ABSTRACT
A novel cyclooxygenase-2 (COX-2) targeted H2S-activated cancer-specific fluorescent probe, namely, COX2-H2S, was designed and synthesized, with naphthalimide as the fluorophore and indomethacin as the targeting group. This H2S-sensing probe was developed to differentiate tumor cells from normal cells and was tested in living cells, Caenorhabditis elegans (C. elegans), and zebrafish. The probe could successfully be used for imaging endogenous and exogenous H2S in living cells, demonstrating high sensitivity and specificity and strong anti-interference. COX2-H2S had the ability to not only discern cancer cells from normal cells but also specifically recognize 9L/lacZ cells from other glioblastoma cells (U87-MG and LN229). It could also be successfully applied for the fluorescent live imaging of H2S in both C. elegans and zebrafish.
Subject(s)
Hydrogen Sulfide , Neoplasms , Animals , Humans , Caenorhabditis elegans , Cyclooxygenase 2 , Fluorescent Dyes , Hydrogen Sulfide/analysis , Neoplasms/diagnostic imaging , Optical Imaging/methods , Zebrafish , Cell Line, TumorABSTRACT
Abnormal microenvironments (viscosity, polarity, pH, etc.) have been verified to be closely associated with numerous pathophysiological processes such as inflammation, neurodegenerative diseases, and cancer. As a result, deep insights into these pathophysiological microenvironments are particularly beneficial for clinical diagnosis and treatment. However, the monitoring of pathophysiological microenvironments is unattainable by the traditional clinical diagnostic techniques such as magnetic resonance imaging, computed tomography, and positron emission tomography. Recently, fluorescence imaging has shown tremendous advantages and potential in the tracing of pathophysiological microenvironment variations. In this context, a general discussion is provided on the state-of-the-art progress of fluorescent probes for visualizing pathophysiological microenvironments (viscosity, pH, and polarity), since 2016, as well as the future perspectives in this challenging field.
Subject(s)
Cellular Microenvironment , Fluorescent Dyes/analysis , Optical Imaging , Animals , FluorescenceABSTRACT
Phosphorene, also known as single- or few-layer black phosphorus (FLBP), is a new member of the two-dimensional (2D) material family and has attracted significant attention in recent years for applications in optoelectronics, energy storage and biomedicine due to its unique physicochemical properties and excellent biocompatibility. FLBP is regarded as a potential biological imaging agent for cancer diagnosis due to its intrinsic fluorescence (FL) and photoacoustic (PA) properties and negligible cytotoxicity. FLBP-based photothermal and photodynamic therapies have emerged with excellent anti-tumour therapeutic efficacies due to their unique physical properties, such as near-infrared (NIR) optical absorbance, large extinction coefficients, biodegradability and reactive oxygen species (ROS) or heat generation upon light irradiation. Furthermore, FLBP is a promising drug delivery platform because of its high drug-loading capacity due to its puckered layer structure with an ultralarge surface area, and FLBP is size-controllable with facile surface chemical modification. Because of the marked advantages of FLBP nanomaterials in biomedical applications, an overview of the latest progress and paradigms of FLBP-based nanoplatforms for multidisciplinary biomedical applications is presented in this tutorial review.
Subject(s)
Drug Carriers/chemistry , Nanostructures/chemistry , Neoplasms/diagnostic imaging , Neoplasms/therapy , Phosphorus/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Biocompatible Materials/chemistry , Biocompatible Materials/therapeutic use , Cell Line , Cell Survival , Contrast Media/chemistry , Contrast Media/therapeutic use , Humans , Molecular Targeted Therapy/methods , Nanostructures/therapeutic use , Phosphorus/therapeutic use , Photochemotherapy/methodsABSTRACT
Protons play crucial roles in many physiological and pathological processes, such as receptor-mediated signal transduction, ion transport, endocytosis, homeostasis, cell proliferation, and apoptosis. The urgent demand for pH imaging and measurement in biological systems has incited the development of fluorescent pH probes. Numerous fluorescent probes have been reported, but many lack the abilities needed for biological applications. Hence, the development of new pH probes with better biocompatibility, sensitivity, and site-specificity is still indispensable. This review highlights the recent trends in the development of fluorescent materials as essential tools for tracing pH variations in the biological processes of diverse living systems.
