the CaCO3 shell exposes the Cu2 O core to be sulfuretted by H2 S to form metabolizable Cu31 S16 nanocrystals that gain remarkably strong near-infrared absorption. After modifying hyaluronic acid, Cu2 O@CaCO3 can achieve synergistic CRC-targeted and TME-triggered photothermal/photodynamic/chemodynamic/calcium-overload-mediated therapy. Moreover, it is found that the generation of hyperthermia and oxidative stress from Cu2 O@CaCO3 nanocomposites can efficiently reprogram the macrophages from the M2 phenotype to the M1 phenotype and initiate a vaccine-like immune effect after primary tumor removal, which further induces an immune-favorable TME and intense immune responses for anti-CD47 antibody to simultaneously inhibit CRC distant metastasis and recurrence by immunotherapy.
Assuntos
Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Carbonato de Cálcio/química , Neoplasias Colorretais/patologia , Cobre/química , Nanocompostos/química , Microambiente Tumoral/efeitos dos fármacos , Animais , Materiais Biocompatíveis/metabolismo , Materiais Biocompatíveis/uso terapêutico , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/imunologia , Terapia Combinada , Humanos , Imunoterapia , CamundongosRESUMO
Although synergistic therapy for tumors has displayed significant promise for effective treatment of cancer, developing a simple and effective strategy to build a multi-functional nanoplatform is still a huge challenge. By virtue of the characteristics of tumor microenvironment, such as hypoxia, slight acidity and H2O2 overexpression, Au2Pt-PEG-Ce6 nanoformulation is constructed for collaborative chemodynamic/phototherapy of tumors. Specifically, the Au2Pt nanozymes with multiple functions are synthesized in one step at room temperature. The photosensitizer chlorin e6 (Ce6) is covalently linked to Au2Pt nanozymes for photodynamic therapy (PDT). Interestingly, the Au2Pt nanozymes possess catalase- and peroxidase-like activities simultaneously, which not only can generate O2 for relaxation of tumor hypoxia and enhancement of PDT efficiency but also can produce âOH for chemodynamic therapy (CDT). In addition, the high photothermal conversion efficiency (η = 31.5%) of Au2Pt-PEG-Ce6 nanoformulation provides the possibility for photoacoustic (PA) and photothermal (PT) imaging guided photothermal therapy (PTT). Moreover, the presence of high-Z elements (Au and Pt) in Au2Pt-PEG-Ce6 nanoformulation endows it with the ability to act as an X-ray computed tomography (CT) imaging contrast agent. All in all, the Au2Pt-PEG-Ce6 exhibits great potential in multimodal imaging-guided synergistic PTT/PDT/CDT with remarkably tumor specificity and enhanced therapy.
Assuntos
Fotoquimioterapia , Porfirinas , Linhagem Celular Tumoral , Clorofilídeos , Peróxido de Hidrogênio , Fármacos Fotossensibilizantes/uso terapêutico , FototerapiaRESUMO
Photoimmunotherapy can not only effectively ablate the primary tumor but also trigger strong antitumor immune responses against metastatic tumors by inducing immunogenic cell death. Herein, Cu2 MoS4 (CMS)/Au heterostructures are constructed by depositing plasmonic Au nanoparticles onto CMS nanosheets, which exhibit enhanced absorption in near-infrared (NIR) region due to the newly formed mid-gap state across the Fermi level based on the hybridization between Au 5d orbitals and S 3p orbitals, thus resulting in more excellent photothermal therapy and photodynamic therapy (PDT) effect than single CMS upon NIR laser irradiation. The CMS and CMS/Au can also serve as catalase to effectively relieve tumor hypoxia, which can enhance the therapeutic effect of O2 -dependent PDT. Notably, the NIR laser-irradiated CMS/Au can elicit strong immune responses via promoting dendritic cells maturation, cytokine secretion, and activating antitumor effector T-cell responses for both primary and metastatic tumors eradication. Moreover, CMS/Au exhibits outstanding photoacoustic and computed tomography imaging performance owing to its excellent photothermal conversion and X-ray attenuation ability. Overall, the work provides an imaging-guided and phototherapy-induced immunotherapy based on constructing CMS/Au heterostructures for effectively tumor ablation and cancer metastasis inhibition.
