Nanoemulsions(NEs) and nanosuspensions(NSs) show great potential in enhancing the ocular bioavailability of therapeutics through topical delivery. However, transocular fate of intact NEs and NSs is still inconclusive....Nanoemulsions(NEs) and nanosuspensions(NSs) show great potential in enhancing the ocular bioavailability of therapeutics through topical delivery. However, transocular fate of intact NEs and NSs is still inconclusive. In this study, an aggregation-caused quenching fluorescent probe is used to track precorneal retention and transocular transportation of intact NEs and NSs, while coumarin 6 is used to mimick the cargo. NEs show superior precorneal retention to NSs. Both the two types of nanocarriers can permeate into but not across the cornea. The smaller NEs(100 nm) permeate better into the cornea than the bigger ones(210 nm). Nanocarriers in the cornea serves as depots. The released cargo molecules can penetrate across the cornea and diffuse into the lens. Moreover, the conjunctiva-scleral route may be potential to deliver drugs to the back of the eye, In conclusion, the study provides useful tools and information in the field of transocular transportation of nanoparticles.展开更多
Intravenous nanosuspensions are attracted growing attention as a viable strategy for development of intravenous formulations of poorly water-soluble drugs.However,only few information about the biological fate of intr...Intravenous nanosuspensions are attracted growing attention as a viable strategy for development of intravenous formulations of poorly water-soluble drugs.However,only few information about the biological fate of intravenous nanosuspensions is currently known,especially amorphous nanosuspensions are not reported yet.In this study,the in vivo fate of herpetrione(HPE)amorphous nanosuspensions following intravenous administration was explored by using an aggregation-caused quenching(ACQ)probe and HPLC methods.The ACQ probe is physically embedded into HPE nanoparticles via anti-solvent method to form HPE hybrid nanosuspensions(HPE-HNSs)for bioimaging.HPE-HNSs emit strong and stable fluorescence,but fluorescence quenches immediately upon the dissolution of HPE-HNSs,confirming the selfdiscrimination of HPE-HNSs.Following intravenous administration of HPE-HNSs,integral HPE-HNSs and HPE show similar degradation and biodistribution,with rapid clearance from blood circulation and obvious accumulation in liver and lung.Due to the slower dissolution and enhanced recognition by reticuloendothelial system,450 nm HPE-HNSs accumulate more in liver,lung and spleen than that of 200 nm HPE-HNSs.These results demonstrate that integral HPE-HNSs determine the in vivo performance of HPEHNSs.This study provides insight into the in vivo fate of intravenous amorphous nanosuspensions.展开更多
The efficacy of photothermal therapy(PTT)in antitumor applications is often limited by inadequate tumor targeting and low photothermal conversion efficiency(PCE)of photosensitizers.In this study,we designed a photothe...The efficacy of photothermal therapy(PTT)in antitumor applications is often limited by inadequate tumor targeting and low photothermal conversion efficiency(PCE)of photosensitizers.In this study,we designed a photothermal nanoparticle,MPF@IR780,to enhance photosensitizers’targeting and PCE.First,MPF@IR780 improves the delivery of photosensitizers to tumor tissue through the enhanced permeability and retention(EPR)effect.Furthermore,hydrophobic ferrocene was incorporated into the nanoparticle core to increase structural compactness,leading to a strong aggregation-caused quenching(ACQ)effect and an improved PCE of the photosensitizer under near-infrared(NIR)irradiation.Mechanistically,MPF@IR780 induces PANoptosis and ferroptosis in cancer cells through thermal damage and oxidative stress,providing an efficient approach for oncotherapy.This strategy of amplifying the effects of PTT by enhancing the ACQ of photosensitizers offers a promising method for advancing the next generation of PTT.展开更多
Environment-responsive fluorophores with aggregation-caused quenching(ACQ)properties have been applied to track nanocarriers with reduced artefacts caused by unbound or free fluorophores but suffer from incomplete flu...Environment-responsive fluorophores with aggregation-caused quenching(ACQ)properties have been applied to track nanocarriers with reduced artefacts caused by unbound or free fluorophores but suffer from incomplete fluorescence quenching and significant re-illumination,which undermine bioimaging accuracy.Herein,through structural modifications to reinforce the hydrophobicity,planarity and rigidity of fluorophores with an aza-BODIPY framework,probes featuring absolute ACQ(aACQ)and negligible re-illumination are developed and evaluated in various nanocarriers.aACQ probes,FD-B21 and FD-C7,exhibit near-infrared emission,high quantum yield,photostability,water sensitivity,and negligible re-illumination in blood,plasma and 1%Tween-80 in contrast to ACQ probe P2 and conventional probe DiR.All nanocarriers can be labeled efficiently by the tested fluorophores.Polymeric micelles(PMs)labeled by different aACQ probes manifest similar biodistribution patterns,which however differ from that of DiR-labeled PMs and could be ascribed to the appreciable re-illumination of DiR.Significantly lower re-illumination is also found in aACQ probes(2%-3%)than DiR(20%-40%)in Caco-2,Hela,and Raw264.7 cells.Molecular dynamics simulations unravel the molecular mechanisms behind aggregation and re-illumination,supporting the hypothesis of planarity dependency.It is concluded that aACQ fluorophores demonstrate excellent water sensitivity and negligible fluorescence re-illumination,making themselves useful tools for more accurate bioimaging of nanocarriers.展开更多
Probing the onset of micellization,or determining the critical micelle concentration(CMC),is of crucial importance while remains to be challenged by growing demand for extraordinary sensitivity and accuracy.Although f...Probing the onset of micellization,or determining the critical micelle concentration(CMC),is of crucial importance while remains to be challenged by growing demand for extraordinary sensitivity and accuracy.Although fluorometry has attracted wide attention owing to its superiority in simplicity and sensitivity over other methods,the presence and fluctuation of background fluorescence of conventional fluorescent probes undermine the accuracy of CMC determination.Herein,a series of novel fluorescent probes without background fluorescence at a concentration below CMC owing to absolute aggregation-caused quenching(aACQ)are utilized for sensitive and accurate measurement of CMC.The aACQ probes aggregate spontaneously and instantly in an aqueous environment owing to molecular π-π stacking with fluorescence quenching absolutely.Therefore,the absence of background fluorescence at a concentration below CMC clears relevant interference associated with conventional fluorophores.In this study,the new method is applied for versatile surfactants with CMCs ranging from nanomolar to millimolar concentrations,especially copolymers with ultralow CMC.The higher sensitivity and accuracy are highlighted by comparison with conventional probes.展开更多