Subject(s)
Fluorescent Dyes/chemistry , Microscopy, Fluorescence/methods , Optical Imaging/methods , Animals , Cell Line , Cellular Microenvironment , Humans , Hydrogen-Ion Concentration , Molecular Structure , Nanoparticles , Signal Transduction , Structure-Activity RelationshipABSTRACT
Activation of apoptosis, the cell death machinery, in tumor cells by organelle-specific delivery of antitumor theranostic agent is the utmost challenge in cancer therapy. Herein, we developed a highly efficient mitochondria-targeting antitumor theranostic prodrug 7 that contained two molecules of drug 5'-deoxy-5-fluorouridine and an apoptotic marker ethidium for self-monitoring intrinsic (mitochondrial) apoptosis after its activation in tumor cells. Theranostic 7 was activated by endogenously produced mitochondrial-overexpressed H2O2 and released drug 5'-deoxy-5-fluorouridine and apoptotic marker ethidium to the tumor cells. The in vitro and in vivo drug release was monitored by observing the fluorescence changes of ethidium. Theranostic 7 exhibited an enhanced cytotoxicity over commercial 5-fluorouracil (an active drug of 5'-deoxy-5-fluorouridine) leading to intrinsic apoptosis monitored by in situ generated ethidium. Enhanced expression of mitochondria-mediated apoptotic genes (NOXA, PUMA, BID, BAX, and BAK), Cyt C, Caspase-3 and -9, and cell surface death receptors was observed after theranostic 7 activation in tumor cells. In vivo and ex vivo xenografts revealed that theranostic 7 significantly inhibited tumor progression and cured the tumor-bearing mice. Such organelle-specific theranostic strategies have great potential for the early diagnosis and precise treatment of cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Lung Neoplasms/pathology , Mitochondria/drug effects , Optical Imaging , Prodrugs/pharmacology , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Floxuridine/chemistry , Floxuridine/pharmacology , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/drug therapy , Mice , Molecular Targeted Therapy , Prodrugs/chemistryABSTRACT
Exposure to even very low levels of lead, cadmium, and mercury ions is known to cause neurological, reproductive, cardiovascular, and developmental disorders, which are more serious problems for children particularly. Accordingly, great efforts have been devoted to the development of fluorescent and colorimetric sensors, which can selectively detect lead, cadmium, and mercury ions. In this critical review, the fluorescent and colorimetric sensors are classified according to their receptors into several categories, including small molecule based sensors, calixarene based chemosensors, BODIPY based chemosensors, polymer based chemosensors, DNA functionalized sensing systems, protein based sensing systems and nanoparticle based sensing systems (197 references).
Subject(s)
Cadmium/analysis , Colorimetry/methods , Lead/analysis , Mercury/analysis , Spectrometry, Fluorescence/methods , Animals , Base Sequence , Biosensing Techniques , Cadmium/chemistry , Humans , Lead/chemistry , Mercury/chemistryABSTRACT
Cholangiocarcinoma (CCA) is an aggressive and lethal malignancy with limited therapeutic options. Despite recent advances in diagnostic imaging for CCA, the early diagnosis of CCA and evaluation of tumor invasion into the bile duct and its surrounding tissues remain challenging. Most patients with CCA are diagnosed at an advanced stage, at which treatment options are limited. Molecular imaging is a promising diagnostic method for noninvasive imaging of biological events at the cellular and molecular level in vivo. Molecular imaging plays a key role in the early diagnosis, staging, and treatment-related evaluation and management of cancer. This review will describe different methods for molecular imaging of CCA, including nuclear medicine, magnetic resonance imaging, optical imaging, and multimodal imaging. The main challenges and future directions in this field are also discussed.
ABSTRACT
External light-independent antitumor PDT is successfully realized with a covalent organic framework (COF)-based host-guest nanosystem. Its highly effective antitumor behavior is fully demonstrated by both H2O2-overexpressed 4T1 and H2O2-less expressed HCT116 and MCF-7 xenograft models.
