- Retro Diels-Alder Fragmentation of Fulvene-Maleimide Bioconjugates for Mass Spectrometric Detection of Biomolecules
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Diels-Alder chemistry is a well-explored avenue for the synthesis of bioactive materials; however, its potential applications have recently expanded following the development of reactions that can be performed in buffered aqueous environments at low temperatures, including fulvene-maleimide [4 + 2] cycloadditions. In this study, we synthesized two novel amine-reactive fulvene linkers to demonstrate the application of this chemistry for generating mass spectrometry-cleavable labels (“mass tags”), which can be used for the labeling and detection of proteins. Successful conjugation of these linkers to maleimide-labeled peptides was observed at low temperatures in phosphate-buffered saline, allowing the non-destructive modification of proteins with such mass tags. The labile nature of fulvene-maleimide adducts in the gas phase also makes them suitable for both matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI) mass spectrometric analysis. Unlike previous examples of MALDI mass tags, we show that fulvene-maleimide cycloaddition adducts fragment predictably upon gas-phase activation without the need for bulky photocleavable groups. Further exploration of this chemistry could therefore lead to new approaches for mass spectrometry-based bioassays.
- Stevens, Katherine G.,McFarlane, Lewis O.,Platts, Kirsten,O’Brien-Simpson, Neil,Li, Wenyi,Blencowe, Anton,Trim, Paul J.,Pukala, Tara L.
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p. 12204 - 12212
(2021/09/15)
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- Novel antibody-drug conjugate with UV-controlled cleavage mechanism for cytotoxin release
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Antibody-drug conjugates (ADCs) are being developed worldwide with the potential to revolutionize current cancer treatment strategies. However, off-target toxicity caused by the instability of linkers remains one of the main issues to be resolved. Developing a novel photocontrol-ADC with good stability and photocontrolled release seemed to be an attractive and practical solution. In this study, we designed, for the first time, a novel ultraviolet (UV) light-controlled ADC by carefully integrating the UV-cleavable o-nitro-benzyl structure into the linker. Our preliminary work indicated that the ADC exhibited good stability and photocontrollability while maintaining a targeting effect similar to that of the naked antibody. Upon irradiation with UV light, the ADC rapidly released free cytotoxins and exerted significant cytotoxicity toward drug-resistant tumor cells. Compared to those of the unirradiated cells, the EC50 values of ADCs increased by up to 50-fold. Furthermore, our research confirmed that the degradation products of unirradiated ADC, Cys-1a, were relatively less toxic, thus potentially reducing the off-target toxicity caused by nonspecific uptake of ADCs. The novel design strategy of UV light-controlled ADCs may provide new perspectives for future research on ADCs and promote the development of photocontrol systems.
- Li, Jiaguo,Xiao, Dian,Xie, Fei,Li, Wei,Zhao, Lei,Sun, Wei,Yang, Xiaohong,Zhou, Xinbo
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- PEG-PEI-modified gated N-doped mesoporous carbon nanospheres for pH/NIR light-triggered drug release and cancer phototherapy
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A novel hybrid drug carrier has been designed, taking N-doped mesoporous carbon (NMCS) as the core and PEG-PEI as the outer shell. NMCS was functionalized with a photocleavable nitrobenzyl-based linker following a click reaction. Gemcitabine was loaded in
- Panda, Snigdharani,Bhol, Chandra Sekhar,Bhutia, Sujit Kumar,Mohapatra, Sasmita
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p. 3666 - 3676
(2021/05/17)
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- Photolabile Linkers: Exploiting Labile Bond Chemistry to Control Mode and Rate of Hydrogel Degradation and Protein Release
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Photolabile moieties have been utilized in applications ranging from peptide synthesis and controlled protein activation to tunable and dynamic materials. The photochromic properties of nitrobenzyl (NB) based linkers are readily tuned to respond to cytocompatible light doses and are widely utilized in cell culture and other biological applications. While widely utilized, little is known about how the microenvironment, particularly confined aqueous environments (e.g., hydrogels), affects both the mode and rate of cleavage of NB moieties, leading to unpredictable limitations in control over system properties (e.g., rapid hydrolysis or slow photolysis). To address these challenges, we synthesized and characterized the photolysis and hydrolysis of NB moieties containing different labile bonds (i.e., ester, amide, carbonate, or carbamate) that served as labile crosslinks within step-growth hydrogels. We observed that NB ester bond exhibited significant rates of both photolysis and hydrolysis, whereas, importantly, the NB carbamate bond had superior light responsiveness and resistance to hydrolysis within the hydrogel microenvironment. Exploiting this synergy and orthogonality of photolytic and hydrolytic degradation, we designed concentric cylinder hydrogels loaded with different cargoes (e.g., model protein with different fluorophores) for either combinatorial or sequential release, respectively. Overall, this work provides new facile chemical approaches for tuning the degradability of NB linkers and an innovative strategy for the construction of multimodal degradable hydrogels, which can be utilized to guide the design of not only tunable materials platforms but also controlled synthetic protocols or surface modification strategies.