Dye-loaded polymeric nanoparticles(NPs)are promising bioimaging agents because of their available surface chemistry,high brightness,and tunable optical properties.However,high dye loadings can cause the aggregation-ca...Dye-loaded polymeric nanoparticles(NPs)are promising bioimaging agents because of their available surface chemistry,high brightness,and tunable optical properties.However,high dye loadings can cause the aggregation-caused quenching(ACQ)of the encapsulated fluorophores.Previously,we proposed to mitigate the ACQ inside polymeric NPs by insulating cationic dyes with bulky hydrophobic counterions.In order to implement new functionalities into dye-loaded NPs,here,we extend the concept of bulky counterions to anionic lanthanide-based complexes.We show that by employing Gd-based counterions with octadecyl rhodamine B loaded NPs at 30 wt% versus polymer,the fluorescence quantum yield can be increased to 10-fold(to 0.34).Moreover,Gd-anion provides NPs with enhanced contrast in electron microscopy.A combination of a luminescent Eu-based counterion with a far-red to near-infrared cyanine 5 dye(DiD)yields Forster resonance energy transfer NPs,where the UV-excited Eu-based counterion transfers energy to DiD,generating delayed fluorescence and large stokes shift of -340 nm.Cellular studies reveal low cytotoxicity of NPs and their capacity to internalize without detectable dye leakage,in contrast to leaky NPs with small counterions.Our findings show that the aggregation behavior of cationic dyes in the polymeric NPs can be controlled by bulky lanthanide anions,which will help in developing bright luminescent multifunctional nanomaterials.展开更多
Lipid-based nanocarriers have staged a remarkable comeback in the oral delivery of proteins and peptides, but delivery efficiency is compromised by lipolysis. β-Lactoglobulin(β-lg) stabilized lipid nanoparticles, in...Lipid-based nanocarriers have staged a remarkable comeback in the oral delivery of proteins and peptides, but delivery efficiency is compromised by lipolysis. β-Lactoglobulin(β-lg) stabilized lipid nanoparticles, including nanoemulsions(NE@β-lg) and nanocapsules(NC@β-lg), were developed to enhance the oral absorption of insulin by slowing down lipolysis due to the protection from β-lg. Cremophor EL stabilized nanoemulsions(NE@Cre-EL) were prepared and set as a control. The lipid nanoparticles produced mild and sustained hypoglycemic effects, amounting to oral bioavailability of 3.0% ± 0.3%, 7.0% ± 1.1%, and7.7% ± 0.8% for NE@Cre-EL, NE@β-lg, and NC@β-lg, respectively. Aggregation-caused quenching(ACQ)probes enabled the identification of intact nanoparticles, which were used to investigate the in vivo and intracellular fates of the lipid nanoparticles. In vitro digestion/lipolysis and ex vivo imaging confirmed delayed lipolysis from β-lg stabilized lipid nanoparticles. NC@β-lg was more resistant to intestinal lipolysis than NE@β-lg due to the Ca^(2+)-induced crosslinking. Live imaging revealed the transepithelial transport of intact nanoparticles and their accumulation in the liver. Cellular studies confirmed the uptake of intact nanoparticles. Slowing down lipolysis via food proteins represents a good strategy to enhance the oral absorption of lipid nanoparticles and thus co-formulated biomacromolecules.展开更多
J-aggregation and H-aggregation are identified as two classical models of function-ally oriented non-covalent interactions,and significant attention has been drawn by researchers.However,due to the scarcity of single-...J-aggregation and H-aggregation are identified as two classical models of function-ally oriented non-covalent interactions,and significant attention has been drawn by researchers.However,due to the scarcity of single-crystal examples of H-aggregation,a comprehensive understanding of the relationship between its stacking mode and optical behaviour has been hindered.In recent studies,two polyaromatic Schiff base compounds,Cl-Salmphen and H-Salmphen,were successfully synthe-sized,and both were found to exhibit H-aggregation.In thefindings,H-Salmphen was shown to display typical C─H···πinteractions,characteristic of Aggregation-Induced Emission(AIE)active molecules,whereas its halogenated counterpart was identified as behaving similar to Aggregation-Caused Quenching(ACQ)active molecules.These types of results suggest that identical intermolecular interactions can produce differing optical behaviours.Light was shed,at least in part,on the for-mation mechanisms of H-type aggregates and their luminescence properties from these observations.Additionally,the high optical signal-to-noise ratio inherent to H-aggregates was utilized for the exploration of water content detection.As an outcome,a high-performancefluorescentfilter paper was developed,enabling easy real-time detection using a smartphone.展开更多
The aggregation-caused quenching(ACQ)rationale has been employed to improve the fluorescence imaging accuracy of nanocarriers by precluding free probe-derived interferences.However,its usefulness is undermined by limi...The aggregation-caused quenching(ACQ)rationale has been employed to improve the fluorescence imaging accuracy of nanocarriers by precluding free probe-derived interferences.However,its usefulness is undermined by limited penetration and low spatiotemporal resolution of NIR-Ⅰ(700-900 nm)bioimaging owing to absorption and diffraction by biological tissues and tissue-derived autofluorescence.This study aimed to develop ACQ-based NIR-Ⅱ(1000-1700 nm)probes to further improve the imaging resolution and accuracy.The strategy employed is to install highly planar and electron-rich julolidine into the 3,5-position of aza-BODIPY based on the larger substituent effects.The newly developed probes displayed remarkable photophysical properties,with intense absorption centered at approximately 850 nm and bright emission in the 950-1300 nm region.Compared with the NIR-Ⅰ counterpart P2,the NIR-Ⅱ probes demonstrated superior water sensitivity and quenching stability.ACQ1 and ACQ6 exhibited more promising ACQ effects with absolute fluorescence quenching at water fractions above 40% and higher quenching stability with less than 2.0% fluorescence reillumination in plasma after 24 h of incubation.Theoretical calculations verified that molecular planarity is more important than hydrophobicity for ACQ properties.Additionally,in vivo and ex vivo reillumination studies revealed less than 2.5% signal interference from prequenched ACQ1,in contrast to 15% for P2.展开更多
