Exploring the World of Curcumin: Photophysics, Photochemistry, and Applications in Nanoscience and Biology.

Curcumin is a bright yellow naturally occurring polyphenol which is the principal component of turmeric. It is used as herbal supplement, cosmetics ingredient, and food coloring agent. Over the years, the therapeutic properties of natural product curcumin have gone unexploited but not unnoticed. Curcumin cannot be employed as a drug due to limitations such as low aqueous solubility and limited bioavailability. Many attempts have been made to overcome these limitations by confining the drug in various confined media to enhance its bioavailability. The biomolecule is emissive and undergoes fundamental excited state processes such as solvation dynamics and excited state intramolecular proton transfer (ESIPT). Curcumin based biomaterials and nanomaterials are also a fast advancing field where curcumin is an intrinsic component necessary for formation of these materials and no longer added as an external free drug. In this review, we will summarise the recent research on the photophysical and photochemical properties of curcumin and its excited state dynamics in various bio-mimicking systems. At the same time we wish to also incorporate the various applications of curcumin, especially in biology. Lastly due to the growing importance of materials science, we will briefly discuss some recent advances on curcumin based biomaterials and nanomaterials.

Interactions between Lipid Vesicle Membranes and Single Amino Acid Fibrils: Probable Origin of Specific Neurological Disorders.

Amyloid fibrils are known to be responsible for several neurological disorders, like Alzheimer's disease (AD), Parkinson's disease (PD), etc. For decades, mostly proteins and peptide-based amyloid fibrils have been focused on, and the topic has acknowledged the rise, development, understanding of, and controversy, as well. However, the single amino acid based amyloid fibrils, responsible for several disorders, such as phenylketonuria, tyrosenimia type II, hypermethioninemia, etc., have gotten scientific attention lately. To understand the molecular level pathogenesis of such disorders originated due to the accumulation of single amino acid-based amyloid fibrils, interaction of these fibrils with phospholipid vesicle membranes is found to be an excellent cell-free in vitro setup. Based on such an in vitro setup, these fibrils show a generic mechanism of membrane insertion driven by electrostatic and hydrophobic effects inside the membrane that reduces the integral rigidity of the membrane. Alteration of such fundamental properties of the membrane, therefore, might be referred to as one of the prime pathological factors for the development of these neurological disorders. Hence, such interactions must be investigated in cellular and intracellular compartments to design suitable therapeutic modulators against fibrils.

Excited State Photophysics of Curcumin and its Modulation in Alkaline Non-Aqueous Medium.

Curcumin, a well-known medicinal pigment, has seen limited applications in biology despite having great potential as a therapeutic drug. Deprotonation is one of the possible ways to enhance solubility of curcumin in polar solvent. Here, we have explored the effect of deprotonation on the ultrafast dynamics of this biomolecule with the help of the time-resolved fluorescence spectroscopic measurements using the femtosecond fluorescence upconversion technique. The excited state photophysics of fully deprotonated curcumin significantly differs from that of neutral curcumin. We have observed that the completely deprotonated curcumin not only has higher quantum yield, but also higher excited state lifetime and slower solvation dynamics in comparison to neutral curcumin. We propose solvation dynamics and intramolecular charge transfer as the excited state processes associated with the radiative decay of the completely deprotonated molecule, while ruling out the possibility of excited state proton exchange or proton transfer. Our results are well supported by time-dependent density-functional theory calculations. Lastly, we have also demonstrated the possibility of modulating the ultrafast dynamics of fully deprotonated curcumin using non-aqueous alkaline binary solvent mixtures. We believe our results will provide significant physical insight towards unveiling the excited state dynamics of this molecule.

Ultrafast Dynamics of the Medicinal Pigment Curcumin inside the Imidazolium Surface Active Ionic Liquid Containing Giant Vesicles and White Light Generation via Triple-FRET Technique.