- Dasgupta, Srimoyee,Kloxin, April M.,Kloxin, Christopher J.,Levalley, Paige J.,Neelarapu, Raghupathi,Sutherland, Bryan P.
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supporting information
p. 4671 - 4679
(2020/04/10)
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- MOLECULAR LOGIC GATES FOR CONTROLLED MATERIAL DEGRADATION
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The present disclosure features, inter alia, a cyclic multifunctional linker, including at least two cleavable moieties; at least two connecting chains connected to the at least two cleavable moieties to provide a cyclic structure; and at least two linkin
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Page/Page column 39; 43; 44
(2018/04/20)
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- COMPOUNDS AND METHODS FOR DETECTION AND ISOLATION OF BIOMOLECULES
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A compound of general formula R1-L1-PCL-L2-R2 is disclosed wherein PCL is a photolabile group; R1 is a reactive moiety capable of modifying biomolecules without activation; L1 is a non-clea
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Paragraph 0120
(2017/05/11)
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- COMPOUNDS FOR PROMOTING LIPOSOMAL AND CELLULAR ADHESION AND COMPOSITIONS AND METHODS OF USE THEREOF
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The present application describes amphiphatic compounds like compound Ila below, compositions and methods for incorporating chemoselective and bio-orthogonal complementary functional groups into liposomes. Such compounds are incorporated in greater number
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Paragraph 00199-00200
(2015/01/09)
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- Photodegradable groups for tunable polymeric materials
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Provided is a method that provides both spatial and temporal control of a polymer degradation process using mono- and multifunctional macromolecular monomers (“macromers”) that degrade via single- and multi-photon photolysis mechanisms over a broad range
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Page/Page column 14; 16
(2013/02/28)
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- Enzymatic- and light-degradable hybrid nanogels: Crosslinking of polyacrylamide with acrylate-functionalized Dextrans containing photocleavable linkers
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Enzymatically cleavable and light-degradable hybrid nanogels were prepared by free radical inverse miniemulsion copolymerization of acrylamide (AAm) with a newly synthesized functional dextran crosslinker containing acrylate moieties attached to the backbone via a photolabile linker, that is, dextran-photolabile linker-acrylate (Dex-PL-A). The Dex-PL-A/AAm feed ratio was systematically varied to investigate the influence of the particle composition on the gel properties. The resulting hydrogel nanoparticles were examined with regard to their degradation behavior upon the appliance of the two orthogonal stimuli by turbidity measurements in combination with dynamic light scattering. Although continuous photolytic cleavage of the photolabile linkers between polyacrylamide chains and dextran molecules was found to proceed fast and quantitatively yielding completely disintegrated networks, stepwise irradiation resulted in partial degradation of crosslinking points. Thus, nanogels of a desired specific degree of swelling (DGS) can be obtained by adjusting the irradiation time accordingly. Partial enzymatic cleavage of the dextran backbones of the Dex-PL-A crosslinking molecules resulted in an increase in the DGS of the nanogels up to a constant value. Subsequent irradiation of those swollen hydrogel particles was used to fully degrade the network structure in a second step. Hence, a two-step degradation profile was realized by the combination of the two orthogonal stimuli.
