共查询到20条相似文献,搜索用时 0 毫秒
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Federica Sodano Prof. Barbara Rolando Prof. Francesca Spyrakis Mariacristina Failla Prof. Loretta Lazzarato Dr. Elena Gazzano Prof. Chiara Riganti Prof. Roberta Fruttero Prof. Alberto Gasco Prof. Salvatore Sortino 《ChemMedChem》2018,13(12):1238-1245
A few compounds in which the nitric oxide (NO) photodonor N‐[4‐nitro‐3‐(trifluoromethyl)phenyl]propane‐1,3‐diamine is joined to the mitochondria‐targeting alkyltriphenylphosphonium moiety via flexible spacers of variable length were synthesized. The lipophilicity of the products was evaluated by measuring their partition coefficients in n‐octanol/water. The obtained values, markedly lower than those calculated, are consistent with the likely collapsed conformation assumed by the compounds in solution, as suggested by molecular dynamics simulations. The capacity of the compounds to release NO under visible light irradiation was evaluated by measuring nitrite production by means of the Griess reaction. The accumulation of compounds in the mitochondria of human lung adenocarcinoma A549 cells was assessed by UPLC–MS. Interestingly, compound 13 [(9‐((3‐((4‐nitro‐3‐(trifluoromethyl)phenyl)amino)propyl)amino)‐9‐oxononyl) triphenylphosphonium bromide] displayed both the highest accumulation value and high toxicity toward A549 cells upon irradiation‐mediated NO release in mitochondria. 相似文献
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Dr. Fargol Taba Dr. Akira Onoda Dr. Urara Hasegawa Toshiaki Enoki Prof. Dr. Yousuke Ooyama Prof. Dr. Joji Ohshita Prof. Dr. Takashi Hayashi 《ChemMedChem》2018,13(1):15-19
Two polyamine derivatives of protoporphyrin IX (PPIX) were tested as photodynamic therapy (PDT) agents in HT29 colorectal cancer and HEP3B liver cancer cell lines. These compounds exhibit excellent singlet oxygen quantum yields and show strong in vitro PDT efficacy after 660 nm laser irradiation, whereas exogenous PPIX itself exhibits much weaker PDT effects. Confocal microscopy imaging studies reveal that a protoporphyrin derivative with eight amine moieties has excellent water solubility, and localizes mainly in the mitochondria of both HT29 and HEP3B cells, whereas the cellular distribution of a protoporphyrin derivative with four amine moieties is not as specific. This work demonstrates that polyamine moieties on macrocycles can enhance PDT efficacy by targeting mitochondria. 相似文献
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Christos Damaskos Nikolaos Garmpis Dimitrios Dimitroulis Anna Garmpi Iason Psilopatis Panagiotis Sarantis Evangelos Koustas Prodromos Kanavidis Dionysios Prevezanos Gregory Kouraklis Michail V. Karamouzis Georgios Marinos Konstantinos Kontzoglou Efstathios A. Antoniou 《International journal of molecular sciences》2022,23(22)
Hepatocellular carcinoma (HCC) remains one of the most common malignancies and the third cause of cancer-related death worldwide, with surgery being the best prognostic tool. Among the well-known causative factors of HCC are chronic liver virus infections, chronic virus hepatitis B (HBV) and chronic hepatitis virus C (HCV), aflatoxins, tobacco consumption, and non-alcoholic liver disease (NAFLD). There is a need for the development of efficient molecular markers and alternative therapeutic targets of great significance. In this review, we describe the general characteristics of HCC and present a variety of targeted therapies that resulted in progress in HCC therapy. 相似文献
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John C. Leach Andrew Wang Kaiming Ye Sha Jin 《International journal of molecular sciences》2016,17(3)
The side effects of radio- and chemo-therapy pose long-term challenges on a cancer patient’s health. It is, therefore, highly desirable to develop more effective therapies that can specifically target carcinoma cells without damaging normal and healthy cells. Tremendous efforts have been made in the past to develop targeted drug delivery systems for solid cancer treatment. In this study, a new aptamer, A10-3-J1, which recognizes the extracellular domain of the prostate specific membrane antigen (PSMA), was designed. A super paramagnetic iron oxide nanoparticle-aptamer-doxorubicin (SPIO-Apt-Dox) was fabricated and employed as a targeted