Multiresonant thermally activated delayedfluorescence(MR-TADF)emitters have been the focus of extensive design efforts as they are recognized to show bright,narrowband emission,which makes them very appealing for displ...Multiresonant thermally activated delayedfluorescence(MR-TADF)emitters have been the focus of extensive design efforts as they are recognized to show bright,narrowband emission,which makes them very appealing for display applications.However,the planar geometry and relatively large singlet–triplet energy gap lead to,respectively,severe aggregation-caused quenching(ACQ)and slow reverse intersys-tem crossing(RISC).Here,a design strategy is proposed to address both issues.Two MR-TADF emitters triphenylphosphine oxide(TPPO)-tBu-DiKTa and tripheny-lamine(TPA)-tBu-DiKTa have been synthesized.Twisted ortho-substituted groups help increase the intermolecular distance and largely suppress the ACQ.In addition,the contributions from intermolecular charge transfer states in the case of TPA-tBu-DiKTa help to accelerate RISC.The organic light-emitting diodes(OLEDs)with TPPO-tBu-DiKTa and TPA-tBu-DiKTa exhibit high maximum external quan-tum efficiencies(EQEmax)of 24.4%and 31.0%,respectively.Notably,the device with 25 wt%TPA-tBu-DiKTa showed both high EQEmax of 28.0%and reduced efficiency roll-off(19.9%EQE at 1000 cd m^(-2))compared to the device with 5 wt%emitter(31.0%EQEmax and 11.0%EQE at 1000 cd m^(-2)).The new emitters were also introduced into single-layer light-emitting electrochemical cells(LECs),equipped with air-stable electrodes.The LEC containing TPA-tBu-DiKTa dispersed at 0.5 wt%in a matrix comprising a mobility-balanced blend-host and an ionic liq-uid electrolyte delivered blue luminance with an EQEmax of 2.6%at 425 cd m^(-2).The high efficiencies of the OLEDs and LECs with TPA-tBu-DiKTa illustrate the potential for improving device performance when the DiKTa core is decorated with twisted bulky donors.展开更多
Self-microemulsifying drug delivery systems(SMEDDSs)have recently returned to the limelight of academia and industry due to their enormous potential in oral delivery of biomacromolecules.However,information on gastroi...Self-microemulsifying drug delivery systems(SMEDDSs)have recently returned to the limelight of academia and industry due to their enormous potential in oral delivery of biomacromolecules.However,information on gastrointestinal lipolysis and trans-epithelial transport of SMEDDS is rare.Aggregation-caused quenching(ACQ)fuorescent probes are utilized to visualize the in vivo behaviors of SMEDDSs,because the released probes during lipolysis are quenched upon contacting water.Two SMEDDSs composed of medium chain triglyceride and different ratios of Tween-80 and PEG-400 are set as models,meanwhile Neoral?was used as a control.The SMEDDS droplets reside in the digestive tract for as long as 24 h and obey frst order kinetic law of lipolysis.The increased chain length of the triglyceride decreases the lipolysis of the SMEDDSs.Ex vivo imaging of main tissues and histological examination confrm the trans-epithelial transportation of the SMEDDS droplets.Approximately 2%-4%of the given SMEDDSs are transported via the lymph route following epithelial uptake,while liver is the main termination.Caco-2 cell lines confrm the cellular uptake and trans-epithelial transport.In conclusion,a fraction of SMEDDSs can survive the lipolysis in the gastrointestinal tract,permeate across the epithelia,translocate via the lymph,and accumulate mainly in the liver.展开更多
In vitro-in vivo correlation(IVIVC)of solid dosage forms should be established basically between in vitro and in vivo dissolution of active pharmaceutical ingredients.Nevertheless,in vivo dissolution profles have neve...In vitro-in vivo correlation(IVIVC)of solid dosage forms should be established basically between in vitro and in vivo dissolution of active pharmaceutical ingredients.Nevertheless,in vivo dissolution profles have never been accurately portrayed.The current practice of IVIVC has to resort to in vivo absorption fractions(Fa).In this proof-of-concept study,in vivo dissolution of a model poorly watersoluble drug fenofbrate(FNB)was investigated by fuorescence bioimaging.FNB crystals were frst labeled by near-infrared fuorophores with aggregation-caused quenching properties.The dyes illuminated FNB crystals but quenched immediately and absolutely once been released into aqueous media,enabling accurate monitoring of residual drug crystals.The linearity established between fuorescence and crystal concentration justifed reliable quantifcation of FNB crystals.In vitro dissolution was frst measured following pharmacopoeia monograph protocols with well-documented IVIVC.The synchronicity between fuorescence and in vitro dissolution of FNB supported using fuorescence as a measure for determination of dissolution.In vitro dissolution correlated well with in vivo dissolution,acquired by either live or ex vivo imaging.The newly established IVIVC was further validated by correlating both in vitro and in vivo dissolution with Faobtained from pharmacokinetic data.展开更多
Organic fluorophores play essential roles in both academic and applied fields.Most of the fluorescent molecules can be divided into aggregation-caused quenching(ACQ)and aggregation-induced emission(AIE)types based on ...Organic fluorophores play essential roles in both academic and applied fields.Most of the fluorescent molecules can be divided into aggregation-caused quenching(ACQ)and aggregation-induced emission(AIE)types based on the diverse emission properties in solution and aggregated states.Currently,a large part of studies focuses on the ACQ-to-AIE one-way transformation and the complex synthesis of chemical bonds is inevitable in all existing methods.To maximize the advantages of ACQ and AIE types fluorophores and avoid complex chemosynthesis,we propose a facile strategy first realizing the reversible ACQAIE transformation with the dynamic Diels-Alder(DA)reactions.Besides,the fluorescent platform can monitor DA reactions in microscale ultra-sensitively and quantitively.The dynamic covalent bonds can help to develop novel fluorophores creatively,and the reversible ACQ-AIE platform is expected to offer fresh insights into the dynamic covalent chemistry.展开更多
Due to the overwhelming percentage of poorly water-soluble drugs,pharmaceutical industry is in urgent need of efficient approaches for solubilization and permeability improvement.Salts consisting of lipophilic fatty a...Due to the overwhelming percentage of poorly water-soluble drugs,pharmaceutical industry is in urgent need of efficient approaches for solubilization and permeability improvement.Salts consisting of lipophilic fatty acid anions and hydrophilic choline cations are found to be surface active and able to form ionic co-aggregates(ICAs)in water.Choline oleate-based ICAs significantly enhance oral absorption of paclitaxel(PTX)as compared with cremophor EL-based micelles(MCs).Aggregation-caused quenching probes enable tracking of intact ICAs in in vivo transport and cellular interaction.Prolonged intestinal retention of ICAs than MCs implies stronger solubilizing capability in vivo.Ex vivo imaging of major organs and intestinal tracts suggests transepithelial transport of intact ICAs.Cellular studies support the enhanced absorption of PTX and transmembrane transport of intact ICAs.In conclusion,ICAs,consisting of lipophilic ions and hydrophilic counter-ions,are of great potential in delivery of poorly water-soluble drugs by enhancing solubility and permeability.展开更多
