RESUMEN
An injectable hydrogel dressing, Zr/Fc-MOF@CuO2@FH, was constructed by combing acid-triggered chemodynamic treatment (CDT) with low-temperature photothermal treatment (LT-PTT) to effectively eliminate bacteria without harming the surrounding normal tissues. The Zr/Fc-MOF acts as both photothermal reagent and nanozyme to generate reactive oxygen species (ROS). The CuO2 nanolayer can be decomposed by the acidic microenvironment of the bacterial infection to release Cu2+ and H2O2, which not only induces Fenton-like reaction but also enhances the catalytic capability of the Zr/Fc-MOF. The generated heat augments ROS production, resulting in highly efficient bacterial elimination at low temperature. Precisely, injectable hydrogel dressing can match irregular wound sites, which shortens the distance of heat dissipation and ROS diffusion to bacteria, thus improving sterilization efficacy and decreasing non-specific systemic toxicity. Both in vitro and in vivo experiments validated the predominant sterilization efficiency of drug-resistant methicillin-resistant Staphylococcus aureus (MRSA) and kanamycin-resistant Escherichia coli (KREC), presenting great potential for application in clinical therapy.
Asunto(s)
Antibacterianos , Cobre , Terapia Fototérmica , Especies Reactivas de Oxígeno , Catálisis , Cobre/química , Cobre/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Especies Reactivas de Oxígeno/metabolismo , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Animales , Ratones , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Circonio/química , Circonio/farmacología , Frío , Pruebas de Sensibilidad Microbiana , Peróxido de Hidrógeno/farmacología , Peróxido de Hidrógeno/química , Tamaño de la Partícula , Propiedades de Superficie , Hidrogeles/química , Hidrogeles/farmacologíaRESUMEN
Low-temperature photothermal therapy (PTT) is a noninvasive method that harnesses the photothermal effect at low temperatures to selectively eliminate tumor cells, while safeguarding normal tissues, minimizing thermal damage, and enhancing treatment safety. First we evaluated the transcriptome of tumor cells at the gene level following low-temperature treatment and observed significant enrichment of genes involved in cell cycle and heat response-related signaling pathways. To address this challenge, we have developed an engineering multifunctional nanoplatform that offered an all-in-one strategy for efficient sensitization of low-temperature PTT. Specifically, we utilized MoS2 nanoparticles as the photothermal core to generate low temperature (40-48 °C). The nanoplatform was coated with DPA to load CPT-11 and Fe2+ and was further modified with PEG and iRGD to enhance tumor specificity (MoS2/Fe@CPT-11-PEG-iRGD). Laser- and acid-triggered release of CPT-11 can significantly increase intracellular H2O2 content, cooperate with Fe2+ ions to increase intracellular lipid ROS content, and activate ferroptosis. Furthermore, CPT-11 induced cell cycle arrest in the temperature-sensitive S-phase, and increased lipid ROS levels contributed to the degradation of HSPs protein expression. This synergistic approach could effectively induce tumor cell death by the sensitized low-temperature PTT and the combination of ferroptosis and chemotherapy. Our nanoplatform can also maximize tumor cell eradication and prolong the survival time of tumor-bearing mice in vivo. The multifunctional approach will provide more possibilities for clinical applications of low-temperature PTT and potential avenues for the development of multiple tumor treatments.
Asunto(s)
Nanopartículas , Neoplasias , Animales , Ratones , Temperatura , Terapia Fototérmica , Irinotecán/uso terapéutico , Molibdeno/uso terapéutico , Especies Reactivas de Oxígeno/uso terapéutico , Peróxido de Hidrógeno , Neoplasias/terapia , Lípidos , Fototerapia/métodos , Línea Celular TumoralRESUMEN
Low-temperature photothermal therapy (PTT) has the advantage of causing less damage to normal tissues and has attracted great attention in recent years. However, the efficacy of low-temperature PTT is restricted by the overexpression of heat shock proteins (HSPs), specifically HSP70 and HSP90. Inhibiting the function of these HSPs is a major strategy used in the development of new cancer therapies. Herein, we designed four T780T-containing thermosensitive nanoparticles to interrupt the energy supply for HSP expression using their TPP-based mitochondrial targeting action. The reversal behavior of the nanoparticles on the gambogic acid (GA)-induced compensatory increase of HSP70 was investigated in vitro by Western blot and in vivo by immunohistochemistry. The in vivo anticancer efficacy of the low-temperature PTT based on these thermosensitive nanoparticles was also systematically examined. The design proposes for the first time to utilize and elucidate the mechanism of the mitochondrial targeting of T780T-containing NPs in synergy with the HSP90 inhibition of GA to achieve an effective low-temperature PTT. This work not only provides a novel pathway for the dual inhibition of HSP70 and HSP90 but also opens up a new approach for low-temperature PTT of tumors.