Assuntos
Cobre , Ouro , Imunoterapia , Nanopartículas Metálicas , Molibdênio , Neoplasias , Fototerapia , Catalase/metabolismo , Cobre/química , Ouro/química , Humanos , Nanopartículas Metálicas/química , Molibdênio/química , Neoplasias/terapiaRESUMO
Nanomaterials with intrinsic peroxidase-like activities are able to catalyze the oxidation of the substrate with the peroxide, which have been widely considered as artificial enzymatic agents in cancer therapy. However, current peroxidase catalytic oxidation treatments generating reactive oxygen species rely highly on hydrogen peroxide and pH, which limit greatly their therapeutic efficiency in the tumor microenvironment. Here, we report a strategy to construct the complex virus-like Fe3O4@Bi2S3 nanocatalysts (F-BS NCs) by connecting typical peroxidase Fe3O4 (MNPs) with a narrow band gap semiconductor Bi2S3 (BS) to enhance the enzymatic activity resorting to the limited intratumoral peroxide and efficient external photothermal stimuli. In this formulation, the integrated F-BS NCs induce cancer-cell death through mild photothermal treatment and sequential photothermal-stimulative catalysis of H2O2 into highly toxic â¢OH under 808 nm laser, which successfully realize a remarkable synergistic anticancer achievement.
Assuntos
Antineoplásicos , Hipertermia Induzida , Nanopartículas de Magnetita/química , Nanomedicina/métodos , Peroxidase , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Sinergismo Farmacológico , Células HeLa , Humanos , Camundongos , Oxirredução , Peroxidase/química , Peroxidase/metabolismo , Peroxidase/farmacologiaRESUMO
To date, the limited light conversion ability and the oxygen-dependent therapeutic process of most photosensitizers make it difficult to achieve satisfactory therapeutic effects in the complex tumor microenvironment, especially the anoxic environment. Herein, the black mesoporous titania (BMT) with large pore size (â¼8 nm) is synthesized as a new-style carrier for radical generator drug (AIBI) loading. The BMT as a light transducer can convert near-infrared (NIR) light energy into thermal energy and chemical energy (â¢OH), contributing to photothermal therapy (PTT) and photodynamic therapy (PDT), respectively. More importantly, AIBI would be thermally decomposed into alkyl radicals (â¢R) for thermodynamic therapy (TDT). The high concentration of free radicals produced by BMT@AIBI NCs resulted in double-strand breaks (DSBs) of DNA and finally induced cancer cell apoptosis. Since the generation of radicals is unrelated to oxygen, the BMT@AIBI NCs with NIR irradiation presented excellent in vitro and in vivo anticancer results under hypoxic conditions. The reported NIR-induced platform based on BMT@AIBI NCs, which could perform triple energy-conversion processes including light energy to thermal energy, to chemical energy, and to thermal energy then to chemical energy, realizes synergetic photo-thermal-dynamic therapy (PTT, PDT, and TDT) to overcome the problem of tumor hypoxia for enhanced anticancer effects.
Assuntos
Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Titânio/química , Animais , Quebras de DNA de Cadeia Dupla , Humanos , Hipertermia Induzida/métodos , Fototerapia/métodosRESUMO
Effective bone tissue reconstitution improves the treatment success rate of dental implantation and preserves natural teeth during periodontal tissue repair. Hydroxyapatite (HAp) has received much attention in bone remodeling field because its mineralized structure is similar to that of the natural bone tissue. For this reason, it has been used as a carrier for growth factors. Although HAp possesses outstanding biomedical properties, its capacity of loading and releasing bone growth factors and promoting osteogenesis is not well understood. In this study, Ln3+ (Ln = Yb3+, Er3+, Gd3+)-doped HAp (HAp:Ln3+) nanorods were synthesized by one-step hydrothermal method. To improve its biocompatibility and surface properties, bone morphogenetic protein-2 (BMP-2) was loaded onto the surface of HAp:Ln3+ nanorods. The results showed that BMP-2 incorporation promoted bone formation and enhanced the expression of early bone-related gene and protein (RunX2, SP7, OPN). In addition, Yb3+- and Er3+-doped HAp nanorods were examined by upconversion luminescence with 980 nm near-infrared laser irradiation to monitor the delivery position of BMP-2 protein. Furthermore, due to the positive magnetism correlated with the concentration of Gd3+, HAp:Ln3+ with enhanced contrast brightening can be deemed as T1 MIR contrast agents. These findings indicate that HAp doped with rare-earth ions and loaded with BMP-2 has the potential to promote bone tissue repair and execute dual-mode imaging.