Subject(s)
Metal-Organic Frameworks , Photochemotherapy , Humans , Hydrogen Peroxide , Metal-Organic Frameworks/pharmacologyABSTRACT
Herin, we report a Cu(ii)-porphyrin-derived nanoscale COF, which can be triggered by endogenous H2S via an intracellular sulfidation reaction to generate a metal-free COF-photosensitizer for PDT against H2S-enriched colon tumors with controllable singlet oxygen release; meanwhile in situ generated CuS can be synchronously used as a photothermal agent for PTT.
Subject(s)
Colonic Neoplasms/therapy , Hydrogen Sulfide/chemistry , Metal-Organic Frameworks/chemistry , Phototherapy/methods , Animals , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Copper/chemistry , HCT116 Cells , Humans , Infrared Rays , Mice , Microscopy, Confocal , Photosensitizing Agents/chemistry , Photosensitizing Agents/therapeutic use , Porphyrins/chemistry , Singlet Oxygen/metabolism , Transplantation, HeterologousABSTRACT
Imaging-guided phototherapy, including photothermal therapy and photodynamic therapy, has been emerging as a promising avenue for precision cancer treatment. However, the utilization of a single laser to induce combination phototherapy and multiple-model imaging remains a great challenge. Herein, we report, the first of its kind, a covalent-organic framework (COF)-based magnetic core-shell nanocomposite, Fe3O4@COF-DhaTph, that is used as a multifunctional nanoagent for cancer theranostics under single 660 nm NIR irradiation. Besides significant photothermal and photodynamic effects, it still permits triple-modal magnetic resonance/photoacoustic/near-infrared thermal (IR) imaging due to its unequaled magnetic and optical performance. We believe that the results obtained herein could obviously promote the application of COF-based multifunctional nanomaterials in cancer theranostics.
Subject(s)
Lasers , Metal-Organic Frameworks/chemistry , Phototherapy/methods , Ferrosoferric Oxide/chemistry , Multimodal Imaging , Nanocomposites/chemistryABSTRACT
The development of multifunctional nanoagents for the simultaneous achievement of high diagnostic and therapeutic performances is significant for precise cancer treatment. Herein, we report on a polydopamine (PDA)-based multifunctional nanoagent, PML, in which the methylene blue (MB) photosensitizer (PS) and l-arginine (l-Arg) tumor-targeting species are equipped. After selectively accumulating in tumor sites, glutathione (GSH)-responsive PML degradation can controllably release loaded MB to produce singlet oxygen (1O2) under near-infrared (NIR) photoirradiation. This GSH-depleted PS release process can not only weaken the body's antioxidant defence ability but also synergistically increase the 1O2 concentration. Therefore, GSH depletion-enhanced photodynamic therapy (PDT) efficiency is logically achieved by regulating the intracellular redox balance. In addition, our nanoagent can guide photoacoustic/NIR thermal dual-modal imaging and convert light into heat for cooperative cancer phototherapy because of the inherent photothermal conversion nature of PDA. As a result, excellent in vivo antitumor phototherapy (PDT + PTT) is achieved under the precise guidance of dual-modal imaging. This work not only realizes the integration of cancer diagnosis and treatment through PDA-based nanocarriers but also delivers dimensions in designing the next generation of multifunctional antitumor nanoagents for enhanced phototherapy and photodiagnosis by regulating the redox balance.
ABSTRACT
A novel two-photon pH probe, 3-benzimidazole-7-hydroxycoumarin (BHC), was designed and synthesized based on the structures of hydroxycoumarin and benzimidazole. BHC showed good linearity in the pH ranges of 3.30-5.40 (pKaâ¯=â¯4.20) and 6.50-8.30 (pKaâ¯=â¯7.20) at a maximum emission wavelength of 480â¯nm. BHC in acidic and alkaline media could be distinguished by an obvious spectral shift of the maximum absorption wavelength from 390â¯nm to 420â¯nm. In addition, BHC was well localized to mitochondria and successfully applied to one-photon and two-photon imaging of pH changes in the mitochondria of HeLa cells. The findings presented herein suggest that BHC can serve as an excellent fluorescent probe for selectively sensing mitochondrial pH changes with remarkable photostability and low cytotoxicity.
