RESUMO
Precise detection and effective treatment are crucial to prolong cancer patients' lives. Surface-enhanced Raman scattering (SERS) imaging coupled with photothermal therapy has been considered a precise and effective strategy for cancer theranostics. Nevertheless, Raman reporters employed in the literature usually possessed multiple shift peaks in the fingerprint region, which are overlapped with background signals from endogenous biological molecules. Herein, we fabricated a new kind of bioorthogonal Raman reporter and aptamer functionalized SERS nanotags. The SERS nanotags demonstrated a strong Raman signal at 2205 cm-1 in the biologically Raman-silent region and recognized MCF-7 breast cancer cells for Raman imaging with high specificity. Laser irradiation induced serious toxicity of MCF-7 cells due to the excellent photothermal capability of the SERS nanotags. After intravenous administration of the SERS nanotags, tumor Raman spectral detection and mapping in living mice were successfully achieved. Further in vivo antitumor experiments manifested that the aptamer-modified SERS nanotags significantly restrained tumor growth after laser irradiation with 99% inhibition rate and good biocompatibility. These results clearly revealed that the SERS nanotags could serve as a novel and precise theranostic platform for in vivo cancer diagnosis and photothermal therapy.
Assuntos
Aptâmeros de Nucleotídeos/uso terapêutico , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/terapia , Ouro/uso terapêutico , Nanotubos , Células 3T3-L1 , Animais , Aptâmeros de Nucleotídeos/análise , Feminino , Ouro/análise , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanotubos/análise , Nanotubos/ultraestrutura , Terapia Fototérmica/métodos , Análise Espectral Raman/métodos , Nanomedicina Teranóstica/métodosRESUMO
The phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) have been regarded as promising targets for the treatment of cancer. Herein, we synthesized a new series of substituted 2-(thiophen-2-yl)-1,3,5-triazine derivatives as novel PI3Kα/mTOR dual inhibitors for cancer therapy. All compounds were evaluated for the IC50 values against three cancer cell lines (A549, MCF-7 and Hela). Most of the target compounds exhibited moderate to excellent anti-tumor activities against these three tested cancer cell lines especially against A549 and Hela cancer cell lines. Among them, the most promising compound 13g showed excellent anti-tumor potency for A549, MCF-7 and Hela cell lines with IC50 values of 0.20 ± 0.05 µM, 1.25 ± 0.11 µM and 1.03 ± 0.24 µM, respectively. Notably, according to the result of enzymatic activity assay, compound 13g was identified as a novel PI3Kα/mTOR dual inhibitor, which had an approximately 10-fold improvement in mTOR inhibition, compared to the class I PI3K inhibitor 1 (pictilisib, GDC-0941), with IC50 values of 525 nM to 48 nM. And western blot analysis indicated compound 13g could efficiently suppress the phosphorylation of AKT at the dose of 0.1 µM, which further demonstrated compound 13g had significant inhibitory effect on the PI3K/Akt/mTOR pathway. Furthermore, compound 13g could stimulate A549 cells arrest at G0/G1 phase in a dose-dependent manner, and induced apoptosis at a low concentration.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Tiofenos/química , Triazinas/química , Triazinas/farmacologia , Células A549 , Células HeLa , Humanos , Triazinas/síntese químicaRESUMO
INTRODUCTION: Immune checkpoint inhibitors (ICIs) have emerged as epochal milestones in the ï¬eld of anti-cancer immunotherapy. With promising clinical effectiveness, ICIs can significantly prolong the overall survival of patients with advanced cancer of different types. Although their remarkable effectiveness has been demonstrated in clinical application, ICIs display limitations in terms of unique response patterns. Only a subset of patients exhibits objective responses, while others show rapid disease progression. Considering that there is a fair representation of both subsets of patients (responders and non-responders), clinicians ought to effectively stratify patients who will potentially benefit from ICI therapy, and optimize a strategy for patient selection. Areas covered: In this review, the authors have summarized several key factors involved in the biomarker development of ICI therapy, such as neoantigen production and presentation, the tumor microenvironment, and alternation in specific gene signaling pathways. Expert opinion: Considering the extreme complexity of the immune system, a single biomarker may fail to appropriately stratify patients for ICI therapy. Therefore, future biomarker research should focus on designing an integrated biomarker system that will successfully guide combination therapies to overcome resistance to immunotherapy.