Asunto(s)
Nanopartículas , Neoplasias , Humanos , Terapia Fototérmica , Temperatura , Frío , Neoplasias/terapia , Mitocondrias , Fototerapia , Línea Celular TumoralRESUMEN
Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, and is ranked the sixth most common neoplasm and the third leading cause of cancer-related deaths. Photothermal therapy (PTT) for thermal ablation of local tumors has recently emerged as a therapeutic strategy. However, the relatively high temperature of over 50 °C may lead to unexpected heat-related damage to tumor-adjacent normal tissues. Herein, we designed and synthesized ataxia telangiectasia mutated (ATM) inhibitor loaded hollow-structured CuS NPs with surface modification with anti-TGF-ß antibody (CuS-ATMi@TGF-ß NPs). CuS-ATMi@TGF-ß NPs are highly photo-stable, can release encapsulated drugs, and increase the temperature to an effective level in a near-infrared (NIR)-responsive manner. Moreover, CuS-ATMi@TGF-ß NPs specifically target tumors and thereby significantly inhibit tumor growth on contribution to synergistic low-temperature PTT and chemotherapy. This system not only achieved low-temperature PTT but also resulted in reduced damage to normal tissues. Modification with anti-TGF-ß antibody enhanced target specificity and immune activation. The combination of PTT and ATM inhibitor showed synergistic effects and significantly attenuated the growth of the HCC via down regulation of heat shock protein (HSP). CuS-ATMi@TGF-ß NPs are a highly promising platform for targeted tumor ablation via hyperthermia-mediated tumor death with minimal damage to normal tissues at a low temperature. STATEMENT OF SIGNIFICANCE: We constructed ataxia telangiectasia mutated (ATM) inhibitor-loaded hollow-structured CuS NPs with surface modification with anti-TGF-ß antibody (CuS-ATMi@TGF-ß NPs). CuS-ATMi@TGF-ß NPs not only achieved low-temperature photothermal therapy (PTT) but also resulted in reduced damage to normal tissues and sufficient biocompatibility. The modification with anti-TGF-ß antibody enhanced targeted specificity, cell endocytosis, and immune activation. In addition, the combination of PTT and ATM inhibitor synergistically attenuated the growth of the HCC via downregulation of heat shock protein (HSP). This study provided proof-of-concept for the ATM inhibitor that mediated low-temperature PTT with a potential for future clinical applications.
Asunto(s)
Ataxia Telangiectasia , Carcinoma Hepatocelular , Hipertermia Inducida , Neoplasias Hepáticas , Nanopartículas , Carcinoma Hepatocelular/tratamiento farmacológico , Cobre/farmacología , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Fototerapia , Terapia Fototérmica , Sulfuros , TemperaturaRESUMEN
Immunotherapy has shown great potential in cancer therapeutics but has limitations of the insufficient activation of dendritic cells (DCs) and immune-suppressive microenvironment. To overcome these obstacles, a cascade synergistic immunotherapy nanosystem (denoted as CpG@PDA-FA) was designed to elevate anticancer immune response. The combination nanosystem including a photothermal agent polydopamine (PDA) and immunomodulator CpG oligodeoxynucleotides (CpG ODNs). On the one hand, polydopamine (PDA) acts as a photothermal agent to induce low-temperature PTT. It leads to immunogenic cell death (ICD), a programmed cell death pathway, which can activate DCs and enhance the antitumor immune response of T cells. On the other hand, CpG ODNs further promote maturation and migration of DCs as well as ameliorates the immunosuppression microenvironment of the tumor (TME). This paper focuses on a cancer synergistic treatment of ICD-induced immunotherapy by low-temperature PTT and ameliorates TME by immunomodulator CpG ODNs. We proved that CpG@PDA-FA NPs realized a remarkable synergistic treatment effect compared with respective single PTT or CpG therapy in the maturation of DCs and activation of T cells. In addition, CpG@PDA-FA NPs also reduced myeloid-derived suppressor cells and regulatory T cells to relieve immunosuppression. Hence, CpG@PDA-FA NPs provide a bidirectional immunotherapy strategy for tumor inhibition and highlight the cascade effects of low-temperature PTT and immunotherapy.
