共查询到20条相似文献,搜索用时 21 毫秒
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《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2018,130(29):9171-9175
The majority of theranostic prodrugs reported so far relay information through a fluorogenic response generated upon release of the active chemotherapeutic agent. A chemiluminescence detection mode offers significant advantages over fluorescence, mainly due to the superior signal‐to‐noise ratio of chemiluminescence. Here we report the design and synthesis of the first theranostic prodrug monitored by a chemiluminescence diagnostic mode. As a representative model, we prepared a prodrug from the chemotherapeutic monomethyl auristatin E, which was modified for activation by β‐galactosidase. The activation of the prodrug in the presence of β‐galactosidase is accompanied by emission of a green photon. Light emission intensities, which increase with increasing concentration of the prodrug, were linearly correlated with a decrease in the viability of a human cell line that stably expresses β‐galactosidase. We obtained sharp intravital chemiluminescent images of endogenous enzymatic activity in β‐galactosidase‐overexpressing tumor‐bearing mice. The exceptional sensitivity achieved with the chemiluminescence diagnostic mode should allow the exploitation of theranostic prodrugs for personalized cancer treatment. 相似文献
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Raoul Walther Anna K. Winther Anne Sofie Fruergaard Wouter vandenAkker Lise Srensen Signe Maria Nielsen Morten T. JarlstadOlesen Yitao Dai Henrik S. Jeppesen Paolo Lamagni Aleksandr Savateev Sren Lykke Pedersen Camilla Kaas Frich Ccile Vigier‐Carrire Nina Lock Mandeep Singh Vipul Bansal Rikke L. Meyer Alexander N. Zelikin 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(1):284-288
Nanozymes, nanoparticles that mimic the natural activity of enzymes, are intriguing academically and are important in the context of the Origin of Life. However, current nanozymes offer mimicry of a narrow range of mammalian enzymes, near‐exclusively performing redox reactions. We present an unexpected discovery of non‐proteinaceous enzymes based on metals, metal oxides, 1D/2D‐materials, and non‐metallic nanomaterials. The specific novelty of these findings lies in the identification of nanozymes with apparent mimicry of diverse mammalian enzymes, including unique pan‐glycosidases. Further novelty lies in the identification of the substrate scope for the lead candidates, specifically in the context of bioconversion of glucuronides, that is, human metabolites and privileged prodrugs in the field of enzyme‐prodrug therapies. Lastly, nanozymes are employed for conversion of glucuronide prodrugs into marketed anti‐inflammatory and antibacterial agents, as well as “nanozyme prodrug therapy” to mediate antibacterial measures. 相似文献
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《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(46):14592-14596
A strategy to expand anti‐Stokes shifting from the far‐red to deep‐blue region in metal‐free triplet–triplet annihilation upconversion (TTA‐UC) is presented. The method is demonstrated by in vivo titration of the photorelease of an anticancer prodrug. This new TTA system has robust brightness and the longest anti‐Stokes shift of any reported TTA system. TTA core–shell‐structured prodrug delivery capsules that benefit from these properties were developed; they can operate with low‐power density far‐red light‐emitting diode light. These capsules contain mesoporous silica nanoparticles preloaded with TTA molecules as the core, and amphiphilic polymers encapsulating anticancer prodrug molecules as the shell. When stimulated by far‐red light, the intense TTA upconversion blue emission in the system activates the anticancer prodrug molecules and shows effective tumor growth inhibition in vivo. This work paves the way to new organic TTA upconversion techniques that are applicable to in vivo photocontrollable drug release and other biophotonic applications. 相似文献