Assuntos
Antineoplásicos Imunológicos/farmacologia , Biomarcadores Tumorais , Pesquisa , Apresentação de Antígeno/imunologia , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Microbioma Gastrointestinal , Regulação da Expressão Gênica , Humanos , Imunomodulação , Terapia de Alvo Molecular , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Microambiente TumoralRESUMO
Developing new nanomaterials with strong and distinctive Raman vibrations in the biological Raman-silent region (1800-2800 cm-1) were highly desirable for Raman hyperspectral detection and imaging in living cells and animals. Herein, polymeric nanoparticles with monomers containing alkyne, cyanide, azide, and carbon-deuterate were prepared as Raman-active nanomaterials (Raman beads) for bioimaging applications. Intense Raman signals were obtained due to the high density of alkyne, cyanide, azide, and carbon-deuterate in single nanoparticles, in absence of metal (such as Au or Ag) as Raman enhancers. We have developed a library of Raman beads for frequency multiplexing through the end-capping substitutions of monomers and demonstrated five-color SRS imaging of mixed nanoparticles with distinct Raman frequencies. In addition, with further surface functionalization of targeting moieties (such as nucleic acid aptamers and targeting peptides), targetable Raman beads were successfully used as probes for tumor targeting and Raman spectroscopic detection, including multicolor SRS imaging in living tumor cells and tissues with high specificity. Further in vivo studies indicated that Raman beads anchored with targeting moieties were successfully employed to target tumors in living mice after tail intravenous injection, and Raman spectral detection of tumor in live mice was achieved only through spontaneous Raman signal at the biological Raman-silent region without any signal enhancement due to a high density of Raman reporters in Raman beads. With further copolymerization of these monomers, Raman beads with supermultiplex barcoding could be readily achieved.
Assuntos
Microesferas , Imagem Molecular/métodos , Análise Espectral Raman/métodos , Animais , Linhagem Celular Tumoral , Cor , Humanos , CamundongosRESUMO
The increased release and accumulation of Bisphenol A (BPA) in contaminated wastewater has resulted in the world wide concerns because of its potential negative effects on human health and aquatic ecosystems. Starting with metal-organic frameworks, we present a simple method to synthesize magnetic porous microcubes (N-doped Fe0/Fe3C@C) with graphitized shell and highly dispersed active kernel via the pyrolysis process under N2 atmosphere. Batch adsorption experimental results showed that N-doped Fe0/Fe3C@C had high adsorption capacity for BPA (â¼138â¯mgâ¯g-1 at pHâ¯=â¯7 and 298â¯K). Degradation of BPA adsorbed on N-doped Fe0/Fe3C@C was further investigated as a function of BPA concentration, persulfate amount, temperature and solution pH. It was found that potassium peroxodisulfate could be activated by N-doped Fe0/Fe3C@C, and a large number of free radicals were generated which was crucial for the degradation of BPA. The concentration of BPA was barely changed in the individual persulfate system. BPA (10â¯mgâ¯L-1) was almost completely degraded within 60â¯min in the presence of N-doped Fe0/Fe3C@C (â¼0.2â¯gâ¯L-1). When the BPA content increased to 25â¯mgâ¯L-1, the removal efficiency of BPA achieved to 98.4% after 150â¯min. From the XRD, Raman, and XPS analysis, the main adsorption mechanism of BPA was π-π interactions between the π orbital on the carbon basal planes and the electronic density in the BPA aromatic rings. While the superior degradation was attributed to the radical generation and evolution in phenol oxidation. This work not only proved the potential application of N-doped Fe0/Fe3C@C in the adsorption and degradation of BPA, but also opened the new possibilities to eliminate organic pollutants using this kind of magnetic materials in organic pollutants' cleanup.
Assuntos
Adsorção , Compostos Benzidrílicos/análise , Compostos Inorgânicos de Carbono/química , Carbono/química , Recuperação e Remediação Ambiental/métodos , Compostos de Ferro/química , Nanopartículas de Magnetita/química , Oxirredução , Fenóis/análise , Humanos , Ferro/química , Compostos de Potássio/química , Sulfatos/químicaRESUMO
Real-time tracking of GGT enzymatic activity in human ovarian cancer cells is a reliable method for accurate prediction of cancer diagnosis and management. Here, we report the two-photon ratiometric tracking of GGT activity in cancer cells based on a probe with switchable Förster resonance energy transfer properties. In the absence of GGT, the designed probe showed two well-resolved emission bands at 461 and 610 nm, corresponding to the 7-hydroxycoumarin donor and BODIPY acceptor, respectively. In contrast, GGT catalyzed cascade reactions including cleavage of the γ-glutamyl group and subsequent aromatic hydrocarbon transfer from the S to N atom increased the distance between the two chromophores, thus decreasing the FRET efficiency, with the recovery of the donor fluorescence at 461 nm. By exploiting this enzyme-triggered ratiometric measurement, successful differentiation of ovarian cancer cells from normal cells with this probe was realized by two-photon fluorescence confocal microscopy.
RESUMO
A surface-enhanced Raman scattering (SERS) technique shows extraordinary features for a range of biological and biomedical applications. Herein, a series of novel bioorthogonal SERS nanoprobes were constructed with Gold nanoflower (AuNF) and Raman reporters, the signals of which were located in a Raman-silent region of biological samples. AS1411 aptamer was also co-conjugated with AuNF through a self-assembled monolayer coverage strategy. Multiplex SERS imaging using these nanoprobes with three different bioorthogonal small-molecule Raman reporters is successfully achieved with high multiplexing capacity in a biologically Raman-silent region. These Raman nanoprobes co-conjugated with AS1411 showed high affinity for tumor cells with overexpressed nucleolin and can be used for selective tumor cell screening and tissue imaging.