Asunto(s)
Factores Inmunológicos/uso terapéutico , Inmunoterapia/métodos , Neoplasias/inmunología , Tropanos/inmunología , Línea Celular Tumoral , Humanos , Factores Inmunológicos/farmacología , TemperaturaRESUMEN
Rattle-structured nanoparticles with movable cores, porous shells and hollow interiors have shown great effectiveness in drug delivery and cancer theranostics. Targeting autophagy and glucose have provided alternative strategies for cancer intervention therapy. Herein, rattle-structured polydopamine@mesoporous silica nanoparticles were prepared for in vivo photoacoustic (PA) imaging and augmented low-temperature photothermal therapy (PTT) via complementary autophagy inhibition and glucose metabolism. Methods: The multifunctional rattle-structured nanoparticles were designed with the nanocore of PDA and the nanoshell of hollow mesoporous silica (PDA@hm) via a four-step process. PDA@hm was then loaded with autophagy inhibitor chloroquine (CQ) and conjugated with glucose consumer glucose oxidase (GOx) (PDA@hm@CQ@GOx), forming a corona-like structure nanoparticle. Results: The CQ and GOx were loaded into the cavity and decorated onto the surface of PDA@hm, respectively. The GOx-mediated tumor starvation strategy would directly suppress the expression of HSP70 and HSP90, resulting in an enhanced low-temperature PTT induced by PDA nanocore. In addition, autophagy inhibition by the released CQ made up for the loss of low-temperature PTT and starvation efficiencies by PTT- and starvation-activated autophagy, realizing augmented therapy efficacy. Furthermore, the PDA nanocore in the PDA@hm@CQ@GOx could be also used for PA imaging. Conclusion: Such a "drugs" loaded rattle-structured nanoparticle could be used for augmented low-temperature PTT through complementarily regulating glucose metabolism and inhibiting autophagy and in vivo photoacoustic imaging.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Portadores de Fármacos/química , Neoplasias/tratamiento farmacológico , Técnicas Fotoacústicas/métodos , Nanomedicina Teranóstica/métodos , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Cloroquina/administración & dosificación , Cloroquina/farmacocinética , Liberación de Fármacos , Femenino , Glucosa Oxidasa/administración & dosificación , Glucosa Oxidasa/farmacocinética , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Hipotermia Inducida/métodos , Indoles/química , Ratones , Nanopartículas/química , Neoplasias/diagnóstico , Neoplasias/patología , Terapia Fototérmica/métodos , Polímeros/química , Dióxido de Silicio/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The limited penetration depth of photothermal agents (PTAs) active in the NIR-I biowindow and the thermoresistance caused by heat shock protein (HSP) significantly limit the therapeutic efficiency of photothermal therapy (PTT). To address the problem, we introduce a strategy of low-temperature nucleus-targeted PTT in the NIR-II region achieving effective tumor killing by combining the vanadium carbide quantum dots (V2C QDs) PTA and an engineered exosomes (Ex) vector. The small fluorescent V2C QDs with good photothermal effect in the NIR-II region were modified with TAT peptides and packaged into Ex with RGD modification (V2C-TAT@Ex-RGD). The resulting nanoparticles (NPs) exhibited good biocompatibility, long circulation time, and endosomal escape ability, and they could target the cell and enter into the nucleus to realize low-temperature PTT with advanced tumor destruction efficiency. The fluorescent imaging, photoacoustic imaging (PAI), and magnetic resonance imaging (MRI) capability of the NPs were also revealed. The low-temperature nucleus-targeted PTT in the NIR-II region provides more possibilities toward successful clinical application of PTT.