The long-circulating effect is revisited by simultaneous monitoring of the drug payloads and nanocarriers following intravenous administration of doxorubicin(DOX)-loaded methoxy polyethylene glycol-polycaprolactone(mP...The long-circulating effect is revisited by simultaneous monitoring of the drug payloads and nanocarriers following intravenous administration of doxorubicin(DOX)-loaded methoxy polyethylene glycol-polycaprolactone(mPEG-PCL) nanoparticles. Comparison of the kinetic profiles of both DOX and nanocarriers verifies the long-circulating effect, though of limited degree, as a result of pegylation. The nanocarrier profiles display fast clearance from the blood despite dense PEG decoration;DOX is cleared faster than the nanocarriers. The nanocarriers circulate longer than DOX in the blood, suggesting possible leakage of DOX from the nanocarriers. Hepatic accumulation is the highest among all organs and tissues investigated, which however is reversely proportionate to blood circulation time. Pegylation and reduction in particle size prove to extend circulation of drug nanocarriers in the blood with simultaneous decrease in uptake by various organs of the mononuclear phagocytic system. It is concluded that the long-circulating effect of mPEG-PCL nanoparticles is reconfirmed by monitoring of either DOX or the nanocarriers, but the faster clearance of DOX suggests possible leakage of a fraction of the payloads. The findings of this study are of potential translational significance in design of nanocarriers towards optimization of both therapeutic and toxic effects.展开更多
We computationally investigated the molecular aggregation effects on the excited state deactivation processes by considering both the direct vibrational relaxation and the S0/S1 surface crossing,that is,the minimum en...We computationally investigated the molecular aggregation effects on the excited state deactivation processes by considering both the direct vibrational relaxation and the S0/S1 surface crossing,that is,the minimum energy conical intersection(MECI).Taking classical AIEgens bis(piperidyl)anthracenes(BPAs)isomers and the substituted silole derivatives as examples,we show that the deformation ofMECI always occurs at the atom with greater hole/electron overlap.Besides,the energetic and structural changes of MECI caused by substituent has been investigated.We find that effective substituent such as the addition of the electron-donating groups,which can polarize the distribution of hole/electron density of molecules,will lead to the pyramidalization deformation of MECI occurring at the substituent position and simultaneously reduce the required energy to reach MECI.And MECI is sterically restricted by the surrounding molecules in solid phase,which remarkably hinders the non-radiative decay through surface crossing.Through quantitative computational assessments of the fluorescence quantum efficiency for both solution and solid phases,we elucidate the role of MECI and its dependence on the substitutions through pyramidalization deformation,which give rise to the aggregation-induced emission(AIE)phenomenon for 9,10-BPA,to aggregation-enhance emission(AEE)behavior for 1,4-BPA,and to conventional aggregation-caused quenching(ACQ)for 1,5-BPA.We further verify such mechanism for siloles,for which we found that the substitutions do not change the AIE behavior.Our findings render a general molecular design approach to manipulating the aggregation effect for optical emission.展开更多
One of the major obstacles of porphyrins is the aggregation-caused quenching(ACQ)of photoluminescence due to the strong intermolecularπ–πinteraction of the planar porphyrin core in the solid state.However,ACQ leads...One of the major obstacles of porphyrins is the aggregation-caused quenching(ACQ)of photoluminescence due to the strong intermolecularπ–πinteraction of the planar porphyrin core in the solid state.However,ACQ leads to the nonradiative deactivation of the photoexcited states which results in short-lived charge-separated states and thus low photoluminescence and singlet quantum yields.This phenomenon would limit the utilization of porphyrins in near-infrared fluorescent bioimaging,photodynamic therapy,photocatalytic hydrogen evolution,electrochemiluminescence,and chiroptical applications.Hence,to address the ACQ property of porphyrins and enhance the performance of the above applications,a limited number of AIEgen-decorated porphyrins have been designed,synthesized,and tested for their applications.It has been found that the introduction of AIEgens,such as tetraphenylethylene,diphenylacrylonitrile,(3,6-bis-(1-methyl-4-vinylpyridinium)-carbazole diiodide,and iridium motif into the porphyrin core,transformed the porphyrins from ACQ to aggregation-induced emission(AIE)in their solid state due to the reduced strong intermolecularπ–πstacking of porphyrins.Consequently,such porphyrins containing AIE features are employed as potential candidates in the above-mentioned applications.In this review,we summarize the AIEgen-decorated porphyrins which have been published to date,and also discuss the benefits of converting porphyrins from ACQ to AIE for enhanced performance within each application.As far as we know,there is no review that summarizes the structures and applications of AIEgen-decorated porphyrins to date.Therefore,we presume that this review would be helpful to design more efficient AIEgen-decorated porphyrins for a wide range of applications in the future.展开更多
基金supported by the National Natural Science Foundation of China(Nos.81872815,81573363,81690263,21372063)the Natural Science Foundation of Shanghai(No.16ZR1403500)
文摘Nanoemulsions(NEs) and nanosuspensions(NSs) show great potential in enhancing the ocular bioavailability of therapeutics through topical delivery. However, transocular fate of intact NEs and NSs is still inconclusive. In this study, an aggregation-caused quenching fluorescent probe is used to track precorneal retention and transocular transportation of intact NEs and NSs, while coumarin 6 is used to mimick the cargo. NEs show superior precorneal retention to NSs. Both the two types of nanocarriers can permeate into but not across the cornea. The smaller NEs(100 nm) permeate better into the cornea than the bigger ones(210 nm). Nanocarriers in the cornea serves as depots. The released cargo molecules can penetrate across the cornea and diffuse into the lens. Moreover, the conjunctiva-scleral route may be potential to deliver drugs to the back of the eye, In conclusion, the study provides useful tools and information in the field of transocular transportation of nanoparticles.
