The development of ultrasound-responsive microcapsule structures has resulted in several spatiotemporally controlled drug delivery systems for macromolecular cargoes,including proteins,nucleic acids,and even cells for...The development of ultrasound-responsive microcapsule structures has resulted in several spatiotemporally controlled drug delivery systems for macromolecular cargoes,including proteins,nucleic acids,and even cells for biomedical applications.However,utilizing microcapsules to transport small molecular cargoes remains a challenge,because the leakage of drugs before ultrasound irradiation might cause side effects such as the undesired toxicity and the decrease of effective drug concentration at the target site.Herein,we present a novel strategy to tackle these shortcomings by employing nanodrugs which refers to nanoparticles coated with small molecule drugs.We showed that the drug leakage was prevented when encapsulating the nanodrug in microcapsules.Moreover,the fabricated drug delivery system was responsive not only to unfocused high-intensity ultrasound but also to the clinically relevant high-intensity focused ultrasound.Finally,as a proof of concept,we showed that the antibacterial activity of the nanodrug@Microcapsules could be activated by applying ultrasound in situ.These results may provide new insights into the development of ultrasound triggered small molecule drug delivery assisted by metallic nanoparticles.展开更多
1 Results Our objective is two fold: we (ⅰ) aim at the development of novel patterning methodologies in order to (ⅱ) achieve control over the positioning and alignment of living cells.The patterning of the biointerf...1 Results Our objective is two fold: we (ⅰ) aim at the development of novel patterning methodologies in order to (ⅱ) achieve control over the positioning and alignment of living cells.The patterning of the biointerfaces is carried out both at the micro-and nanometer scale and involve (bio)chemical as well as topographic patterns.The former are relatively easily obtained by patterning techniques adapted from (conventional) soft lithography,e.g.by means of micro-contact printing (μ-CP).The topographic pat...展开更多
The covalent attachment of cargo molecules(e.g.,drugs and fluorophores)inβ-position to a disulfide moiety through carbamate and carbonate bonds finds many applications in responsive release systems.Recently,we showed...The covalent attachment of cargo molecules(e.g.,drugs and fluorophores)inβ-position to a disulfide moiety through carbamate and carbonate bonds finds many applications in responsive release systems.Recently,we showed that the combination of this release process with polymer mechanochemistry-induced disulfide scission enabled the remote-controlled release of small molecule drugs and fluorophores from their inactive parent macromolecules using ultrasound.The nature of the linker bond largely governed the subsequent release kinetics,an aspect that has not been investigated so far.To compare the differences,we here employ disulfide-centered polymers releasing either hydroxyl-or amino-naphthalimides from their respectiveβ-carbonate or-carbamate linkers by forceinduced intramolecular 5-exo-trig cyclization.We present the synthesis,characterization,and cell imaging evaluation of three naphthalimides featuring colorimetric and green fluorescence turn-on upon release,allowing monitoring of the release process.We believe that the insights gained from these experiments would advance the tailoring of release rates for force-induced pharmacotherapy.展开更多
文摘细胞色素P450s是用于生物合成的多功能催化剂.在P450催化循环中,需要两个电子来还原血红素铁,并通过电子转移途径(eTPs)激活随后的还原,该步骤是反应的限速步骤.本文重新设计了巨大芽孢杆菌P450 BM3的e TPs,大幅提高了其催化性能.通过在P450 BM3的e TP中引入芳香族氨基酸,“最佳”变体P2H02(A399Y/Q403F)的催化效率比P450 BM3野生型催化效率提高了12.9倍(kcat/KM从65.8 L mol^(-1)s^(-1)提高到913.5 L mol^(-1)s^(-1)).分子动力学模拟和电子传递分析表明,在辅因子FMN和血红素之间引入的芳香族氨基酸可以显著提高电子转移速率和酶催化性能.同时,在电子传递途径中引入酪氨酸可以保护P450的催化中心,使其避免被氧化性中间产物所破坏,从而提高其催化效率.此外,引入芳香族氨基酸的策略被证明对其他P450(如CYP116B3)同样有效,改造后的酶表现出显著提高的催化效率.综上,本文策略有望拓展到其他带有长程电子传递链的氧化还原酶上,成为改造的通用策略.
基金the European Research Council through the Advanced Grant“Suprabiotics”(No.694610)J.L.F.was supported by a CSC scholarship.M.J.X.thanks the Alexander von Humboldt Foundation for a fellowship and financial support(No.3.5-CHN-1210658-HFST-P)L.F.Z.acknowledges financial support from Wenzhou Institute,University of Chinese Academy of Sciences(No.WIUCASQD2020015).
文摘The development of ultrasound-responsive microcapsule structures has resulted in several spatiotemporally controlled drug delivery systems for macromolecular cargoes,including proteins,nucleic acids,and even cells for biomedical applications.However,utilizing microcapsules to transport small molecular cargoes remains a challenge,because the leakage of drugs before ultrasound irradiation might cause side effects such as the undesired toxicity and the decrease of effective drug concentration at the target site.Herein,we present a novel strategy to tackle these shortcomings by employing nanodrugs which refers to nanoparticles coated with small molecule drugs.We showed that the drug leakage was prevented when encapsulating the nanodrug in microcapsules.Moreover,the fabricated drug delivery system was responsive not only to unfocused high-intensity ultrasound but also to the clinically relevant high-intensity focused ultrasound.Finally,as a proof of concept,we showed that the antibacterial activity of the nanodrug@Microcapsules could be activated by applying ultrasound in situ.These results may provide new insights into the development of ultrasound triggered small molecule drug delivery assisted by metallic nanoparticles.
文摘1 Results Our objective is two fold: we (ⅰ) aim at the development of novel patterning methodologies in order to (ⅱ) achieve control over the positioning and alignment of living cells.The patterning of the biointerfaces is carried out both at the micro-and nanometer scale and involve (bio)chemical as well as topographic patterns.The former are relatively easily obtained by patterning techniques adapted from (conventional) soft lithography,e.g.by means of micro-contact printing (μ-CP).The topographic pat...
基金supported by the European Union(European Research Council Advanced Grant SUPRABIOTICS no.694610)R.G.is grateful for support from a Freigeist Fellowship of the Volkswagen Foundation(no.92888)Parts of the analytical investigations were performed at the Center for Chemical Polymer Technology(CPT),supported by the European Commission and the Federal State of North Rhine-Westphalia(no.300088302).
文摘The covalent attachment of cargo molecules(e.g.,drugs and fluorophores)inβ-position to a disulfide moiety through carbamate and carbonate bonds finds many applications in responsive release systems.Recently,we showed that the combination of this release process with polymer mechanochemistry-induced disulfide scission enabled the remote-controlled release of small molecule drugs and fluorophores from their inactive parent macromolecules using ultrasound.The nature of the linker bond largely governed the subsequent release kinetics,an aspect that has not been investigated so far.To compare the differences,we here employ disulfide-centered polymers releasing either hydroxyl-or amino-naphthalimides from their respectiveβ-carbonate or-carbamate linkers by forceinduced intramolecular 5-exo-trig cyclization.We present the synthesis,characterization,and cell imaging evaluation of three naphthalimides featuring colorimetric and green fluorescence turn-on upon release,allowing monitoring of the release process.We believe that the insights gained from these experiments would advance the tailoring of release rates for force-induced pharmacotherapy.