The naturally occurring yellow polyphenolic medicinal pigment curcumin shows ultrafast dynamics in the excited states. These ultrafast dynamics are strongly influenced by the rigidity of the environments of the systems. The present investigation unveils the ultrafast excited-state intramolecular hydrogen atom transfer (ESIHT) (which is involved in the antioxidant mechanism) and the solvation dynamics of curcumin inside the imidazolium surface active ionic liquid (SAIL), 1-hexadecyl-3-methylimidazolium chloride ([C16mim]Cl) micelle, and giant vesicles after introducing sorbitan monoesters (Span 20 and Span 80) in the aqueous medium. Interestingly, the short hydrocarbon chain containing Span 20 forms smaller, less rigid vesicles, and the long hydrocarbon chain containing Span 80 forms larger, more rigid giant vesicles after being assembled with [C16mim]Cl. The ESIHT and the solvation dynamics are slower in Span 80, containing rigid vesicles, than that in Span 20, comprising less rigid vesicles. Finally, we have established a three-component fluorescence resonance energy transfer (Triple-FRET) system to generate white light (WL) in the micelle and giant vesicles. Here the hydrophobic dye 1,6-diphenyl-1,3,5-hexatriene (DPH) acts as the donor, and the hydrophilic anticancer drug doxorubicin hydrochloride (DOX) serves as the acceptor along with the intermediate donor, curcumin. At a specific combination of the concentrations of these dyes in a particular self-assembled system, WL is generated due to the triple-FRET phenomena.

Insights into the Strong Emission Enhancement of Molecular Rotor Thioflavin T in Aqueous Cellulose Nanocrystal Dispersion: White Light Generation in Protein and Micellar Media.

Thioflavin t (THT) is a well-known molecular rotor extensively used to detect amyloid-like structures. But THT shows very weak emission in water. In this article, we have found that THT shows very strong emission in the presence of cellulose nanocrystals (CNCs). Steady-state and time-resolved emission techniques have been used to study the strong emission of THT in aqueous CNC dispersion. The time-resolved study showed that in the presence of CNCs, the lifetime increased by ∼1500 fold compared to pure water (<1 ps). To know the nature of interaction and also the reason for this increase in emission zeta potential, stimuli-dependent and temperature-dependent studies have been carried out. These studies proposed that electrostatic interaction is the main factor for this binding of THT with CNCs. Further, the addition of another anionic lipophilic dye, merocyanine 540 (MC540), with CNCs-THT in both BSA protein (CIE: 0.33, 0.32) and TX-100 micellar (4.5 mM) (CIE: 0.32, 0.30) solutions produced excellent white light emission. Lifetime decay and absorption studies proposed a possible fluorescence resonance energy transfer mechanism in this generation of white light emission.

Amyloids Formed by Nonaromatic Amino Acid Methionine and Its Cross with Phenylalanine Significantly Affects Phospholipid Vesicle Membrane: An Insight into Hypermethioninemia Disorder.

The incorrect metabolic breakdown of the nonaromatic amino acid methionine (Met) leads to the disorder called hypermethioninemia via an unknown mechanism. To understand the molecular level pathogenesis of this disorder, we prepared a DMPC lipid membrane, the mimicking setup of the cell membrane, and explored the effect of the millimolar level of Met on it. We found that Met forms toxic fibrillar aggregates that disrupt the rigidity of the membrane bilayer, and increases the dynamic response of water molecules surrounding the membrane as well as the heterogeneity of the membrane. Such aggregates strongly deform red blood cells. This opens the requirement to consider therapeutic antagonists either to resist or to inhibit the toxic amyloid aggregates against hypermethioninemia. Moreover, such disrupting effect on membrane bilayer and cytotoxicity along with deformation effect on RBC by the cross amyloids of Met and Phenylalanine (Phe) was found to be most virulent. This exclusive observation of the enhanced virulent effect of the cross amyloids is expected to be an informative asset to explain the coexistence of two amyloid disorders.

State of the Art and Perspectives on the Biofunctionalization of Fluorescent Metal Nanoclusters and Carbon Quantum Dots for Targeted Imaging and Drug Delivery.