基金supported by the National Natural Science Foundation of China(Nos.81873092,81573697,82174074,81803741)。
文摘Intravenous nanosuspensions are attracted growing attention as a viable strategy for development of intravenous formulations of poorly water-soluble drugs.However,only few information about the biological fate of intravenous nanosuspensions is currently known,especially amorphous nanosuspensions are not reported yet.In this study,the in vivo fate of herpetrione(HPE)amorphous nanosuspensions following intravenous administration was explored by using an aggregation-caused quenching(ACQ)probe and HPLC methods.The ACQ probe is physically embedded into HPE nanoparticles via anti-solvent method to form HPE hybrid nanosuspensions(HPE-HNSs)for bioimaging.HPE-HNSs emit strong and stable fluorescence,but fluorescence quenches immediately upon the dissolution of HPE-HNSs,confirming the selfdiscrimination of HPE-HNSs.Following intravenous administration of HPE-HNSs,integral HPE-HNSs and HPE show similar degradation and biodistribution,with rapid clearance from blood circulation and obvious accumulation in liver and lung.Due to the slower dissolution and enhanced recognition by reticuloendothelial system,450 nm HPE-HNSs accumulate more in liver,lung and spleen than that of 200 nm HPE-HNSs.These results demonstrate that integral HPE-HNSs determine the in vivo performance of HPEHNSs.This study provides insight into the in vivo fate of intravenous amorphous nanosuspensions.
基金supported by National Natural Science Foundation of China,Grant/Award Number:82373166The Science and Technology Development Fund of Macao SAR,Grant/Award Number:0090/2022/A+3 种基金Guangdong Basic and Applied Basic Research Foundation,Grant/Award Numbers:2020A1515110640 and 2023A1515012320Youth Medical Innovation and Practice Research Program of Guangzhou,Grant/Award Number:2023QNYXYB012Science and Technology Projects in Guangzhou,Grant/Award Numbers:2023A03J0965 and 2023A03J0969Guangzhou Science and Technology Plan project,Grant/Award Number:202201020346.
文摘The efficacy of photothermal therapy(PTT)in antitumor applications is often limited by inadequate tumor targeting and low photothermal conversion efficiency(PCE)of photosensitizers.In this study,we designed a photothermal nanoparticle,MPF@IR780,to enhance photosensitizers’targeting and PCE.First,MPF@IR780 improves the delivery of photosensitizers to tumor tissue through the enhanced permeability and retention(EPR)effect.Furthermore,hydrophobic ferrocene was incorporated into the nanoparticle core to increase structural compactness,leading to a strong aggregation-caused quenching(ACQ)effect and an improved PCE of the photosensitizer under near-infrared(NIR)irradiation.Mechanistically,MPF@IR780 induces PANoptosis and ferroptosis in cancer cells through thermal damage and oxidative stress,providing an efficient approach for oncotherapy.This strategy of amplifying the effects of PTT by enhancing the ACQ of photosensitizers offers a promising method for advancing the next generation of PTT.
基金Shanghai Municipal Commission of Science and Technology,Grant/Award Numbers:21430760800,19XD1400300National Natural Science Foundation of China,Grant/Award Numbers:81872826,81872815,81973247,82030107。
文摘Environment-responsive fluorophores with aggregation-caused quenching(ACQ)properties have been applied to track nanocarriers with reduced artefacts caused by unbound or free fluorophores but suffer from incomplete fluorescence quenching and significant re-illumination,which undermine bioimaging accuracy.Herein,through structural modifications to reinforce the hydrophobicity,planarity and rigidity of fluorophores with an aza-BODIPY framework,probes featuring absolute ACQ(aACQ)and negligible re-illumination are developed and evaluated in various nanocarriers.aACQ probes,FD-B21 and FD-C7,exhibit near-infrared emission,high quantum yield,photostability,water sensitivity,and negligible re-illumination in blood,plasma and 1%Tween-80 in contrast to ACQ probe P2 and conventional probe DiR.All nanocarriers can be labeled efficiently by the tested fluorophores.Polymeric micelles(PMs)labeled by different aACQ probes manifest similar biodistribution patterns,which however differ from that of DiR-labeled PMs and could be ascribed to the appreciable re-illumination of DiR.Significantly lower re-illumination is also found in aACQ probes(2%-3%)than DiR(20%-40%)in Caco-2,Hela,and Raw264.7 cells.Molecular dynamics simulations unravel the molecular mechanisms behind aggregation and re-illumination,supporting the hypothesis of planarity dependency.It is concluded that aACQ fluorophores demonstrate excellent water sensitivity and negligible fluorescence re-illumination,making themselves useful tools for more accurate bioimaging of nanocarriers.
基金National Natural Science Foundation of China,Grant/Award Numbers:81872815,82030107,81690263Science and Technology Commission of Shanghai Municipality,Grant/Award Number:19XD1400300。
文摘Probing the onset of micellization,or determining the critical micelle concentration(CMC),is of crucial importance while remains to be challenged by growing demand for extraordinary sensitivity and accuracy.Although fluorometry has attracted wide attention owing to its superiority in simplicity and sensitivity over other methods,the presence and fluctuation of background fluorescence of conventional fluorescent probes undermine the accuracy of CMC determination.Herein,a series of novel fluorescent probes without background fluorescence at a concentration below CMC owing to absolute aggregation-caused quenching(aACQ)are utilized for sensitive and accurate measurement of CMC.The aACQ probes aggregate spontaneously and instantly in an aqueous environment owing to molecular π-π stacking with fluorescence quenching absolutely.Therefore,the absence of background fluorescence at a concentration below CMC clears relevant interference associated with conventional fluorophores.In this study,the new method is applied for versatile surfactants with CMCs ranging from nanomolar to millimolar concentrations,especially copolymers with ultralow CMC.The higher sensitivity and accuracy are highlighted by comparison with conventional probes.
