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.

基于AIE效应的内源性硫化氢荧光探针的研究进展

合理设计监测内源性硫化氢的荧光探针分子有助于充分了解其生理和病理功能.目前,在研的检测硫化氢的小分子荧光探针多存在聚集诱导猝灭效应,因此克服此缺陷的聚集诱导发光效应荧光探针的研究受到越来越多的关注.本文结合研究实践简要综述了近几年具有聚集诱导发光效应的化学反应型硫化氢活体成像荧光探针的研究进展及设计思想并进行展望,以期对该领域研究提供一些借鉴和思考.

Permeation into but not across the cornea:Bioimaging of intact nanoemulsions and nanosuspensions using aggregation-caused quenching probes

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.

Insight into the in vivo fate of intravenous herpetrione amorphous nanosuspensions by aggregation-caused quenching probes

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.

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.

Lanthanide-based bulky counterions against aggregation-caused quenching of dyes in fluorescent polymeric nanoparticles

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.

固液双态高效发光的液晶分子的合成、相结构及光物理性质

常见的有机发光分子主要有聚集导致猝灭(ACQ)分子和聚集诱导发光(AIE)分子。前者仅在单分子态(如稀溶液)高效发光,而后者仅在聚集态(如固态)高效发光。本工作中,我们合成了一种在稀溶液和聚集态均能高效发光的液晶分子(MS-12),并表征了其液晶性质和光物理性质。MS-12的两端为树枝单元,中间为长棒状的刚性核,可看作典型的Phasmid型液晶基元;刚性核由氰基二苯乙烯(AIE单元)和苯炔苯(ACQ单元)单元构成;由于氰基的强吸电子效应,MS-12具有D-A-π-A-D的结构特征。MS-12在固态形成六方柱状液晶相,单分子层厚度(~0.44 nm)的单胞内含有~4个分子;其在稀溶液态高效发光,在四氢呋喃中荧光量子产率(QY)~78.1%,在固态表现出AIE分子的性质,在本体液晶态的QY~59.6%。本研究为多态发光分子的设计,尤其是多态发光液晶分子的设计提供了有效的方案。

一种三态发光的液晶基元合成、自组装及光物理性质

聚集导致猝灭(ACQ)分子在单分子态(如稀溶液)高效发光,而聚集诱导发光(AIE)分子在聚集态(如固态)高效发光。这一单态发光的特性严重制约着发光材料的应用。本工作中,我们合成了一种三态(溶液、凝胶、液晶)发光的phasmid液晶基元(PHAgen-12),并考察了其自组装性质与光物理性质。PHAgen-12的两端为一代树枝单元,中间为“二苯基氰基乙烯(AIE)+二苯基丁二炔(ACQ)+二苯基氰基乙烯(AIE)”的刚性核,具有D-A-π-A-D的特征。该分子在普通溶剂(如THF、DCM)中可以溶解;在选择性溶剂烷烃中形成柱状胶束,并可凝胶化;在固态形成六方柱状液晶相,单分子层厚度(~0.44 nm)的单胞内含有~4个分子。PHAgen-12在单分子态表现出ACQ分子的性质,在氯仿中荧光量子产率(QY)为~90.3%;在聚集态表现出AIE性质,PHAgen-12/十二烷凝胶体系(质量百分比为30%)的QY为58.5%,本体液晶态的QY为85.5%。

Highly Fluorescent Conducting Polymer Hybrid Materials Based on Polyaniline-Polyethylene Glycol-Arsenic Sulphide

Highly fluorescent binary and ternary hybrid materials based on polyaniline, polyethylene glycol (PEG) and arsenic sulphide have been prepared via oxidative chemical polymerization and characterized by FT-IR and powder X-ray diffraction techniques. Thermogravimetric analysis showed that all the materials are thermally stable up to 250℃. The optical behaviour was investigated using UV-Vis. and fluorescence spectroscopy. Fluorescence spectra of polyaniline and its hybrids were found to be concentration dependent, and concentrations were optimized to achieve maximum intensity of emission. Aggregation caused quenching (ACQ) may be the possible reason for concentration dependent emission. Hybrids showed significantly enhanced fluorescence than polyaniline. The AC electrical conductivity was also measured and found to be better for hybrids than the polyaniline. In the PAni-PEG-As2S3 hybrid, the conductivity was found to be 9.57 × 10-1 S/cm at 100 KHz. This valuable improvement in luminescent property and conducting behaviour may be useful in various optoelectronic and electronic applications.

