RESUMEN
Pentamethyl cyanine dyes are promising fluorophores for fluorescence sensing and imaging. However, advanced biomedical applications require enhanced control of their excited-state properties. Herein, a synthetic approach for attaching aryl substituents at the C2' position of the thio-pentamethine cyanine (TCy5) dye structure is reported for the first time. C2'-aryl substitution enables the regulation of both the twisted intramolecular charge transfer (TICT) and photoinduced electron transfer (PET) mechanisms to be regulated in the excited state. Modulation of these mechanisms allows the design of a nitroreductase-activatable TCy5 fluorophore for hypoxic tumor photodynamic therapy and fluorescence imaging. These C2'-aryl TCy5 dyes provide a tunable platform for engineering cyanine dyes tailored to sophisticated biological applications, such as photodynamic therapy.
Asunto(s)
Neoplasias , Fotoquimioterapia , Humanos , Fármacos Fotosensibilizantes , Colorantes Fluorescentes/química , Imagen Óptica/métodosRESUMEN
Prodrug is a potential regime to overcome serious adverse events and off-target effects of chemotherapy agents. Among various prodrug activators, hypoxia stands out owing to the generalizability and prominence in tumor micro-environment. However, existing hypoxia activating prodrugs generally face the limitations of stringent structural requirements, the lack of feedback and the singularity of therapeutic modality, which is imputed to the traditional paradigm that recognition groups must be located at the terminus of prodrugs. Herein, a multifunctional nano-prodrug Mal@Cy-NTR-CB has been designed. In this nano-prodrug, a self-destructive tether is introduced to break the mindset, and achieves the activation by hypoxia of chemotherapy based on Chlorambucil (CB), whose efficacy can be augmented and traced by photodynamic therapy (PDT) and fluorescence from Cyanine dyes (Cy). In addition, Maleimide (Mal) carried by the nano-shells can regulate glutathione (GSH) content, preventing 1O2 scavenging, so as to realize PDT sensitization. Experiments demonstrate that Mal@Cy-NTR-CB specifically responds to hypoxic tumors, and achieve synchronous activation, enhancement and feedback of chemotherapy and PDT, inhibiting the tumor growth effectively. This study broadens the design ideas of activatable prodrugs and provides the possibility of multifunctional nano-prodrugs to improve the generalization and prognosis in precision oncology.
Asunto(s)
Nanopartículas , Neoplasias , Fotoquimioterapia , Profármacos , Humanos , Neoplasias/tratamiento farmacológico , Profármacos/química , Medicina de Precisión , Hipoxia/tratamiento farmacológico , Línea Celular Tumoral , Fármacos Fotosensibilizantes/uso terapéutico , Nanopartículas/química , Microambiente TumoralRESUMEN
The regulation of electrostatic electric fields through electrical stimulation is an efficient method to increase the catalytic activity of nanozymes and improve the therapeutic effect of nanozyme catalytic therapy. Piezoelectric materials, which are capable of generating a built-in electric field under ultrasound (US), not only improve the activity of nanozymes but also enable piezoelectric sonodynamic therapy (SDT). In this study, a sonosensitizer based on a Hf-based metal-organic framework (UIO-66) and Au nanoparticles (NPs) was produced. Under US irradiation, UIO-66 can generate a built-in electric field inside the materials, which promotes electron-hole separation and produces reactive oxygen species (ROS). The introduction of Au NPs facilitated the electron transfer, which inhibited the recombination of the electron-hole pairs and improved the piezoelectric properties of UIO-66. The value of the piezoelectric constant (d33) increased from 71 to 122 pmV-1 after the deposition of Au NPs. In addition, the intrinsic catalase and peroxidase activities of the Au NPs were increased 2-fold after the stimulation from the built-in electric field induced through US exposure. In vivo and in vitro experiments revealed that the proposed sonosensitizer can kill cancer cells and inhibit tumor growth in mice through the enhanced piezoelectric SDT and nanozyme catalytic therapy. The piezoelectric sensitizer proposed in this work proved to be an efficient candidate that can be used for multiple therapeutic modalities in tumor therapy.