drug delivery platform for cancer therapy. This DNA RNA hybridized aptamer antitumor agent was able to enhance the cytotoxicity of targeted cells while minimizing collateral damage to non-targeted cells. This SPIO-Apt-Dox nanoparticle has specificity to PSMA+ prostate cancer cells. Aptamer inhibited nonspecific uptake of membrane-permeable doxorubic to the non-target cells, leading to reduced untargeted cytotoxicity and endocytic uptake while enhancing targeted cytotoxicity and endocytic uptake. The experimental results indicate that the drug delivery platform can yield statistically significant effectiveness being more cytotoxic to the targeted cells as opposed to the non-targeted cells. 相似文献
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Sabrina Orzetti Federica Tommasi Antonella Bertola Giorgia Bortolin Elisabetta Caccin Sara Cecco Emanuela Ferrarin Elisa Giacomin Paolo Baldo 《International journal of molecular sciences》2022,23(6)
The impressive advances in the knowledge of biomarkers and molecular targets has enabled significant progress in drug therapy for crucial diseases such as cancer. Specific areas of pharmacology have contributed to these therapeutic outcomes—mainly targeted therapy, immunomodulatory therapy, and gene therapy. This review focuses on the pharmacological profiles of these therapeutic classes and intends, on the one hand, to provide a systematic definition and, on the other, to highlight some aspects related to pharmacovigilance, namely the monitoring of safety and the identification of potential toxicities and adverse drug reactions. Although clinicians often consider pharmacovigilance a non-priority area, it highlights the risk/benefit ratio, an essential factor, especially for these advanced therapies, which represent the most innovative and promising horizon in oncology. 相似文献
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BODIPY‐Appended 2‐(2‐Pyridyl)benzimidazole Platinum(II) Catecholates for Mitochondria‐Targeted Photocytotoxicity
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Dr. Koushambi Mitra Srishti Gautam Prof. Paturu Kondaiah Prof. Akhil R. Chakravarty 《ChemMedChem》2016,11(17):1956-1967
Platinum(II) complexes of the type [Pt(L)(cat)] ( 1 and 2 ), in which H2cat is catechol and L represents two 2‐(2‐pyridyl)benzimidazole ligands with 4,4‐difluoro‐4‐bora‐3a,4a‐diaza‐s‐indacene (BODIPY) pendants, were synthesized to achieve mitochondria‐targeted photocytotoxicity. The complexes showed strong absorptions in the range λ=510–540 nm. Complex 1 exhibited intense emission at λ=525 nm in 1 % DMSO/water solution (fluorescence quantum yield of 0.06). Nanosecond transient absorption spectral features indicated an enhanced population of the triplet excited state in di‐iodinated complex 2 . The generation of singlet oxygen by complex 2 upon exposure to visible light, as evidenced from experiments with 1,3‐diphenylisobenzofuran, is suitable for photodynamic therapy because of the remarkable photosensitizing ability. The complexes resulted in excellent photocytotoxicity in HaCaT cells (half maximal inhibitory concentration IC50≈3 μm , λ=400–700 nm, light dose=10 J cm?2), but they remained non‐toxic in the dark (IC50>100 μm ). Confocal microscopy images of 1 and Pt estimation from isolated mitochondria showed colocalization of the complexes in the mitochondria. Complex 2 displayed generation of reactive oxygen species induced by visible light, disruption of the mitochondrial membrane potential, and apoptosis. 相似文献
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Lei Dang Jin Liu Fangfei Li Luyao Wang Defang Li Baosheng Guo Xiaojuan He Feng Jiang Chao Liang Biao Liu Shaikh Atik Badshah Bing He Jun Lu Cheng Lu Aiping Lu Ge Zhang 《International journal of molecular sciences》2016,17(3)
Abnormalities in the integral components of bone, including bone matrix, bone mineral and bone cells, give rise to complex disturbances of skeletal development, growth and homeostasis. Non-specific drug delivery using high-dose systemic administration may decrease therapeutic efficacy of drugs and increase the risk of toxic effects in non-skeletal tissues, which remain clinical challenges in the treatment of skeletal disorders. Thus, targeted delivery systems are urgently needed to achieve higher drug delivery efficiency, improve therapeutic efficacy in the targeted cells/tissues, and minimize toxicities in non-targeted cells/tissues. In this review, we summarize recent progress in the application of different targeting moieties and nanoparticles for targeted drug delivery in skeletal disorders, and also discuss the advantages, challenges and perspectives in their clinical translation. 相似文献