基金European Research Council ERC Consolidator grant Bright Sens,Grant/Award Number:648528。
文摘Dye-loaded polymeric nanoparticles(NPs)are promising bioimaging agents because of their available surface chemistry,high brightness,and tunable optical properties.However,high dye loadings can cause the aggregation-caused quenching(ACQ)of the encapsulated fluorophores.Previously,we proposed to mitigate the ACQ inside polymeric NPs by insulating cationic dyes with bulky hydrophobic counterions.In order to implement new functionalities into dye-loaded NPs,here,we extend the concept of bulky counterions to anionic lanthanide-based complexes.We show that by employing Gd-based counterions with octadecyl rhodamine B loaded NPs at 30 wt% versus polymer,the fluorescence quantum yield can be increased to 10-fold(to 0.34).Moreover,Gd-anion provides NPs with enhanced contrast in electron microscopy.A combination of a luminescent Eu-based counterion with a far-red to near-infrared cyanine 5 dye(DiD)yields Forster resonance energy transfer NPs,where the UV-excited Eu-based counterion transfers energy to DiD,generating delayed fluorescence and large stokes shift of -340 nm.Cellular studies reveal low cytotoxicity of NPs and their capacity to internalize without detectable dye leakage,in contrast to leaky NPs with small counterions.Our findings show that the aggregation behavior of cationic dyes in the polymeric NPs can be controlled by bulky lanthanide anions,which will help in developing bright luminescent multifunctional nanomaterials.
基金funded by the Science and Technology Committee of Shanghai Municipality (Nos.19430741400, 23S11901500,23ZR1413100, and 21430760800)the National Natural Science Foundation of China (Nos.81973247 and 82030107)。
文摘Lipid-based nanocarriers have staged a remarkable comeback in the oral delivery of proteins and peptides, but delivery efficiency is compromised by lipolysis. β-Lactoglobulin(β-lg) stabilized lipid nanoparticles, including nanoemulsions(NE@β-lg) and nanocapsules(NC@β-lg), were developed to enhance the oral absorption of insulin by slowing down lipolysis due to the protection from β-lg. Cremophor EL stabilized nanoemulsions(NE@Cre-EL) were prepared and set as a control. The lipid nanoparticles produced mild and sustained hypoglycemic effects, amounting to oral bioavailability of 3.0% ± 0.3%, 7.0% ± 1.1%, and7.7% ± 0.8% for NE@Cre-EL, NE@β-lg, and NC@β-lg, respectively. Aggregation-caused quenching(ACQ)probes enabled the identification of intact nanoparticles, which were used to investigate the in vivo and intracellular fates of the lipid nanoparticles. In vitro digestion/lipolysis and ex vivo imaging confirmed delayed lipolysis from β-lg stabilized lipid nanoparticles. NC@β-lg was more resistant to intestinal lipolysis than NE@β-lg due to the Ca^(2+)-induced crosslinking. Live imaging revealed the transepithelial transport of intact nanoparticles and their accumulation in the liver. Cellular studies confirmed the uptake of intact nanoparticles. Slowing down lipolysis via food proteins represents a good strategy to enhance the oral absorption of lipid nanoparticles and thus co-formulated biomacromolecules.
基金the Program for Innovative Research Team(in Science and Technology)in Universities of Yunnan Province(IRTSTYN),the Recruitment Program of Yunnan Province Experts Provincial Young Talents(2019HB098)the Ten-Thousand Talents Program of Yunnan Province(YNWR-QNBJ-2018-273).
文摘J-aggregation and H-aggregation are identified as two classical models of function-ally oriented non-covalent interactions,and significant attention has been drawn by researchers.However,due to the scarcity of single-crystal examples of H-aggregation,a comprehensive understanding of the relationship between its stacking mode and optical behaviour has been hindered.In recent studies,two polyaromatic Schiff base compounds,Cl-Salmphen and H-Salmphen,were successfully synthe-sized,and both were found to exhibit H-aggregation.In thefindings,H-Salmphen was shown to display typical C─H···πinteractions,characteristic of Aggregation-Induced Emission(AIE)active molecules,whereas its halogenated counterpart was identified as behaving similar to Aggregation-Caused Quenching(ACQ)active molecules.These types of results suggest that identical intermolecular interactions can produce differing optical behaviours.Light was shed,at least in part,on the for-mation mechanisms of H-type aggregates and their luminescence properties from these observations.Additionally,the high optical signal-to-noise ratio inherent to H-aggregates was utilized for the exploration of water content detection.As an outcome,a high-performancefluorescentfilter paper was developed,enabling easy real-time detection using a smartphone.
基金supported by the National Natural Science Foundation of China(Nos.82273867 and 82030107)the Science and Technology Commission of Shanghai Municipality(No.21430760800,China).
文摘The aggregation-caused quenching(ACQ)rationale has been employed to improve the fluorescence imaging accuracy of nanocarriers by precluding free probe-derived interferences.However,its usefulness is undermined by limited penetration and low spatiotemporal resolution of NIR-Ⅰ(700-900 nm)bioimaging owing to absorption and diffraction by biological tissues and tissue-derived autofluorescence.This study aimed to develop ACQ-based NIR-Ⅱ(1000-1700 nm)probes to further improve the imaging resolution and accuracy.The strategy employed is to install highly planar and electron-rich julolidine into the 3,5-position of aza-BODIPY based on the larger substituent effects.The newly developed probes displayed remarkable photophysical properties,with intense absorption centered at approximately 850 nm and bright emission in the 950-1300 nm region.Compared with the NIR-Ⅰ counterpart P2,the NIR-Ⅱ probes demonstrated superior water sensitivity and quenching stability.ACQ1 and ACQ6 exhibited more promising ACQ effects with absolute fluorescence quenching at water fractions above 40% and higher quenching stability with less than 2.0% fluorescence reillumination in plasma after 24 h of incubation.Theoretical calculations verified that molecular planarity is more important than hydrophobicity for ACQ properties.Additionally,in vivo and ex vivo reillumination studies revealed less than 2.5% signal interference from prequenched ACQ1,in contrast to 15% for P2.
