Ultralow Critical Micelle Concentration Research Articles

Zwitterionic nanoparticles from indocyanine green dimerization for imaging-guided cancer phototherapy

Indocyanine green (ICG), the only near-infrared (NIR) dye approved for clinical use, has received increasing attention as a theranostic agent wherein diagnosis (fluorescence) is combined with therapy (phototherapy), but suffers rapid hepatic clearance, poor photostability, and limited accumulation at tumor sites. Here we report that dimerized ICG can self-assemble to form zwitterionic nanoparticles (ZN-dICG), which generate fluorescence self-quenching but exhibit superior photothermal and photodynamic properties over ICG. The zwitterionic moieties confer ZN-dICG an ultralow critical micelle concentration and high colloidal stability with low non-specific binding in vivo. In addition, ZN-dICG can respond to the over-generated reactive oxygen species (ROSs) and dissociate to restore NIR fluorescence of ICG, amplifying the sensitivity via albumin binding for low-background imaging of tumors. Following systemic administration, ZN-dICG accumulated in tumors of xenograft-bearing mice for imaging primary and metastatic tumors, and induced tumor ablation under laser irradiation. The discovery of ZN-dICG would contribute to the design of translational phototheranostic platform with high biocompatibility. Statement of significanceIndocyanine green (ICG) has been extensively studied as a phototheranostic agent that combines imaging with phototherapies, but it suffers from rapid hepatic clearance, poor photostability, and limited accumulation at tumor sites. Here, we report a strategy to construct ICG dimers (ICG-tk-ICG) by conjugating two ICG molecules via a thioketal bond, which can self-assemble into zwitterionic nanoparticles (ZN-dICG) at ultralow critical micelle concentrations, exhibiting superior photothermal and photodynamic properties over ICG. ZN-dICG responds to the over-generated ROS in tumors and dissociates to restore the NIR fluorescence of ICG, enhancing the sensitivity via albumin binding for low-background imaging of tumors. This study offers a supramolecular strategy that may potentiate the clinical translation of ICG in imaging-guided cancer phototherapy.

Long‐lasting chemiluminescence by aggregation‐induced emission surfactant with ultralow critical micelle concentration

AbstractThe development of green and simple chemiluminescence (CL) systems with intensive and long‐lasting emission is highly desirable in lighting and extension of their applications. In this study, it is found that the involvement of aggregation‐induced emission (AIE) surfactant could greatly enhance the CL of luminol–H2O2–Co2+ system. The inserted hydrophobic tetraphenylethylene fluorophore in AIE is able to increase the hydrophobicity of alkyl chain and decrease the critical micelle concentration (CMC) of surfactant. The synergistic effect of micelle‐improved enrichment and CL resonance energy transfer endows luminol–H2O2–Co2+ system intensive and long‐lasting emission under neutral pH conditions (pH 7.4). The visible emission is still observed even after 60 min. Our study has opened a new avenue for exploring green and simple effective CL systems through AIE surfactant with unltralow CMC toward various applications in lighting, optical sensing, and photocatalysis, etc.

Multifunctional amphiphilic peptide dendrimer as nonviral gene vectors for effective cancer therapy via combined gene/photodynamic therapies

Gene therapy holds great promise for treatment of gene-associated diseases. However, safe and successful clinical application urgently requires further advancement of constructing efficient delivery systems. Herein, three amphiphilic peptide dendrimers (TTC-L-KRR/KKK/KHH), containing the natural amino acid residues (lysine K, arginine R, and histidine H) and AIE-based photosensitizer (tetraphenylethenethiophene modified cyanoacrylate, TTC) modified with alkyl chain (L), have been designed and prepared for improving therapeutic potency via the combination of gene therapy (GT) and photodynamic therapy (PDT). All three compounds possessed typical aggregation-induced emission (AIE) characteristics and ultralow critical micelle concentrations (CMCs). The liposomes consisting of amphiphilic peptide dendrimers and dioleoylphosphatidylethanolamine (DOPE) can effectively bind DNA into nanoparticles with appropriate sizes, regular morphology and good biocompatibility. Among them, liposomes TTC-L-KKK/DOPE exhibited the highest transfection efficiency up to 5.7-fold as compared with Lipo2000 in HeLa cells. Meanwhile, rapid endocytosis, successful endo/lysosomal escape, gene release and rapid nuclear delivery of DNA revealed the superiority of liposomes TTC-L-KKK/DOPE during gene delivery process. More importantly, efficient reactive oxygen species (ROS) generation by TTC-L-KKK/DOPE led to effective PDT, thus improving therapeutic potency via combining with p53 mediated-gene therapy. Our work brought novel insight and direction for the construction of bio-safe and bio-imaging liposome as the multifunctional nonviral gene vectors for the effective combined gene/photodynamic therapies.