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Yaying Ji Todd J. Toops Uschi M. Graham Gary Jacobs Mark Crocker 《Catalysis Letters》2006,110(1-2):29-37
NO oxidation was studied over Pt/CeO2 and Pt/SiO2 catalysts. Apparent activation energies (E
a) of 31.4 and 40.6 kJ/mole were determined for Pt/CeO2 and Pt/SiO2, respectively, while reaction orders for NO and O2 were fractional and positive for both catalysts. Pre-treatment of the catalysts with SO2 caused a decrease in the E
a values, while the reaction orders were only slightly changed. In situ DRIFTS measurements indicated that high concentrations of nitrate species were formed on the surface of Pt/CeO2 during NO oxidation, while almost no surface species could be detected on Pt/SiO2. The addition of SO2 resulted in the formation of a highly stable sulfate at the expense of nitrate species and caused an irreversible loss of
catalytic activity for Pt/CeO2. 相似文献
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Vestibular schwannoma (VS) is a benign tumor that originates from Schwann cells in the vestibular component. Surgical treatment for VS has gradually declined over the past few decades, especially for small tumors. Gamma knife radiosurgery has become an accepted treatment for VS, with a high rate of tumor control. For neurofibromatosis type 2 (NF2)-associated VS resistant to radiotherapy, vascular endothelial growth factor (VEGF)-A/VEGF receptor (VEGFR)-targeted therapy (e.g., bevacizumab) may become the first-line therapy. Recently, a clinical trial using a VEGFR1/2 peptide vaccine was also conducted in patients with progressive NF2-associated schwannomas, which was the first immunotherapeutic approach for NF2 patients. Targeted therapies for the gene product of SH3PXD2A-HTRA1 fusion may be effective for sporadic VS. Several protein kinase inhibitors could be supportive to prevent tumor progression because merlin inhibits signaling by tyrosine receptor kinases and the activation of downstream pathways, including the Ras/Raf/MEK/ERK and PI3K/Akt/mTORC1 pathways. Tumor-microenvironment-targeted therapy may be supportive for the mainstays of management. The tumor-associated macrophage is the major component of immunosuppressive cells in schwannomas. Here, we present a critical overview of targeted therapies for VS. Multimodal therapy is required to manage patients with refractory VS. 相似文献
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NO对环境的影响日益严重,如果不有效将其消除掉,将会对环境及人的健康产生极大的危害。因此,目前各国都在研究廉价消除NO污染的方法。采用共沉淀法制备了催化剂CuO/Ce1-xZrxO2,利用XRD对其晶相进行表征,H2-TPR研究了其氧化还原能力,以NO的转化效率作为评价指标。结果表明:适当比例zr的加入以及适当比例的CuO能提高活性。 相似文献
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Alice Indini Fausto Roila Francesco Grossi Daniela Massi Mario Mandal 《International journal of molecular sciences》2022,23(1)
Mucosal melanoma is a rare and aggressive subtype of melanoma. Unlike its cutaneous counterpart, mucosal melanoma has only gained limited benefit from novel treatment approaches due to the lack of actionable driver mutations and poor response to immunotherapy. Over the last years, whole-genome and exome sequencing techniques have led to increased knowledge on the molecular landscape of mucosal melanoma. Molecular studies have underlined noteworthy findings with potential therapeutic implications, including the presence of KIT mutations, which are potential targets of tyrosine kinase inhibitors currently in use in the clinic (imatinib), but also SF3B1 mutation, CDK4 amplifications, and CDKN2A gene deletions, which are presently under investigation in clinical trials. Recent results from a pooled analysis of patients with mucosal melanoma treated with immunotherapy have suggested that the combination of immune checkpoint inhibitors might improve survival outcomes in this subset of patients, as compared with single-agent immunotherapy. However, these results are not confirmed across different studies, and combo-immunotherapy correlates with a higher rate of adverse events. In this review, we describe the clinical, biological, and genetic features of mucosal melanoma. We also provide an update on the results of approved systemic treatment in this setting and overview the therapeutic strategies currently under investigation in clinical trials. 相似文献