基金Engineering and Physical Sciences Research Council,Grant/Award Numbers:EP/R035164/1,EP/W007517/1,EP/W015137/1China Scholarship Council,Grant/Award Number:202006250026+3 种基金Swedish Energy Agency,Grant/Award Numbers:50779-1,P2021-00032Swedish Research Council,Grant/Award Numbers:2019-02345,2021-04778European Research Council,Grant/Award Number:101096650Knut och Alice Wallenbergs Stiftelse,Grant/Award Number:WISE-AP01-D02。
文摘Multiresonant thermally activated delayedfluorescence(MR-TADF)emitters have been the focus of extensive design efforts as they are recognized to show bright,narrowband emission,which makes them very appealing for display applications.However,the planar geometry and relatively large singlet–triplet energy gap lead to,respectively,severe aggregation-caused quenching(ACQ)and slow reverse intersys-tem crossing(RISC).Here,a design strategy is proposed to address both issues.Two MR-TADF emitters triphenylphosphine oxide(TPPO)-tBu-DiKTa and tripheny-lamine(TPA)-tBu-DiKTa have been synthesized.Twisted ortho-substituted groups help increase the intermolecular distance and largely suppress the ACQ.In addition,the contributions from intermolecular charge transfer states in the case of TPA-tBu-DiKTa help to accelerate RISC.The organic light-emitting diodes(OLEDs)with TPPO-tBu-DiKTa and TPA-tBu-DiKTa exhibit high maximum external quan-tum efficiencies(EQEmax)of 24.4%and 31.0%,respectively.Notably,the device with 25 wt%TPA-tBu-DiKTa showed both high EQEmax of 28.0%and reduced efficiency roll-off(19.9%EQE at 1000 cd m^(-2))compared to the device with 5 wt%emitter(31.0%EQEmax and 11.0%EQE at 1000 cd m^(-2)).The new emitters were also introduced into single-layer light-emitting electrochemical cells(LECs),equipped with air-stable electrodes.The LEC containing TPA-tBu-DiKTa dispersed at 0.5 wt%in a matrix comprising a mobility-balanced blend-host and an ionic liq-uid electrolyte delivered blue luminance with an EQEmax of 2.6%at 425 cd m^(-2).The high efficiencies of the OLEDs and LECs with TPA-tBu-DiKTa illustrate the potential for improving device performance when the DiKTa core is decorated with twisted bulky donors.
基金supported by the National Natural Science Foundation of China(Nos.82030107,81973247,81872815,81872826,and 81690263)Science and Technology Commission of Shanghai Municipality(Nos.19XD1400300,19430741400,and 19410761200,China)。
文摘Self-microemulsifying drug delivery systems(SMEDDSs)have recently returned to the limelight of academia and industry due to their enormous potential in oral delivery of biomacromolecules.However,information on gastrointestinal lipolysis and trans-epithelial transport of SMEDDS is rare.Aggregation-caused quenching(ACQ)fuorescent probes are utilized to visualize the in vivo behaviors of SMEDDSs,because the released probes during lipolysis are quenched upon contacting water.Two SMEDDSs composed of medium chain triglyceride and different ratios of Tween-80 and PEG-400 are set as models,meanwhile Neoral?was used as a control.The SMEDDS droplets reside in the digestive tract for as long as 24 h and obey frst order kinetic law of lipolysis.The increased chain length of the triglyceride decreases the lipolysis of the SMEDDSs.Ex vivo imaging of main tissues and histological examination confrm the trans-epithelial transportation of the SMEDDS droplets.Approximately 2%-4%of the given SMEDDSs are transported via the lymph route following epithelial uptake,while liver is the main termination.Caco-2 cell lines confrm the cellular uptake and trans-epithelial transport.In conclusion,a fraction of SMEDDSs can survive the lipolysis in the gastrointestinal tract,permeate across the epithelia,translocate via the lymph,and accumulate mainly in the liver.
基金supported by the National Natural Science Foundation of China(Nos.81973247,81872815,81872826 and 81690263)Science and Technology Commission of Shanghai Municipality(19XD1400300,China)。
文摘In vitro-in vivo correlation(IVIVC)of solid dosage forms should be established basically between in vitro and in vivo dissolution of active pharmaceutical ingredients.Nevertheless,in vivo dissolution profles have never been accurately portrayed.The current practice of IVIVC has to resort to in vivo absorption fractions(Fa).In this proof-of-concept study,in vivo dissolution of a model poorly watersoluble drug fenofbrate(FNB)was investigated by fuorescence bioimaging.FNB crystals were frst labeled by near-infrared fuorophores with aggregation-caused quenching properties.The dyes illuminated FNB crystals but quenched immediately and absolutely once been released into aqueous media,enabling accurate monitoring of residual drug crystals.The linearity established between fuorescence and crystal concentration justifed reliable quantifcation of FNB crystals.In vitro dissolution was frst measured following pharmacopoeia monograph protocols with well-documented IVIVC.The synchronicity between fuorescence and in vitro dissolution of FNB supported using fuorescence as a measure for determination of dissolution.In vitro dissolution correlated well with in vivo dissolution,acquired by either live or ex vivo imaging.The newly established IVIVC was further validated by correlating both in vitro and in vivo dissolution with Faobtained from pharmacokinetic data.
基金supported by the National Natural Science Foundation of China(21788102)。
文摘Organic fluorophores play essential roles in both academic and applied fields.Most of the fluorescent molecules can be divided into aggregation-caused quenching(ACQ)and aggregation-induced emission(AIE)types based on the diverse emission properties in solution and aggregated states.Currently,a large part of studies focuses on the ACQ-to-AIE one-way transformation and the complex synthesis of chemical bonds is inevitable in all existing methods.To maximize the advantages of ACQ and AIE types fluorophores and avoid complex chemosynthesis,we propose a facile strategy first realizing the reversible ACQAIE transformation with the dynamic Diels-Alder(DA)reactions.Besides,the fluorescent platform can monitor DA reactions in microscale ultra-sensitively and quantitively.The dynamic covalent bonds can help to develop novel fluorophores creatively,and the reversible ACQ-AIE platform is expected to offer fresh insights into the dynamic covalent chemistry.