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Hongzhong Chen Xiaowei Zeng Huijun Phoebe Tham Soo Zeng Fiona Phua Wei Cheng Wenfeng Zeng Haoran Shi Lin Mei Yanli Zhao 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(23):7723-7728
The co‐delivery of photosensitizers with prodrugs sensitive to reactive oxygen species (ROS) for light‐triggered ROS generation and cascaded prodrug activation has drawn tremendous attention. However, the absence of a feasible method to deliver the two components at a precise ratio has impaired the application potential. Herein, we report an efficient method to produce a nanosized platform for the delivery of an optimized ratio of the two components by the means of host–guest strategy for maximizing the combination therapy efficacy of cancer treatment. The key features of this host–guest strategy for the combination therapy are that the ratio between photosensitizer and ROS‐sensitive prodrug can be easily tuned, near‐infrared (NIR) irradiation can sensitize the photosensitizer and activate the paclitaxel prodrug for its release, and the accumulation process can be tracked by NIR imaging to maximize the efficacy of photodynamic and chemotherapy. 相似文献
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Esterase‐Sensitive Prodrugs with Tunable Release Rates and Direct Generation of Hydrogen Sulfide
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Yueqin Zheng Bingchen Yu Dr. Kaili Ji Zhixiang Pan Vayou Chittavong Prof. Binghe Wang 《Angewandte Chemie (International ed. in English)》2016,55(14):4514-4518
Prodrugs that release hydrogen sulfide upon esterase‐mediated cleavage of an ester group followed by lactonization are described herein. By modifying the ester group and thus its susceptibility to esterase, and structural features critical to the lactonization rate, H2S release rates can be tuned. Such prodrugs directly release hydrogen sulfide without the involvement of perthiol species, which are commonly encountered with existing H2S donors. Additionally, such prodrugs can easily be conjugated to another non‐steroidal anti‐inflammatory agent, leading to easy synthesis of hybrid prodrugs. As a biological validation of the H2S prodrugs, the anti‐inflammatory effects of one such prodrug were examined by studying its ability to inhibit LPS‐induced TNF‐α production in RAW 264.7 cells. This type of H2S prodrugs shows great potential as both research tools and therapeutic agents. 相似文献
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《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(38):11697-11702
We developed a novel PtIV prodrug that simultaneously releases four different bioactive moieties inside the cancer cell. Its cytotoxicity against monolayer cultures (2D) and spheroid (3D) cancer cells is significantly better than cisplatin. It is 200–450‐fold more potent than cisplatin against KRAS mutated pancreatic and colon cancers and is 40‐fold more selective towards KRAS mutated cells compared to non‐cancerous. This is important since RAS proteins play a role in regulating cell differentiation, proliferation, and survival and KRAS is mutated in 90 % of pancreatic adenocarcinomas, 45 % of colorectal cancers, and 35 % of lung adenocarcinomas. The selectivity index, determined by dividing the IC50 value in non‐cancerous cells by that of a cancerous cell line, is two‐fold better than cisplatin, attesting to preferential cytotoxicity towards neoplastic cells. 相似文献
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《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(49):15751-15755
Cancer cells produce elevated levels of reactive oxygen species, which has been used to design cancer specific prodrugs. Their activation relies on at least a bimolecular process, in which a prodrug reacts with ROS. However, at low micromolar concentrations of the prodrugs and ROS, the activation is usually inefficient. Herein, we propose and validate a potentially general approach for solving this intrinsic problem of ROS‐dependent prodrugs. In particular, known prodrug 4‐(N ‐ferrocenyl‐N ‐benzylaminocarbonyloxymethyl)phenylboronic acid pinacol ester was converted into its lysosome‐specific analogue. Since lysosomes contain a higher concentration of active ROS than the cytoplasm, activation of the prodrug was facilitated with respect to the parent compound. Moreover, it was found to exhibit high anticancer activity in a variety of cancer cell lines (IC50=3.5–7.2 μm ) and in vivo (40 mg kg−1, NK/Ly murine model) but remained weakly toxic towards non‐malignant cells (IC50=15–30 μm ). 相似文献