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Hans‐Jörg Breyholz Dr. Stefan Wagner Dr. Andreas Faust Dr. Burkhard Riemann Prof. Dr. Carsten Höltke Dr. Sven Hermann Dr. Otmar Schober Prof. Dr. Michael Schäfers Prof. Dr. Klaus Kopka Priv.‐Doz. Dr. 《ChemMedChem》2010,5(5):777-789
Matrix metalloproteinases (MMPs) are zinc‐ and calcium‐dependent endopeptidases. Representing a subfamily of the metzincin superfamily, MMPs are involved in the proteolytic degradation of components of the extracellular matrix. Unregulated MMP expression, MMP dysregulation and locally increased MMP activity are common features of various diseases, such as cancer, atherosclerosis, stroke, arthritis, and others. Therefore, activated MMPs are suitable biological targets for the specific visualization of such pathologies, in particular by using radiolabeled MMP inhibitors (MMPIs). The aim of this work was to develop a radiofluorinated molecular probe for noninvasive in vivo imaging for the detection of up‐regulated levels of activated MMPs in the living organism. Fluorinated MMPIs ( 26 , 31 and 38 ) based on the pyrimidine‐2,4,6‐trione lead structure RO 28‐2653 ( 1 ) were synthesized, and their MMP inhibition potency was evaluated in vitro. The radiosynthesis and the in vivo biodistribution of the first 18F‐labeled prototype, MMP‐targeted tracer [18F] 26 , suitable for molecular imaging by means of positron emission tomography (PET) were realized. 相似文献
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Ayelet David 《Israel journal of chemistry》2010,50(2):204-219
A variety of strategies and carrier molecules have been used to direct therapeutic agents to tumor sites. The incorporation of a specific targeting moiety to drug carrier may result in active drug uptake by malignant cells. Carbohydrates are important mediators of cell–cell recognition events and have been implicated in related processes such as cell signaling regulation, cellular differentiation, and immune response. The biocompatibility of carbohydrates and their ability to be specifically recognized by cell-surface receptors indicate their potential utility as ligands in targeted drug delivery for therapeutic applications. Yet, carbohydrates are not ideal targeting ligands because they are difficult to synthesize, bind weakly to carbohydrate receptors, and are prone to suffer from enzyme degradation due to labile glycosidic linkages. This review describes the design and development of HPMA-based biomedical copolymers to facilitate the selective delivery of drugs to tumor tissues via carbohydrate–endogenous lectin interactions. Various carbohydrate-decorated HPMA copolymer–drug conjugates are presented and the application of the copolymers for drug delivery is discussed. Current efforts to increase the affinity of carbohydrate ligands for their target receptors through multivalent display are also discussed. These novel HPMA copolymer carbohydrate conjugates hold promise as clinically relevant drug delivery systems for cancer therapy. 相似文献
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Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common cancers worldwide. More than half of patients with HNSCC eventually experience disease recurrence and/or metastasis, which can threaten their long-term survival. HNSCCs located in the oral cavity and larynx are usually associated with tobacco and/or alcohol use, whereas human papillomavirus (HPV) infection, particularly HPV16 infection, is increasingly recognized as a cause of oropharyngeal HNSCC. Despite clinical, histologic, and molecular differences between HPV-positive and HPV-negative HNSCCs, current treatment approaches are the same. For recurrent disease, these strategies include chemotherapy, immunotherapy with PD-1-inhibitors, or a monoclonal antibody, cetuximab, that targets epidermal growth factor; these therapies can be administered either as single agents or in combination. However, these treatment strategies carry a high risk of toxic side effects; therefore, more effective and less toxic treatments are needed. The landscape of HNSCC therapy is changing significantly; numerous clinical trials are underway to test novel therapeutic options like adaptive cellular therapy, antibody-drug conjugates, new targeted therapy agents, novel immunotherapy combinations, and therapeutic vaccines. This review helps in understanding the various developments in HNSCC therapy and sheds light on the path ahead in terms of further research in this field. 相似文献