- Klinger, Daniel,Landfester, Katharina
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scheme or table
p. 1062 - 1075
(2012/06/01)
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- Near infrared light triggered release of biomacromolecules from hydrogels loaded with upconversion nanoparticles
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Using a photosensitive hybrid hydrogel loaded with upconversion nanoparticles (UCNPs), we show that continuous-wave near-infrared (NIR) light (980 nm) can be used to induce the gel-sol transition and release large, inactive biomacromolecules (protein and
- Yan, Bin,Boyer, John-Christopher,Habault, Damien,Branda, Neil R.,Zhao, Yue
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supporting information
p. 16558 - 16561
(2013/01/15)
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- Dual stimuli-responsive poly(2-hydroxyethyl methacrylate-co-methacrylic acid) microgels based on photo-cleavable cross-linkers: PH-dependent swelling and light-induced degradation
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Dual stimuli-responsive p(HEMA-co-MAA) microgels were prepared in a facile way by inverse miniemulsion copolymerization of 2-hydroxyethyl methacrylate (HEMA) with methacrylic acid (MAA) and two kinds of newly synthesized photodegradable cross-linkers. The pH-dependent swelling behavior induced by the protonation/deprotonation of the methacrylic acid groups in the network-forming polymer was investigated by means of the particle volume change as determined by DLS measurements. Photolytic degradation experiments were conducted by irradiation with UV light which led to particle disintegration caused by cleavage of the photolabile cross-linking points. The degradation behavior of the microgels was investigated with respect to degradation rates and changes in the degree of swelling. Those parameters were found to depend on the pH value of the solvent, the light intensities, and the irradiation wavelengths applied. For similar conditions, the degradation profile was demonstrated to strongly depend not only on the molecular structure of the cross-linking molecule but also on the molecular weight of the network-forming copolymers. The particular combination of the stimuli described is designed as a new strategy to two different swelling/degradation profiles. This dual stimuli-responsiveness was shown to enable the efficient loading and subsequent release of myoglobin as a model protein. Here a slow diffusion controlled release (induced by changes of the pH) was combined with a fast degradation controlled (induced by irradiation) on-demand release. This novel two-step release profile is proposed to bear great potential for delivery applications.
- Klinger, Daniel,Landfester, Katharina
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scheme or table
p. 9758 - 9772
(2012/04/04)
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- Dextran based photodegradable hydrogels formed via a Michael addition
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A photodegradable, covalently crosslinked hydrogel system has been constructed from the biocompatible polymers dextran and poly(ethylene glycol) using the acrylate-thiol Michael addition as the crosslinking method. Light sensitivity of the hydrogel was in
- Peng, Ke,Tomatsu, Itsuro,Van Den Broek, Bram,Cui, Chao,Korobko, Alexander V.,Van Noort, John,Meijer, Annemarie H.,Spaink, Herman P.,Kros, Alexander
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body text
p. 4881 - 4887
(2012/03/08)
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- Synthesis of hydroxamic acid derivatives
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This invention is direct to a solid phase reaction product of a solid substrate carrying a plurality of covalently bound hydroxylamine or protected hydroxylamine groups. The solid solid phase reaction product may be used for the synthesis of hydroxamic ac
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- Model Studies for New o-Nitrobenzyl Photolabile Linkers: Substituent Effects on the Rates of Photochemical Cleavage
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Both a model phenacyl and o-nitrobenzyl photolabile linker from the literature along with four new o-nitrobenzyl linkers were prepared and the kinetics of their photolytic cleavage examined in solution. The linkers were prepared by amidation of the carboxylic acid anchoring tether with benzylamine, and the cleavable benzylic substituent was chosen to be either acetic acid or acetamide. Irradiation of the linkers in four solvents (methanol, p-dioxane, and aqueous buffer ± dithiothreitol) at 365 nm and analysis via HPLC afforded kinetic rates of cleavage suitable for comparative purposes. The phenacyl linker was found to cleave slowly under aqueous conditions with no detectable cleavage being observed in the organic solvents. Known o-nitrobenzyl linker 4 showed modest rates of cleavage in aqueous and organic solvents. Incorporation of two alkoxy groups in the benzene ring to generate the veratryl-based linker 13a increased the rate of cleavage dramatically, and introduction of an additional benzylic methyl group (13b) increased the rate of cleavage by an additional 5 fold. Increasing the length of the anchoring carboxylic acid tether from acetic to butyric acid (19) improved the cleavage kinetics modestly in organic media and slightly diminished the rates in water. The amide model linker 21 cleaved from 3 to 7 times faster than the corresponding ester linkage 19. An amide-generating linker 26 was prepared, and its performance to generate photolabile solid supports was briefly examined. The stability of the linker and subsequent cleavage upon photolysis from the support of an isotopically enriched 4-thiazolidinone was demonstrated by gel phase 13C NMR.
- Holmes, Christopher P.
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p. 2370 - 2380
(2007/10/03)
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- An improved synthesis and selective coupling of a hydroxy based photolabile linker for solid phase organic synthesis
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Photolabile linkers have become an important orthogonal technique for substrate cleavage off the resin in solid-phase organic synthesis. Herein, we report an improved synthesis and selective coupling of a hydroxy based photolinker to a hydroxy based solid-phase resin, thereby removing the necessity for protection or on-resin manipulation.
- Whitehouse, Darren L.,Savinov, Sergey N.,Austin, David J.
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p. 7851 - 7852
(2007/10/03)
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