Subject(s)
Benzimidazoles/chemistry , Coumarins/chemistry , Fluorescent Dyes/chemistry , Microscopy, Fluorescence, Multiphoton/methods , Mitochondria , Umbelliferones/chemistry , HeLa Cells , Humans , Hydrogen-Ion Concentration , Mitochondria/chemistry , Mitochondria/physiologyABSTRACT
This study aimed to develop a novel and practical fluorescent method for GSH detection in complex biological samples. To this end, a series of coumarin-based fluorescent probes was designed and synthesized using various aliphatic halogens as the sensing group. By using a new evaluation method of GSH/Cys/Hcy coexisting conditions, the probe with chloropropionate (CBF3) showed a high selectivity, excellent sensitivity, good stability for GSH detection. The reaction mechanism is proposed as nucleophilic substitution/cyclization and intramolecular charge transfer (ICT), which was confirmed by LC-MS and NMR analysis, as well as density functional theory calculations. In addition, CBF3 was demonstrated to be competent not only for the quantitative detection of GSH in real serum samples, but also for sensing GSH changes in different oxidative stress models in living cells and nematodes. This study showed a practical strategy for constructing GSH-specific fluorescent probes, and provided a sensitive tool for real-time sensing of GSH in real biological samples. The findings would greatly facilitate further investigations on GSH-associated clinical diagnosis and biomedical studies.
Subject(s)
Fluorescent Dyes/chemistry , Glutathione/blood , Hydrocarbons, Chlorinated/chemistry , Propionates/chemistry , Animals , Caenorhabditis elegans/isolation & purification , Density Functional Theory , Fluorescent Dyes/chemical synthesis , Hep G2 Cells , Humans , Hydrocarbons, Chlorinated/chemical synthesis , Molecular Structure , Optical Imaging , Propionates/chemical synthesis , Tumor Cells, CulturedABSTRACT
We developed a small-molecule-based binary drug delivery system (BDDS) with two anticancer drugs, SN-38 and 5'-DFUR. The drug release from the prodrug BDDS can be achieved upon its reaction with intracellular H2O2, overexpressed in cancer cells. The efficacy of BDDS was demonstrated by a comparative study along with that of a single drug conjugate (SDDS), bearing SN-38 alone.
ABSTRACT
A colorimetric and fluorescent probe ER-ClO was presented in this work to detect cellular hypochlorite with high selectivity and sensitivity. With an organelle targeting unit, ER-ClO was successfully applied in the bio-imaging of exogenous and endogenous hypochlorite in the endoplasmic reticulum in a ratiometric manner.
ABSTRACT
The toxic effects of particulate matter have been linked to polycyclic aromatic hydrocarbons (PAHs) such as benzopyrene. PAHs are potent inducers of the aryl hydrocarbon receptor (AhR), which is an expressed nuclear receptor that senses environmental stimuli and modulates gene expression. Even though several studies have shown that the benzopyrene (BP) of chemical pollutants significantly impaired stem cell activity, the exact molecular mechanisms were not clearly elucidated. In the present study, we aimed to investigate the effects of BP on placenta-derived mesenchymal stem cells (PD-MSCs) in vitro. We found that the AhR in PD-MSCs was expressed under the treatment of BP, and its activation markedly disrupted osteogenic differentiation through the alteration of stemness activity of PD-MSCs. Moreover, BP treatment significantly reduced the proliferation activity of PD-MSCs and expression of pluripotent markers through the induction of AhR. Treatment with StemRegenin 1 (SR1), a purine derivative that antagonizes the AhR, effectively prevented BP-induced reduction of the proliferation and differentiation activity of PD-MSCs. In this study, we found that BP treatment in PD-MSCs markedly obstructs PD-MSC stemness through AhR signaling. Noteworthy, SR1-mediated MSC application will contribute to new perspectives on MSC-based therapies for air pollution-related bone diseases.