The interface of nanobio science and cancer nanomedicine is one of the most important current frontiers in research, being full of opportunities and challenges. Ultrasmall fluorescent metal nanoclusters (MNCs) and carbon quantum dots (CQDs) have emerged as promising fluorescent nanomaterials due to their unique physicochemical and optical properties, facile surface functionalization, good photostability, biocompatibility, and aqueous dispersity. These characteristics make them advantageous over conventional fluorophores such as organic dye molecules and semiconductor quantum dots (QDs) for the detection, diagnosis, and treatment of various diseases including cancer. Recently, researchers have focused on the biofunctionalization strategy of the MNCs and CQDs which can tailor their physicochemical and biological properties and, in turn, can empower these biofunctionalized nanoprobes for diverse applications including imaging, drug delivery, theranostics, and other biomedical applications. In this invited feature article, we first discuss some fundamental structural and physicochemical characteristics of the fluorescent biocompatible quantum-sized nanomaterials which have some outstanding features for the development of multiplexed imaging probes, delivery vehicles, and cancer nanomedicine. We then demonstrate the diverse surface engineering of these fluorescent nanomaterials with reactive target specific functional groups which can help to construct multifunctional nanoprobes with improved targeting capabilities having minimal toxicity. The promising future of the biofunctionalized fluorescent quantum-sized nanomaterials in the field of bioanalytical and biomedical research is elaborately demonstrated, showing selected recent works with relevant applications. This invited feature article finally ends with a short discussion of the current challenges and future prospects of the development of these bioconjugated/biofunctionalized nanomaterials to provide insight into this burgeoning field of MNC- and CQD-based diagnostics and therapeutic applications.

A Comparative Study on DMSO-Induced Modulation of the Structural and Dynamical Properties of Model Bilayer Membranes.

Modulating the structures and properties of biomembranes via permeation of small amphiphilic molecules is immensely important, having diverse applications in cell biology, biotechnology, and pharmaceuticals, because their physiochemical and biological interactions lead to new pathways for transdermal drug delivery and administration. In this work, we have elucidated the role of dimethyl sulfoxide (DMSO), broadly used as a penetration-enhancing agent and cryoprotective agent on model lipid membranes, using a combination of fluorescence microscopy and time-resolved fluorescence spectroscopy. Spatially resolved fluorescence lifetime imaging microscopy (FLIM) has been employed to unravel how the fluidity of the DMSO-induced bilayer regulates the structural alteration of the vesicles. Moreover, we have also shown that the dehydration effect of DMSO leads to weakening of the hydrogen bond between lipid headgroups and water molecules and results in faster solvation dynamics as demonstrated by femtosecond time-resolved fluorescence spectroscopy. It has been gleaned that the water dynamics becomes faster because bilayer rigidity decreases in the presence of DMSO, which is also supported by time-resolved rotational anisotropy measurements. The enhanced diffusivity and increased membrane fluidity in the presence of DMSO are further ratified at the single-molecule level through fluorescence correlation spectroscopy (FCS) measurements. Our results indicate that while the presence of DMSO significantly affects the 1,2-dimyristoyl-rac-glycero-3-phosphocholine (DMPC) and 1,2-dipalmitoyl-rac-glycero-3-phosphatidylcholine (DPPC) bilayers, it has a weak effect on 1,2-dimyristoyl-sn-glycero-3-phospho-rac-glycerol (DMPG) vesicles, which might explain the preferential interaction of DMSO with the positively charged choline group present in DMPC and DPPC vesicles. The experimental findings have also been further verified with molecular dynamics simulation studies. Moreover, it has been observed that DMSO is likely to have a differential effect on heterogeneous bilayer membranes depending on the structure and composition of their headgroups. Our results illuminate the importance of probing the lipid structure and composition of cellular membranes in determining the effects of cryoprotective agents.

Modulation of Membrane Fluidity to Control Interfacial Water Structure and Dynamics in Saturated and Unsaturated Phospholipid Vesicles.

The structure and dynamics of interfacial water in biological systems regulate the biochemical reactions. But, it is still enigmatic how the behavior of the interfacial water molecule is controlled. Here, we have investigated the effect of membrane fluidity on the structure and dynamics of interfacial water molecules in biologically relevant phopholipid vesicles. This study delineates that modulation of membrane fluidity through interlipid separation and unsaturation not only mitigate membrane rigidity but also disrupt the strong hydrogen bond (H-bond) network around the lipid bilayer interface. As a result, a disorder in H-bonding between water molecules arises several layers beyond the first hydration shell of the polar headgroup, which essentially modifies the interfacial water structure and dynamics. Furthermore, we have also provided evidence of increasing transportation through these modulated membranes, which enhance the membrane mediated isomerization reaction rate.