Asunto(s)
Nanopartículas del Metal , Estructuras Metalorgánicas , Neoplasias , Compuestos Organometálicos , Terapia por Ultrasonido , Animales , Ratones , Estructuras Metalorgánicas/uso terapéutico , Oro/uso terapéutico , Línea Celular Tumoral , Neoplasias/tratamiento farmacológico , Terapia por Ultrasonido/métodos , Compuestos Organometálicos/uso terapéutico , Especies Reactivas de Oxígeno/uso terapéuticoRESUMEN
Hypoxia is one of the prominent features of solid tumors. Hypoxia activated prodrugs (HAPs), selectively killing hypoxic cells, possess the potential to transform hypoxia from a nuisance to an advantage in precision therapy. Exhibiting a more significant hypoxic microenvironment, gliomas, as the most frequent and incurable neurological tumors, provide HAPs a more attractive therapeutic prospect. However, the insufficient hypoxia and the obstruction of the blood-brain barrier (BBB) severely limit the activation and bio-availability of HAPs. Herein, a novel nanoparticle iRGD@ZnPc + TPZ was designed and synthesized to achieve gliomas inhibition by encapsulating tirapazamine (TPZ) as a HAP and zinc phthalocyanine (ZnPc) as a photosensitizer to enhance hypoxia. iRGD@ZnPc + TPZ can realize breakthrough BBB, deep penetration, and significant retention in gliomas, which is attributed to the iRGD-mediated receptor targeting and active transport. After being internalized by tumor cells and radiated, ZnPc efficiently consumes intratumoral O2 to produce reactive oxygen species, which not only implements tumor suppression, but also intensify hypoxia to activate TPZ for amplifying chemotherapy. The photosensitizer-enhanced activation of HAPs inhibits gliomas growth. This study provides a new strategy with sensitizing and activating HAPs for gliomas treatment in clinical.
Asunto(s)
Antineoplásicos , Glioma , Neoplasias , Profármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Glioma/tratamiento farmacológico , Humanos , Hipoxia/tratamiento farmacológico , Indoles/uso terapéutico , Isoindoles , Neoplasias/tratamiento farmacológico , Compuestos Organometálicos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Profármacos/farmacología , Profármacos/uso terapéutico , Especies Reactivas de Oxígeno , Tirapazamina/uso terapéutico , Microambiente Tumoral , Compuestos de ZincRESUMEN
Isosteviol sodium (STVNa), which is a derivate of the natural sweettasting glycoside stevioside, has recently been developed and it has been determined that this compound exhibits neuro and cardioprotective properties. In the current study, whether STVNa interferes with the development of cardiac hypertrophy, which is induced by isoprenaline (Iso), was investigated in an experimental rat model. Rats were treated with a vehicle (0.9% NaCl; control), isoprenaline (Iso; 5 mg/kg) or Iso (5 mg/kg) with STVNa (4 mg/kg; Iso + STVNa). Cardiomyocytes were isolated using enzymatic dissociation and were treated with 5 µM Iso for 24 h and cotreated with 5 µM STVNa. Brain natriuretic peptide (BNP) mRNA expression was determined using PCR analysis. Cell surface area, intracellular reactive oxygen species (ROS), mitochondrial transmembrane potential (ΔΨm), cytoplasmic Ca2+ and Ca2+ and contractile function were examined using a laser scanning confocal microscope. The current study demonstrated that STVNa inhibited Isoinduced cardiac hypertrophy by inhibiting cardiomyocyte size. STVNa significantly reduced cell surface area and decreased BNP mRNA expression in ventricular cardiomyocyte Isoinduced hypertrophy. STVNa was also revealed to restore ΔΨm and reduce ROS generation and intracellular Ca2+ concentration when compared with the Isotreated group. Additionally, STVNa preserved Ca2+ transients in hypertrophic cardiomyocytes. In conclusion, the present study demonstrated that STVNa protects against Isoinduced myocardial hypertrophy by reducing oxidative stress, restoring ΔΨm and maintaining Ca2+ homeostasis.