ABSTRACT
Anti-angiogenesis, i.e., blocking the angiogenic pathway, has been considered as an important component in current cancer therapeutic modalities. However, the associated benefits have proven to be modest as tumor angiogenesis and regrowth persist, probably due to other ill-defined complex angiogenic mechanisms. Herein, we developed an indomethacin (IMC) incorporating system to mediate hypoxia responsive prodrug (TA) and diagnostic agent (DA) in cancer theranostic applications. Cyclooxygenase 2 (COX-2) elevated expression in several cancer types is closely associated with severe tumor supporting vascularization factors. Our strategy utilizing COX-2 inhibition augmented the anti-angiogenetic induced hypoxia responsive prodrug activation well. Both in vitro and in vivo results proved that DA and TA exhibited specificity towards COX-2 positive (+ve) HeLa and A549 cancer cell lines and activation under hypoxic conditions. Compared with controls (R1, and anticancer drug SN-38), TA displayed prolonged tumor retention and enhanced therapeutic efficacy in xenograft mouse models at a reduced dosage. Our results significantly highlighted the importance of COX-2 blockade mediated anti-angiogenesis in complementing the hypoxia-responsive drug delivery systems (DDSs) and could to beneficial for the rapid development of more efficacious antitumor therapeutics.
Subject(s)
Angiogenesis Inhibitors/administration & dosage , Cyclooxygenase 2 Inhibitors/administration & dosage , Indomethacin/administration & dosage , Neoplasms/drug therapy , Prodrugs/administration & dosage , A549 Cells , Angiogenesis Inhibitors/therapeutic use , Animals , Cell Line, Tumor , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/therapeutic use , Drug Delivery Systems , HeLa Cells , Humans , Indomethacin/therapeutic use , Mice, Inbred BALB C , Mice, Nude , Neoplasms/metabolism , Neoplasms/pathology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Prodrugs/therapeutic use , Theranostic Nanomedicine , Tumor Hypoxia/drug effectsABSTRACT
As significantly expressed during cell division, polo-like kinase 1 (PLK1) plays crucial roles in numerous mitotic events and has attracted interest as a potential therapeutic marker in oncological drug discovery. We prepared two small molecular fluorescent probes, 1 and 2, conjugated to SBE13 (a type II PLK1 inhibitor) to investigate the PLK1-targeted imaging of cancer cells and tumors. Enzymatic docking studies, molecular dynamics simulations, and in vitro and in vivo imaging experiments all supported the selective targeting and visualization of PLK1 expressing cells by probes 1 and 2, and probe 2 was successfully demonstrated to image PLK1-upregulated tumors with remarkable signal-to-background ratios. These findings represent the first example of small-molecule based fluorescent imaging of tumors using PLK1 as a target, which could provide new avenues for tumor diagnosis and precision therapeutics.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Fluorescent Dyes/chemistry , Molecular Imaging/methods , Neoplasms/diagnostic imaging , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Signal-To-Noise Ratio , Humans , Image Processing, Computer-Assisted/methods , Microscopy, Fluorescence , Neoplasms/drug therapy , Neoplasms/pathology , Tumor Cells, Cultured , Polo-Like Kinase 1ABSTRACT
Despite encouraging results from preliminary studies of anticancer therapies, the lack of tumor specificity remains an important issue in the modern pharmaceutical industry. New findings indicate that biotin or biotin-conjugates could be favorably assimilated by tumor cells that over-express biotin-selective transporters. Furthermore, biotin can form stable complexes with avidin and its bacterial counterpart streptavidin. The strong bridging between avidin and biotin moieties on other molecules is a proven adaptable tool with broad biological applications. Under these circumstances, a biotin moiety is certainly an attractive choice for live-cell imaging, biosensing, and target delivery.
Subject(s)
Biosensing Techniques , Biotin/chemistry , Drug Delivery Systems , Animals , Avidin/chemistry , HumansABSTRACT
Abnormal concentrations of Cys have been reported to be implicated in various health problems, including cancer, neuropathy, and cardiomyopathy. We present a novel two-photon fluorescent probe for the specific recognition of cysteine over homocysteine and glutathione, and the bioapplication of this probe for the imaging of live cancerous cells and thick tissues.