Antagonist Effects of l-Phenylalanine and the Enantiomeric Mixture Containing d-Phenylalanine on Phospholipid Vesicle Membrane.

One of the congenital flaws of metabolism, phenylketonuria (PKU), is known to be related to the self-assembly of toxic fibrillar aggregates of phenylalanine (Phe) in blood at elevated concentrations. Our experimental findings using l-phenylalanine (l-Phe) at millimolar concentration suggest the formation of fibrillar morphologies in the dry phase, which in the solution phase interact strongly with the model membrane composed of 1,2-diacyl-sn-glycero-phosphocholine (LAPC) lipid, thereby decreasing the rigidity (or increasing the fluidity) of the membrane. The hydrophobic interaction, in addition to the electrostatic attraction of Phe with the model membrane, is found to be responsible for such phenomena. On the contrary, various microscopic observations reveal that such fibrillar morphologies of l-Phe are severely ruptured in the presence of its enantiomer d-phenylalanine (d-Phe), thereby converting the fibrillar morphologies into crushed flakes. Various biophysical studies, including the solvation dynamics experiment, suggest that this l-Phe in the presence of d-Phe, when interacting with the same model membrane, now reverts the rigidity of the membrane, i.e., increases the rigidity of the membrane, which was lost due to interaction with l-Phe exclusively. Fluorescence anisotropy measurements also support this reverse rigid character of the membrane in the presence of an enantiomeric mixture of amino acids. A comprehensive understanding of the interaction of Phe with the model membrane is further pursued at the single-molecular fluorescence detection level using fluorescence correlation spectroscopy (FCS) experiments. Therefore, our experimental conclusion interprets a linear correlation between increased permeability and enhanced fluidity of the membrane in the presence of l-Phe and certifies d-Phe as a therapeutic modulator of l-Phe fibrillar morphologies. Further, the study proposes that the rigidity of the membrane lost due to interaction with l-Phe was reinstated-in fact, increased-in the presence of the enantiomeric mixture containing both d- and l-Phe.

Denaturant-Mediated Modulation of the Formation and Drug Encapsulation Responses of Gold Nanoparticles.

The extensive and diversified applications of the well-known plasmonic nanoparticle systems along with their easy and environment-friendly synthesis strategies drive us to investigate in-depth this important research field. In the current scenario, our present study deals with an important plasmonic nanomaterial, i.e., globular protein, and human serum albumin (HSA)-conjugated gold nanoparticle (HSA-Au NP) system. The well-known chemical denaturants, urea and guanidine hydrochloride (GdnHCl or GnHCl), are investigated to show detrimental effects toward the formation of gold nanoparticles; however, the effect of GdnHCl is observed to be much prominent compared to that of urea. The synthesized nanoparticle system is found to be highly biocompatible from the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-based cytotoxicity assay, and therefore, the applications of encapsulation of the well-known anticancer drug molecule, doxorubicin hydrochloride (Dox), in the nanoparticle system are further studied. In this drug encapsulation study, drug-metal complexation between Dox and HAuCl4·3H2O has been discussed elaborately. Similar to the nanoparticle formation, the effects of denaturants on drug encapsulation have also been discovered, and interestingly, it has been observed that urea plays a positive role, whereas GdnHCl plays a negative or detrimental role toward drug encapsulation in the synthesized gold nanoparticle system. The detailed photophysical mechanisms behind the drug encapsulation in the synthesized plasmonic nanosystem at every stage have also been explored. Overall, this study will conclusively explain the influences of the extensively used chemical denaturants on the synthesis and drug encapsulation behaviors of a well-known protein-conjugated gold nanoparticle, and as a consequence, it can be highly useful and acceptable to the biomedical and pharmaceutical research communities.

Selective Self-Assembly of 5-Fluorouracil through Nonlinear Solvent Response Modulates Membrane Dynamics.