β-Lactoglobulin stabilized lipid nanoparticles enhance oral absorption of insulin by slowing down lipolysis

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.

Julolidinyl aza-BODIPYs as NIR-Ⅱ fluorophores for the bioimaging of nanocarriers

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.

基于有机小分子的聚集诱导猝灭(ACQ)-聚集诱导发射(AIE)转换研究进展

传统的有机荧光分子大多数具有不良的聚集诱导猝灭(ACQ)效应,限制了他们在很多领域的应用.因此,如何保持传统共轭分子功能特性的同时实现ACQ向聚集诱导发射(AIE)的转变具有十分重要的意义.近年来许多课题组在该领域做了大量的突破性工作,根据聚集诱导发射发光分子(AIEgen)的构建方式和结构特点,将其分为基于分子内运动受限(RIM)机理使用典型AIE基元(如四苯乙烯单元)修饰ACQ基元,以及基于RIM机理引入三苯胺或氰基乙烯等功能性单元实现零起点构建AIE分子两大类.在后者中,一些涉及同分异构与激发态分子内质子转移(ESIPT)机制的其他AIEgen体系的构建在近年比较突出.基于此分类,从AIEgen的结构、性能、机制和应用四个方面,重点综述了近5年国内外从ACQ分子出发合成AIE分子的构建策略.

“Living”fluorophores:thermo-driven reversible ACQ-AIE transformation and ultra-sensitive in-situ monitor for dynamic Diels-Alder reactions

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.

Substituent-controlled aggregate luminescence:Computational unraveling of S_(1)/S_(0)surface crossing

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.

An overview on AIEgen-decorated porphyrins:Current status and applications

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.

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.

Gastrointestinal lipolysis and trans-epithelial transport of SMEDDS via oral route

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.

An acid-triggered porphyrin-based block copolymer for enhanced photodynamic antibacterial efficacy

Bacterial infection, especially multidrug-resistant(MDR) bacterial infection has threatened public health drastically. Here, we fabricate an "acid-triggered" nanoplatform for enhanced photodynamic antibacterial activity by reducing the aggregation of photosensitizers(PSs) in bacterial acidic microenvironment. Specifically, a functional amphiphilic block copolymer was first synthesized by using a pH-sensitive monomer, 2-(diisopropylamino) ethyl methacrylate(DPA) and porphyrin-based methacrylate(TPPC6MA) with poly(oligo(ethylene glycol) methyl ether methacrylate)(POEGMA) as the macromolecular chain transfer agent, and POEGMA-b-[PDPA-co-PTPPC6MA] block copolymer was further self-assembled into spherical nanoparticles(PDPA-TPP). PDPA-TPP nanoparticles possess an effective electrostatic adherence to negatively charged bacterial cell membrane, since they could rapidly achieve positive charge in acidic bacterial media. Meanwhile, the acid-triggered dissociation of PDPA-TPP nanoparticles could reduce the aggregation caused quenching(ACQ) of the photosensitizers, leading to around 5 folds increase of the singlet oxygen(1O2) quantum yield. In vitro results demonstrated that the "acid-triggered" PDPA-TPP nanoparticles could kill most of MDR S. aureus(Gram-positive) and MDR E. coli(Gram-negative) by enhanced photodynamic therapy, and they could resist wound infection and accelerate wound healing effectively in vivo. Furthermore, PDPA-TPP nanoparticles could well disperse the biofilm and almost kill all the biofilm-containing bacteria. Thus, by making use of the bacterial acidic microenvironment, this "acid-triggered" nanoplatform in situ will open a new path to solve the aggregation of photosensitizers for combating broad-spectrum drug-resistant bacterial infection.

The long-circulating effect of pegylated nanoparticles revisited via simultaneous monitoring of both the drug payloads and nanocarriers

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.

Ionic co-aggregates(ICAs)based oral drug delivery:Solubilization and permeability improvement

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.