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Wei Chen Tetsuro Matsunaga Deshka L. Neill Chun‐tao Yang Takaaki Akaike Ming Xian 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(45):16213-16216
Thionitrous acid (HSNO), the smallest S‐nitrosothiol, is emerging as a potential key intermediate in cellular redox regulation linking two signaling molecules H2S and NO. However, the chemical biology of HSNO remains poorly understood. A major hurdle is the lack of methods for selective detection of HSNO in biological systems. Herein, we report the rational design, synthesis, and evaluation of the first fluorescent probe TAP‐1 for HSNO detection. TAP‐1 showed high selectivity and sensitivity to HSNO in aqueous media and cells, providing a useful tool for understanding the functions of HSNO in biology. 相似文献
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《化学:亚洲杂志》2017,12(2):176-180
Traditional enzyme–prodrug therapy (EPT) is a two‐step strategy, which has many serious deficiencies, so having a one‐step EPT treatment becomes a problem of immediate interest. This study aims to achieve an effective co‐delivery of horseradish peroxidase (HRP) as a kind of enzyme for prodrug activation and ethyl 3‐indoleacetate (EIA) as anticancer prodrug. A ternary block copolymer PEG‐PAsp(AED)‐CA consisting of poly(ethylene glycol) (PEG), reduction‐sensitive poly (N ‐(2,2′‐dithiobis(ethylamine)) aspartamide) PAsp(AED), and cholic acid (CA) was synthesized and assembled into spherical micelles which encapsulated EIA in its hydrophobic core and HRP in a reduction‐sensitive interlayer. TEM photographs show that the polymer micelle is around 40 nm, and the cell survival rate test shows that the EIA/HRP polymer micelle is highly lethal to human lung adenocarcinoma cells. Thus, co‐delivery of EIA and HRP demonstrates great potential in cancer therapy, offering a structurally simple and highly tunable platform for the synchronous delivery of enzymes and prodrugs in EPT. 相似文献
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Preparation of a Camptothecin Prodrug with Glutathione‐Responsive Disulfide Linker for Anticancer Drug Delivery 下载免费PDF全文
Dr. Zhigang Xu Dongdong Wang Shuang Xu Dr. Xiaoyan Liu Prof. Dr. Xiaoyu Zhang Prof. Dr. Haixia Zhang 《化学:亚洲杂志》2014,9(1):199-205
We present here a novel camptothecin (CPT) prodrug based on polyethylene glycol monomethyl ether‐block‐poly(2‐methacryl ester hydroxyethyl disulfide‐graft‐CPT) (MPEG‐SS‐PCPT). It formed biocompatible nanoparticles (NPs) with diameters of approximately 122 nm with a CPT loading content as high as approximately 25 wt % in aqueous solution. In in vitro release studies, these MPEG‐SS‐PCPT NPs could undergo triggered disassembly and much faster release of CPT under glutathione (GSH) stimulus than in the absence of GSH. The CPT prodrug had high antitumor activity, and another anticancer drug, doxorubicin hydrochloride (DOX ? HCl), could also be introduced into the prodrug with a high loading amount. The DOX ? HCl‐loaded CPT prodrug could deliver two anticancer drugs at the same time to produce a collaborative cytotoxicity toward cancer cells, which suggested that this GSH‐responsive NP system might become a promising carrier to improve drug‐delivery efficacy. 相似文献
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Anna Leisvuori Zafar Ahmed Mikko Ora Leonid Beigelman Lawrence Blatt Harri Lönnberg 《Helvetica chimica acta》2012,95(9):1512-1520