Controllable self-assembly and understanding of the interaction between single metabolite fibrils and live-cell membranes have paramount importance in providing minimal treatment in several neurodegenerative disorders. Here, utilizing the nonlinear nature and peculiar hydrogen bonding behavior of the dimethyl sulfoxide (DMSO)-water mixture, the selective self-assembly of a single metabolite 5-fluorouracil (5-FU) is achieved. A direct correlation between water availability and selective self-assembly of 5-FU is ratified from the excited-state dynamics. The specific fibrillar structures of 5-FU exhibit a great potential to modulate live cell membrane fluidity and model membrane lipid distribution. After 5-FU fibril addition, a disorder of H-bonded water molecules arises several layers beyond the first hydration shell of the polar headgroups, which essentially modifies interfacial water structure and dynamics. Overall, our results shed light on the role of solvent to govern specific self-assembly and also lay the foundation accounting for the earlier stage of several diseases and multidrug resistance.

Modulation of Membrane Fluidity Performed on Model Phospholipid Membrane and Live Cell Membrane: Revealing through Spatiotemporal Approaches of FLIM, FAIM, and TRFS.

We have elucidated the role of unsaturated fatty acid in the in vitro model phospholipid membrane and in vivo live cell membrane. Fluorescence microscopy and time-resolved fluorescence spectroscopy have been employed to uncover how modulation of vesicle bilayer fluidity persuades structural transformation. This unsaturation induced structural transformation due to packing disorder in bilayer has been delineated through spatially resolved fluorescence lifetime imaging microscopy (FLIM) and fluorescence polarization or anisotropy imaging microscopy (FPIM/FAIM). Structure-function relationship of phospholipid vesicle is also investigated by monitoring intervesicular water dynamics behavior, which has been demonstrated by temporally resolved fluorescence spectroscopy (TRFS) techniques. Nevertheless, it has also been manifested from this study that loss of rigidity in bilayer breaks down the strong hydrogen bond (H-bond) network around the charged lipid head groups. The disruption of this H-bond network increases the bilayer elasticity, which helps to evolve various kinds of vesicular structure. Furthermore, the significant influence of unsaturated fatty acid on membrane bilayer has been ratified through in vivo live cell imaging.

The role of viscosity in various dynamical processes of different fluorophores in ionic liquid-cosolvent mixtures: a femtosecond fluorescence upconversion study.

Literature reports provide ample evidence of the dynamical studies of various fluorophores in different room-temperature ionic liquid (RTIL)-cosolvent mixtures. However, most of the experimental and simulation studies reveal that ∼50% of the spectral relaxation dynamics is fast and cannot be resolved using traditional time correlated single photon counting (TCSPC) measurements. Our group has also investigated the dynamics of a solvatochromic probe coumarin 153 (C153) in a RTIL-cosolvent mixture using a TCSPC setup (S. Sarkar, R. Pramanik, C. Ghatak, P. Setua and N. Sarkar, J. Phys. Chem. B, 2010, 114, 2779-2789). Consequently, a major portion of the solvation dynamics remained undetected and moreover we could not monitor the dynamics beyond 0.4 mole fraction of the cosolvents. Thus in this study, we have rekindled our interest to sufficiently capture the rotational anisotropy and solvation dynamics of C153 beyond 0.4 mole fraction of the cosolvents in the RTIL-cosolvent mixture employing femtosecond fluorescence upconversion measurements. Additionally, we have utilized another RTIL with a higher alkyl chain length and viscosity to obtain a comprehensive and quantitative picture of the role of viscosity on the dynamics of the probe molecule. The most interesting observation of the present work is that the viscosities of different RTIL-cosolvent mixtures can efficiently control the cis-trans isomerization kinetics of the anionic fluorophore merocyanine 540 (MC 540) and the translational diffusion of a hydrophobic probe. The optimization of geometrical structures of [EmimOs]- and [EmimOs]-cosolvent mixtures followed by frequency analyses in both gas and solution phases have been carried out using quantum chemical calculations with the aid of density functional theory (DFT) methods. The computation based on the bond distances, electron densities and non-covalent interactions (NCI) has also been used to investigate the existence of the hydrogen-bond (H-bond). Again to comprehend van der Waals interactions and the conventional hydrogen-bond, the evolution of NCI plots are simulated. Therefore, the detailed experimental and theoretical studies presented in this manuscript lead to the inference that addition of the conventional solvents finely tunes the physicochemical properties of RTILs and broadens their scope of applications in the fields of chemistry and biology.

