Ultrasound(US)activation of mechanophores in polymers that initiates cascade chemical reactions is a promising strategy for on-demand molecule release.However,the typical US frequency used for mechanochemistry is arou...Ultrasound(US)activation of mechanophores in polymers that initiates cascade chemical reactions is a promising strategy for on-demand molecule release.However,the typical US frequency used for mechanochemistry is around 20 kHz,producing inertial cavitation that exceeds the tolerance threshold of biological systems.Here,high-intensity focused US(HIFU)as a mechanical stimulus is introduced to drive the activation of disulfide mechanophores in hyperbranched star polymers(HBSPs)and microgels(MGLs).The mechanism of molecular release is attributed to the thiol-disulfide exchange reaction and subsequent intramolecular cyclization.We reveal that HBSPs and MGLs effectively transduce HIFU as mechanical input to chemical output,demonstrated by the quantification of the release of fluorescent umbelliferone(UMB).Moreover,an in vitro study of drug release is carried out using camptothecin as the model drug,which is covalently loaded in MGLs,demonstrating the potential of our system for controlled drug delivery to cancer cells.展开更多
Although there are no effective therapies to block or reverse Alzheimer’s disease(AD)progression at present,a promising therapeutic strategy is to reduce levels of amyloid𝛽(Aβ)proteins,which drive the format...Although there are no effective therapies to block or reverse Alzheimer’s disease(AD)progression at present,a promising therapeutic strategy is to reduce levels of amyloid𝛽(Aβ)proteins,which drive the formation of amyloid plaque,a primary hallmark in AD brains.Herein,we report that amphiphilic lipid-DNA molecules(LD)were designed by incorporating a long alkyl chain into the nucleotide base.It significantly down-regulated Alzheimer’s Aβ levels in vivo and in vitro.In contrast to small-molecule chemical drugs and antibody therapies,the assembled DNA nanoparticles allowed them to effectively cross the blood-brain barrier(BBB)and accumulate in the brain,increasing the therapeutic effects.Notably,lipid-DNA downregulated the levels of Aβ peptides significantly in vitro.AD mice model experiments demonstrated that the LD-treated groups exhibited a rapid cognition behavioral improvement,which was associated with brain engagement of LD and reduced Aβ levels.Thus,the molecularly engineered DNA nanomaterials effectively regulated Aβ peptides.This work might provide a promising DNA engineering strategy for AD treatment.展开更多
Protein folding,stability,and function are usually in-fluenced by pH.And free energy plays a fundamental role in analysis of such pH-dependent properties.Elec-trostatics-based theoretical framework using dielectric so...Protein folding,stability,and function are usually in-fluenced by pH.And free energy plays a fundamental role in analysis of such pH-dependent properties.Elec-trostatics-based theoretical framework using dielectric solvent continuum model and solving Poisson-Boltzm-ann equation numerically has been shown to be very successful in understanding the pH-dependent proper-ties.However,in this approach the exact computation of pH-dependent free energy becomes impractical for proteins possessing more than several tens of ioni-zable sites(e.g.>30),because exact evaluation of the partition function requires a summation over a vast number of possible protonation microstates.Here we present a method which computes the free energy us-ing the average energy and the protonation probabili-ties of ionizable sites obtained by the well-established Monte Carlo sampling procedure.The key feature is to calculate the entropy by using the protonation prob-abilities.We used this method to examine a well-studied protein(lysozyme)and produced results which agree very well with the exact calculations.Applications to the optimum pH of maximal stability of proteins and pro-tein-DNA interactions have also resulted in good agreement with experimental data.These examples recommend our method for application to the elucidation of the pH-dependent properties of proteins.展开更多
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
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
基金supported by the German Research Foundation(grant nos.331065168,191948804,and 503981124)the National Natural Science Foundation of China(grant no.22277018)+2 种基金the Zhejiang Provincial Natural Science Foundation for Distinguished Young Scholars(grant no.LR23B030001)Wenzhou Institute,University of the Chinese Academy of Sciences(grant no.WIUCASQD2020015)M.X.acknowledges the financial support of the Alexander von Humboldt Foundation(grant no.3.5-CHN-1210658-HFST-P).