2′‐C‐Methylnucleosides are known to exhibit antiviral activity against Hepatitis C virus. Since the inhibitory activity depends on their intracellular conversion to 5′‐triphosphates, dosing as appropriately protected 5′‐phosphates or 5′‐phosphorothioates appears attractive. For this purpose, four potential pro‐drugs of 2′‐C‐methylguanosine, i.e., 3′,5′‐cyclic phosphorothioate of 2′‐C‐methylguanosine and 2′‐C,O6‐dimethylguanosine, 1 and 2 , respectively, the S‐[(pivaloyloxy)methyl] ester of 2′‐C,O6‐dimethylguanosine 3′,5′‐cyclic phosphorothioate and the O‐methyl ester of 2′‐C,O6‐dimethylguanosine 3′,5′‐cyclic phosphate, 3 and 4 , respectively, have been prepared. 相似文献
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Xiao‐Gang Wang Lei Xu Min‐Jie Li Xian‐Zheng Zhang 《Angewandte Chemie (International ed. in English)》2020,59(41):18078-18086
Multi‐component MOFs contain multiple sets of unique and hierarchical pores, with different functions for different applications, distributed in their inter‐linked domains. Herein, we report the construction of a class of precisely aligned flexible‐on‐rigid hybrid‐phase MOFs with a unique rods‐on‐octahedron morphology. We demonstrated that hybrid‐phase MOFs can be constructed based on two prerequisites: the partially matched topology at the interface of the two frameworks, and the structural flexibility of MOFs with acs topology, which can compensate for the differences in lattice parameters. Furthermore, we achieved domain selective loading of multiple guest molecules into the hybrid‐phase MOF, as observed by scanning transmission electron microscopy–energy‐dispersive X‐ray spectrometry elemental mapping. Most importantly, we successfully applied the constructed hybrid‐phase MOF to develop a dual‐drug delivery system with controllable loading ratio and release kinetics. 相似文献
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Jingchao Li Dong Cui Jiaguo Huang Shasha He Zebin Yang Yan Zhang Yu Luo Kanyi Pu 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(36):12810-12817
In this study, an organic semiconducting pro‐nanostimulant (OSPS) with a near‐infrared (NIR) photoactivatable immunotherapeutic action for synergetic cancer therapy is presented. OSPS comprises a semiconducting polymer nanoparticle (SPN) core and an immunostimulant conjugated through a singlet oxygen (1O2) cleavable linkers. Upon NIR laser irradiation, OSPS generates both heat and 1O2 to exert combinational phototherapy not only to ablate tumors but also to produce tumor‐associated antigens. More importantly, NIR irradiation triggers the cleavage of 1O2‐cleavable linkers, triggering the remote release of the immunostimulants from OSPS to modulate the immunosuppressive tumor microenvironment. Thus, the released tumor‐associated antigens in conjunction with activated immunostimulants induce a synergistic antitumor immune response after OSPS‐mediated phototherapy, resulting in the inhibited growth of both primary/distant tumors and lung metastasis in a mouse xenograft model, which is not observed for sole phototherapy. 相似文献
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Nicholas R. Lees Li‐Chen Han Matthew J. Byrne Jonathan A. Davies Alice E. Parnell Pollyanna E. J. Moreland James E. M. Stach Marc W. vanderKamp Christine L. Willis Paul R. Race 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(8):2327-2331
Spirotetronate and spirotetramate natural products include a multitude of compounds with potent antimicrobial and antitumor activities. Their biosynthesis incorporates many unusual biocatalytic steps, including regio‐ and stereo‐specific modifications, cyclizations promoted by Diels–Alderases, and acetylation‐elimination reactions. Here we focus on the acetate elimination catalyzed by AbyA5, implicated in the formation of the key Diels–Alder substrate to give the spirocyclic system of the antibiotic abyssomicin C. Using synthetic substrate analogues, it is shown that AbyA5 catalyzes stereospecific acetate elimination, establishing the (R)‐tetronate acetate as a biosynthetic intermediate. The X‐ray crystal structure of AbyA5, the first of an acetate‐eliminating enzyme, reveals a deviant acetyl esterase fold. Molecular dynamics simulations and enzyme assays show the use of a His‐Ser dyad to catalyze either elimination or hydrolysis, via disparate mechanisms, under substrate control. 相似文献