Self-Assembly of Amphiphiles into Vesicles and Fibrils: Investigation of Structure and Dynamics Using Spectroscopy and Microscopy Techniques.

Amphiphiles are a class of molecules which are known to assemble into a variety of nanostructures. The understanding and applications of self-assembled systems are based on what has been learned from biology. Among the vast number of self-assemblies, in this article, we have described the formation, characterization, and dynamics of two important biologically inspired assemblies: vesicles and fibrils. Vesicles, which can be classified into several categories depending on the sizes and components, are of great interest due to their potential applications in drug delivery and as nanoscale reactors. The structure and dynamics of vesicles can also mimic the complex geometry of the cell membrane. On the other hand, the self-assembly of proteins, peptides, and even single amino acids leads to a number of degenerative disorders. Thus, a complete understanding of these self-assembled systems is necessary. In this article, we discuss recent work on vesicular aggregates composed of phospholipids, fatty acids, and ionic as well as nonionic surfactants and single amino acid-based fibrils such as phenylalanine and tyrosine. Beside the characterization, we also emphasize the excited-state dynamics inside the aggregates for a proper understanding of the organization, reactivity, and heterogeneity of the aggregates.

Unveiling the Aggregation Behavior of Doxorubicin Hydrochloride in Aqueous Solution of 1-Octyl-3-methylimidazolium Chloride and the Effect of Bile Salt on These Aggregates: A Microscopic Study.

In this article, we have unveiled the aggregation behavior of a potent chemotherapeutic drug, doxorubicin hydrochloride (Dox) in a well-known imidazolium based surface active ionic liquid (SAIL), 1-octyl-3-methylimidazolium chloride (C8mimCl). The aggregates formed by Dox in C8mimCl have been characterized using dynamic light scattering (DLS), fluorescence lifetime imaging microscopy (FLIM), high-resolution transmission electron microscopy (HR-TEM), analytical transmission electron microscopy (analytical TEM), field emission scanning electron microscopy (FESEM), atomic force microscopy (AFM), and Fourier-transform infrared spectroscopy (FTIR) measurements. It is found that Dox forms large spherical aggregates in the presence of C8mimCl SAIL. We have also explored the driving force behind this aggregation behavior of Dox in C8mimCl. Furthermore, it is observed that in the presence of a common bile salt, sodium cholate (NaCh), Dox/C8mimCl spherical aggregates disrupt to form rodlike fibrillar aggregates. Therefore, formation of spherical aggregates and also its disruption into rodlike fibrillar aggregates have been performed, and this is expected to open a new scope for the design of a new generation smart drug delivery system where the drug itself aggregates to form the delivery system.

Light-induced morphological transition between unconjugated bilirubin photoisomers.

Morphology switching by an external stimulus creates the possibility to detect and control the activity and functionality of bio-molecules. Unconjugated bilirubin (UCB), a waste product resulting from heme catabolism, is highly sensitive towards blue light induced configurational conversion from (4Z,15Z) to (4Z,15E)-bilirubin. UCB has a distinct elongated nanostructure which is readily photoswitchable to spherical by external blue light (470 nm) irradiation. Herein, the morphology alteration by blue light was nicely correlated with the photoisomerisation of UCB, using different microscopic and spectroscopic techniques. To restrict the other photo-incidents during phototreatment on UCB, a suitable time frame was calibrated by monitoring the absorption, HPLC, lifetime distribution and 1H NMR studies. Furthermore, by the help of this morphological transition as a marker, UCB early stage photoisomerisation has also been triggered by two-photon irradiation (940 nm).

Membrane perturbation through novel cell-penetrating peptides influences intracellular accumulation of imatinib mesylate in CML cells.