基金supported by the National Natural Science Foundation of China(Nos.82030107,81973247,81872815,81872826,and 81690263)Science and Technology Commission of Shanghai Municipality(Nos.19XD1400300,19430741400,and 19410761200,China).
文摘Due to the overwhelming percentage of poorly water-soluble drugs,pharmaceutical industry is in urgent need of efficient approaches for solubilization and permeability improvement.Salts consisting of lipophilic fatty acid anions and hydrophilic choline cations are found to be surface active and able to form ionic co-aggregates(ICAs)in water.Choline oleate-based ICAs significantly enhance oral absorption of paclitaxel(PTX)as compared with cremophor EL-based micelles(MCs).Aggregation-caused quenching probes enable tracking of intact ICAs in in vivo transport and cellular interaction.Prolonged intestinal retention of ICAs than MCs implies stronger solubilizing capability in vivo.Ex vivo imaging of major organs and intestinal tracts suggests transepithelial transport of intact ICAs.Cellular studies support the enhanced absorption of PTX and transmembrane transport of intact ICAs.In conclusion,ICAs,consisting of lipophilic ions and hydrophilic counter-ions,are of great potential in delivery of poorly water-soluble drugs by enhancing solubility and permeability.
基金supported by the National Natural Science Foundation of China(Nos.81872815,82030107,and 81690263)Science and Technology Commission of Shanghai Municipality(No.19XD1400300,China)。
文摘The long-circulating effect is revisited by simultaneous monitoring of the drug payloads and nanocarriers following intravenous administration of doxorubicin(DOX)-loaded methoxy polyethylene glycol-polycaprolactone(mPEG-PCL) nanoparticles. Comparison of the kinetic profiles of both DOX and nanocarriers verifies the long-circulating effect, though of limited degree, as a result of pegylation. The nanocarrier profiles display fast clearance from the blood despite dense PEG decoration;DOX is cleared faster than the nanocarriers. The nanocarriers circulate longer than DOX in the blood, suggesting possible leakage of DOX from the nanocarriers. Hepatic accumulation is the highest among all organs and tissues investigated, which however is reversely proportionate to blood circulation time. Pegylation and reduction in particle size prove to extend circulation of drug nanocarriers in the blood with simultaneous decrease in uptake by various organs of the mononuclear phagocytic system. It is concluded that the long-circulating effect of mPEG-PCL nanoparticles is reconfirmed by monitoring of either DOX or the nanocarriers, but the faster clearance of DOX suggests possible leakage of a fraction of the payloads. The findings of this study are of potential translational significance in design of nanocarriers towards optimization of both therapeutic and toxic effects.
基金National Natural Science Foundation of China,Grant/Award Numbers:21788102,2017YFA0204501。
文摘We computationally investigated the molecular aggregation effects on the excited state deactivation processes by considering both the direct vibrational relaxation and the S0/S1 surface crossing,that is,the minimum energy conical intersection(MECI).Taking classical AIEgens bis(piperidyl)anthracenes(BPAs)isomers and the substituted silole derivatives as examples,we show that the deformation ofMECI always occurs at the atom with greater hole/electron overlap.Besides,the energetic and structural changes of MECI caused by substituent has been investigated.We find that effective substituent such as the addition of the electron-donating groups,which can polarize the distribution of hole/electron density of molecules,will lead to the pyramidalization deformation of MECI occurring at the substituent position and simultaneously reduce the required energy to reach MECI.And MECI is sterically restricted by the surrounding molecules in solid phase,which remarkably hinders the non-radiative decay through surface crossing.Through quantitative computational assessments of the fluorescence quantum efficiency for both solution and solid phases,we elucidate the role of MECI and its dependence on the substitutions through pyramidalization deformation,which give rise to the aggregation-induced emission(AIE)phenomenon for 9,10-BPA,to aggregation-enhance emission(AEE)behavior for 1,4-BPA,and to conventional aggregation-caused quenching(ACQ)for 1,5-BPA.We further verify such mechanism for siloles,for which we found that the substitutions do not change the AIE behavior.Our findings render a general molecular design approach to manipulating the aggregation effect for optical emission.
基金Science,Technology and Innovation Committee of Shenzhen Municipality,Grant/Award Number:JCYJ20180507183413211RGC Senior Research Fellowship Scheme,Grant/Award Number:SRFS2021-5S01+3 种基金National Natural Science Foundation of China,Grant/Award Number:52073242Hong Kong Polytechnic UniversityGeneral Research Fund,Grant/Award Number:12304320Hong Kong Research Grants Council。
文摘One of the major obstacles of porphyrins is the aggregation-caused quenching(ACQ)of photoluminescence due to the strong intermolecularπ–πinteraction of the planar porphyrin core in the solid state.However,ACQ leads to the nonradiative deactivation of the photoexcited states which results in short-lived charge-separated states and thus low photoluminescence and singlet quantum yields.This phenomenon would limit the utilization of porphyrins in near-infrared fluorescent bioimaging,photodynamic therapy,photocatalytic hydrogen evolution,electrochemiluminescence,and chiroptical applications.Hence,to address the ACQ property of porphyrins and enhance the performance of the above applications,a limited number of AIEgen-decorated porphyrins have been designed,synthesized,and tested for their applications.It has been found that the introduction of AIEgens,such as tetraphenylethylene,diphenylacrylonitrile,(3,6-bis-(1-methyl-4-vinylpyridinium)-carbazole diiodide,and iridium motif into the porphyrin core,transformed the porphyrins from ACQ to aggregation-induced emission(AIE)in their solid state due to the reduced strong intermolecularπ–πstacking of porphyrins.Consequently,such porphyrins containing AIE features are employed as potential candidates in the above-mentioned applications.In this review,we summarize the AIEgen-decorated porphyrins which have been published to date,and also discuss the benefits of converting porphyrins from ACQ to AIE for enhanced performance within each application.As far as we know,there is no review that summarizes the structures and applications of AIEgen-decorated porphyrins to date.Therefore,we presume that this review would be helpful to design more efficient AIEgen-decorated porphyrins for a wide range of applications in the future.
