Near-infrared fluorophores with absolute aggregation-caused quenching and negligible fluorescence re-illumination for in vivo bioimaging of nanocarriers

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.

In vivo dissolution of poorly water-soluble drugs:Proof of concept based on fluorescence bioimaging

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.

Editorial of Special Issue of Hot Topic Reviews in Drug Delivery

Research in the cross-disciplines of drug delivery is developing at an accelerated speed never seen before,as witnessed by the soaring number of yearly publications.A quick search of the database of Web of Science by utilizing the keyword"drug delivery"gives a total number of 251,538,3385,13484,48550,129263 and 338627 publications by the year range of 1900e1960,1961e1970,1971e1980,1981e1990,1991e2000,2001e2010and 2011e2020,respectively.More impressively,there seems to be no sign of deceleration.

Accurate and sensitive probing of onset of micellization based on absolute aggregation-caused quenching effect

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.