Assuntos
Proteína Morfogenética Óssea 2/farmacologia , Diferenciação Celular/efeitos dos fármacos , Durapatita/química , Nanotubos/química , Animais , Proteína Morfogenética Óssea 2/química , Bovinos , Linhagem Celular , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Durapatita/efeitos da radiação , Durapatita/toxicidade , Feminino , Expressão Gênica/efeitos dos fármacos , Raios Infravermelhos , Elementos da Série dos Lantanídeos/química , Elementos da Série dos Lantanídeos/efeitos da radiação , Elementos da Série dos Lantanídeos/toxicidade , Camundongos , Microscopia de Fluorescência/métodos , Nanotubos/efeitos da radiação , Nanotubos/toxicidade , Osteogênese/efeitos dos fármacos , Osteopontina/genética , Osteopontina/metabolismo , Soroalbumina Bovina/química , Fator de Transcrição Sp7/genética , Fator de Transcrição Sp7/metabolismoRESUMO
The unique tumor microenvironment (TME) facilitates cancer proliferation and metastasis, and it is hard to cure cancer completely via monotherapy. Herein, a multifunctional cascade bioreactor based on hollow mesoporous Cu2 MoS4 (CMS) loaded with glucose oxidase (GOx) is constructed for synergetic cancer therapy by chemo-dynamic therapy (CDT)/starvation therapy/phototherapy/immunotherapy. The CMS harboring multivalent elements (Cu1+/2+ , Mo4+/6+ ) exhibit Fenton-like, glutathione (GSH) peroxidase-like and catalase-like activity. Once internalized into the tumor, CMS could generate ·OH for CDT via Fenton-like reaction and deplete overexpressed GSH in TME to alleviate antioxidant capability of the tumors. Moreover, under hypoxia TME, the catalase-like CMS could react with endogenous H2 O2 to generate O2 for activating the catalyzed oxidation of glucose by GOx for starvation therapy accompanied with the regeneration of H2 O2 . The regenerated H2 O2 can devote to Fenton-like reaction for realizing GOx-catalysis-enhanced CDT. Meanwhile, the CMS under 1064 nm laser irradiation shows remarkable tumor-killing ability by phototherapy due to its excellent photothermal conversion efficiency (η = 63.3%) and cytotoxic superoxide anion (·O2 - ) generation performance. More importantly, the PEGylated CMS@GOx-based synergistic therapy combined with checkpoint blockade therapy could elicit robust immune responses for both effectively ablating primary tumors and inhibiting cancer metastasis.
Assuntos
Cobre/química , Portadores de Fármacos/química , Imunoterapia/métodos , Molibdênio/química , Fototerapia/métodos , Animais , Linhagem Celular Tumoral , Terapia Combinada , Glucose Oxidase/química , Glucose Oxidase/uso terapêutico , CamundongosRESUMO
Although neodymium vanadate (NdVO4) has been investigated and applied in some fields owing to its intensive ultraviolet (UV) light absorption, weak absorption in visible (Vis) and near infrared (NIR) regions constrains its environmental remediation and biomedical applications. Herein, plasmonic precious metal Au as light trapping agent is deposited onto NdVO4 to form metal/semiconductor hybrid nanostructure for improving the Vis/NIR light absorption. NdVO4/Au heterojunction nanocrystals (NCs) were synthesized by NdVO4 nanorods (NRs) and plasmonic Au nanoparticles (NPs), followed by introducing polyvinylpyrrolidone (PVP) to enhance stability and biocompatibility, which exhibit elevated photocatalytic performance for organic dye degradation, photothermal conversion effect as high as 32.15% and cytotoxic reactive oxygen species (ROS) production ability. NdVO4/Au can be internalized efficiently via endocytosis and cause apparent phototoxicity on HeLa cells. In vivo experiments further show that NdVO4/Au can act as a high-efficiency NIR light-triggered anticancer agent with excellent tumor inhibition effect. In addition, based on outstanding light-to-heat conversion performance and thermal expansion effect under NIR irradiation, NdVO4/Au provides photothermal (PT) and photoacoustic (PA) dual-modal imaging platform for precise cancer diagnosis and treatment. STATEMENTS OF SIGNIFICANCE: It's the first report on integrating precious metal Au and rare earth orthovanadates semiconductor into NdVO4/Au heterojunction NCs. The as-prepared NdVO4/Au heterojunction NCs exhibits improved absorption in Vis/NIR region and increased generation efficiency of photo-induced electron/hole pairs due to the LSPR effect, which results in enhanced photothermal conversion efficiency and the production ability of cytotoxic O2- and OH in comparison with pristine NdVO4. For further clinical application, NdVO4/Au heterojunction NCs could be served as anticancer therapeutic agent for PA/PT dual-modal imaging guided and NIR-triggered photothermal/photodynamic synergistic anticancer treatment.