Chronic myeloid leukemia is a stem cell disease with the presence of Philadelphia chromosome generated through reciprocal translocation of chromosome 9 and 22. The use of first- and second-generation tyrosine kinase inhibitors has been successful to an extent. However, resistance against such drugs is an emerging problem. Apart from several drug-resistant mechanisms, drug influx/efflux ratio appears to be one of the key determinants of therapeutic outcomes. In addition, intracellular accumulation of drug critically depends on cell membrane fluidity and lipid raft dynamics. Previously, we reported two novel cell-penetrating peptides (CPPs), namely, cationic IR15 and anionic SR11 present in tryptic digest of Abrus agglutinin. Here, the potential of IR15 and SR11 to influence intracellular concentration of imatinib has been evaluated. Fluorescent correlation spectroscopy and lifetime imaging were employed to map membrane fluidity and lipid raft distribution following peptide-drug co-administration. Results show that IR15 and SR11 are the two CPPs which can modulate membrane fluidity and lipid raft distribution in K562 cells. Both IR15 and SR11 significantly reduce the viability of CML cells in the presence of imatinib by increasing the intracellular accumulation of the drug.

Unveiling the Self-Assembling Behavior of 5-Fluorouracil and its N,N'-Dimethyl Derivative: A Spectroscopic and Microscopic Approach.

Under physiological conditions, 5-fluorouracil (5-FU), an anticancer drug, self-assembles into fibrils by strong hydrogen-bonding network, whereas its N,N'-dimethyl derivative, 5-fluoro-1,3-dimethyluracil (5-FDMU), does not make fibrils due to lack of strong hydrogen-bonding motif. In vitro, 5-FU self-assembly is sensitive to physicochemical conditions like the pH and ionic strength of the solution, which tune the strength of the noncovalent driving forces. Here we report a surprising finding that the buffer, which is necessary to control the pH and is typically considered to be inert, also significantly influences 5-FU self-assembly, which indicates an important role of counterions in the fibril formation. We have also monitored concentration- and time-dependent fibrillar growth of 5-FU. Again, fibril growth process is probed under dynamic conditions using microfluidic platform. The self-assembly of 5-FU compared with its N,N'-dimethyl derivative shows lower cytotoxicity to the cultured human erythroleukemic cells (K562 cells), which plausibly states the reason behind the greater effectiveness of 5-FU derivative drugs than 5-FU itself.

Concentration-Driven Fascinating Vesicle-Fibril Transition Employing Merocyanine 540 and 1-Octyl-3-methylimidazolium Chloride.

In this article, anionic lipophilic dye merocyanine 540(MC540) and cationic surface-active ionic liquid (SAIL) 1-octyl-3-methylimidazolium chloride (C8mimCl) are employed to construct highly ordered fibrillar and vesicular aggregates exploiting an ionic self-assembly (ISA) strategy. It is noteworthy that the concentration of the counterions has exquisite control over the morphology, in which lowering the concentration of both the building blocks in a stoichiometric ratio of 1:1 provides a vesicle to fibril transition. Here, we have reported the concentration-controlled fibril-vesicle transition utilizing the emerging fluorescence lifetime imaging microscopy (FLIM) technique. Furthermore, we have detected this morphological transformation by means of other microscopic techniques such as field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), and cryogenic-transmission electron microscopy (cryo-TEM) to gain additional support. Besides, multiwavelength FLIM (MW-FLIM) and atomic force microscopy (AFM) techniques assist us in knowing the microheterogeneity and the height profile of the vesicles, respectively. We have replaced the SAIL, C8mimCl, by an analogous traditional surfactant, n-octyltrimethylammonium bromide (OTAB), and it provides a discernible change in morphology similar to that of C8mimCl, whereas 1-octanol is unable to exhibit any structural aggregation and thus reveals the importance of electrostatic interaction in supramolecular aggregate formation. However, the SAILs having the same imidazolium headgroup with different chain lengths other than C8mimCl are unable to display any structural transition and determine the importance of the correct chain length for efficient packing of the counterions to form a specific self-assembly. Therefore, this study reveals the synergistic interplay of electrostatic, hydrophobic, and π-π stacking interactions to construct the self-assembly and their concentration-dependent morphological transition.