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Govindan Ravikumar Meisam Bagheri Dr. Deepak Kumar Saini Dr. Harinath Chakrapani 《Chembiochem : a European journal of chemical biology》2017,18(15):1529-1534
Nitric oxide (NO) plays significant signalling roles in cells; the controlled generation of NO is of therapeutic relevance. Although a number of methods for the delivery and detection of NO are available, these events are typically mutually exclusive. Furthermore, the efficiency of delivery of NO can be compromised by detection technologies that consume NO. Here, we report FLUORO/NO, an esterase‐activated diazeniumdiolate‐based NO donor with an in‐built fluorescence reporter. We demonstrate that this compound is capable of enhancing NO within cells in a dose‐dependent manner, accompanied by a similar increase in fluorescence. The compatibility of this tool to study NO‐mediated signalling as well as NO‐mediated stress is demonstrated. FLUORO/NO is a convenient tool that shows NO‐like activity and allows monitoring of NO release. This tool will help interrogate the redox biology of NO. 相似文献
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Throughout recent years, there has been a rapidly increasing interest regarding the evaluation of so-called targeted therapies. These therapies are assumed to show a greater benefit in a pre-specified subgroup of patients—commonly identified by a predictive biomarker—as compared to the total patient population of interest. This situation has led to the necessity to develop biostatistical methods allowing an efficient evaluation of such treatments. Among others, adaptive enrichment designs have been proposed as a solution. These designs allow the selection of the most promising patient population based on an efficacy analysis at interim and restricting recruitment to these patients afterwards. As has recently been shown, the performance of the applied interim decision rule in such a design plays a crucial role in ensuring a successful trial. In this work, we investigate the situation when the primary outcome of the trial is a binary variable. Optimal decision rules are derived which incorporate the uncertainty about the treatment effects. These optimal decision rules are evaluated with respect to their performance in an adaptive enrichment design in terms of correct selection probability and power, and are compared to proposed ad hoc decision rules. Our methods are illustrated by means of a clinical trial example. 相似文献
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In the United States, breast cancer is among the most frequently diagnosed cancers in women. Breast cancer is classified into four major subtypes: human epidermal growth factor receptor 2 (HER2), Luminal-A, Luminal-B, and Basal-like or triple-negative, based on histopathological criteria including the expression of hormone receptors (estrogen receptor and/or progesterone receptor) and/or HER2. Primary breast cancer treatments can include surgery, radiation therapy, systemic chemotherapy, endocrine therapy, and/or targeted therapy. Endocrine therapy has been shown to be effective in hormone receptor-positive breast cancers and is a common choice for adjuvant therapy. However, due to the aggressive nature of triple-negative breast cancer, targeted therapy is becoming a noteworthy area of research in the search for non-endocrine-targets in breast cancer. In addition to HER2-targeted therapy, other emerging therapies include immunotherapy and targeted therapy against critical checkpoints and/or pathways in cell growth. This review summarizes novel targeted breast cancer treatments and explores the possible implications of combination therapy. 相似文献