文摘Ultrasound(US)activation of mechanophores in polymers that initiates cascade chemical reactions is a promising strategy for on-demand molecule release.However,the typical US frequency used for mechanochemistry is around 20 kHz,producing inertial cavitation that exceeds the tolerance threshold of biological systems.Here,high-intensity focused US(HIFU)as a mechanical stimulus is introduced to drive the activation of disulfide mechanophores in hyperbranched star polymers(HBSPs)and microgels(MGLs).The mechanism of molecular release is attributed to the thiol-disulfide exchange reaction and subsequent intramolecular cyclization.We reveal that HBSPs and MGLs effectively transduce HIFU as mechanical input to chemical output,demonstrated by the quantification of the release of fluorescent umbelliferone(UMB).Moreover,an in vitro study of drug release is carried out using camptothecin as the model drug,which is covalently loaded in MGLs,demonstrating the potential of our system for controlled drug delivery to cancer cells.
基金supported by the National Natural Science Foundation of China(22020102003,22388101,22125701,22277064)National Key R&D Program of China(2021YFF1200300,2021YFF0701800,and 2022YFF0710000)China Postdoctoral Science Foundation(2022M711785)。
文摘Although there are no effective therapies to block or reverse Alzheimer’s disease(AD)progression at present,a promising therapeutic strategy is to reduce levels of amyloid𝛽(Aβ)proteins,which drive the formation of amyloid plaque,a primary hallmark in AD brains.Herein,we report that amphiphilic lipid-DNA molecules(LD)were designed by incorporating a long alkyl chain into the nucleotide base.It significantly down-regulated Alzheimer’s Aβ levels in vivo and in vitro.In contrast to small-molecule chemical drugs and antibody therapies,the assembled DNA nanoparticles allowed them to effectively cross the blood-brain barrier(BBB)and accumulate in the brain,increasing the therapeutic effects.Notably,lipid-DNA downregulated the levels of Aβ peptides significantly in vitro.AD mice model experiments demonstrated that the LD-treated groups exhibited a rapid cognition behavioral improvement,which was associated with brain engagement of LD and reduced Aβ levels.Thus,the molecularly engineered DNA nanomaterials effectively regulated Aβ peptides.This work might provide a promising DNA engineering strategy for AD treatment.
基金This study was supported in part by grants from the National Natural Sci-ence Foundation of China(Grant No.30570406)the HI-tech Re-search and Development Program of China(Grant No.2008AA02Z311)the Shanghai Leading Academic Discipline Project(B111).
文摘Protein folding,stability,and function are usually in-fluenced by pH.And free energy plays a fundamental role in analysis of such pH-dependent properties.Elec-trostatics-based theoretical framework using dielectric solvent continuum model and solving Poisson-Boltzm-ann equation numerically has been shown to be very successful in understanding the pH-dependent proper-ties.However,in this approach the exact computation of pH-dependent free energy becomes impractical for proteins possessing more than several tens of ioni-zable sites(e.g.>30),because exact evaluation of the partition function requires a summation over a vast number of possible protonation microstates.Here we present a method which computes the free energy us-ing the average energy and the protonation probabili-ties of ionizable sites obtained by the well-established Monte Carlo sampling procedure.The key feature is to calculate the entropy by using the protonation prob-abilities.We used this method to examine a well-studied protein(lysozyme)and produced results which agree very well with the exact calculations.Applications to the optimum pH of maximal stability of proteins and pro-tein-DNA interactions have also resulted in good agreement with experimental data.These examples recommend our method for application to the elucidation of the pH-dependent properties of proteins.
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.
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.