Ultra-stable dextran conjugated prodrug micelles for oxidative stress and glycometabolic abnormality combination treatment of Alzheimer's disease

Sophisticated nanomedicines are continually being developed, but big obstacles remain before they finish the drug release mission. The first challenge is rupture possibility of structure when infinite dilution, competitive reaction of electrolytes and protein in blood circulation. In addition, low responsive drug release efficiency in the lesion site remains the major challenge for clinical application of nanomedicine combination treatment. In this study, we discussed the opportunities for Alzheimer's disease (AD) combination therapy based on the thermodynamically ultra-stable dextran conjugated prodrug micelles. Dextran-nateglinide conjugated prodrug micelles (NA) and dextran-vitamin E succinate conjugated prodrug micelles (VES) presented ultra-low critical micelle concentration of ~10−5 mM and high physiological stability when challenged by NaCl, sodium dodecyl sulphate (SDS), dodecyl dimethyl benzyl ammonium chloride (DDBAC) and no rupture of structure happened. The NA/insulin polymer-drug conjugate micelles (NA/INS PDC) and VES/insulin polymer-drug conjugate micelles (VES/INS PDC) efficiently cleaved by reactive oxygen species (ROS), leading to over 80% release of the encapsulated and conjugated drugs. The combination of nateglinide and insulin, vitamin E succinate and insulin improved the glucose metabolism, reduced oxidative stress, improved the mitochondrial function and recovered the cognitive capacity of mice. This work demonstrated a paradigm for specific and high efficacy AD combination therapy.

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

AbstractProbing 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.

12]aneN3-Based Gemini-Type Amphiphiles with Two-Photon Absorption Properties for Enhanced Nonviral Gene Delivery and Bioimaging.

Although a plethora of nonviral gene vectors have been developed for potential gene therapy, imageable gemini surfactants with stimuli-responsiveness and high transfection efficiency are still scarce for gene delivery. Herein, three gemini amphiphiles (DEDPP-4/8/12) consisting of an aggregation-induced emission (AIE) central fluorophore: 5,6-diphenylpyrazine-2,3-diester (DEDPP), decorated with triazole-[12]aneN3 as the hydrophilic moiety and alkyl chains of various lengths as the hydrophobic moiety, were designed and synthesized for trackable gene delivery via optical imaging. All three amphiphiles exhibited ultralow critical micelle concentrations (CMCs) (up to 3.40 × 10-6 M), prominent two-photon absorption properties, and solvatochromic fluorescence. Gel electrophoresis assays demonstrated that the migration of plasmid DNA was completely retarded after condensation with these gemini amphiphiles at low concentrations (up to 10 μM). In addition, the ester bond in these amphiphiles may facilitate vector degradation and DNA release, in response to esterase and the acidic environment inside cells. Upon self-assembly with DOPE to form liposomes, DEDPP-8/DOPE achieved the best transfection efficiency in four cell lines, and the transfection efficiency of DEDPP-8/DOPE in HeLa cell lines was 23.5-fold higher than that of Lipo2000, which is unusually high for small organic molecule-based nonviral vectors. Furthermore, excellent transfection efficiency of DEDPP-8/DOPE was obtained in the presence of serum, and the red fluorescence protein (RFP) gene was successfully transfected in zebrafish embryos. Both one- and two-photon fluorescence imaging clearly demonstrated the delivery process of plasmid DNA. This study demonstrated that gemini-type amphiphiles composed of a two-photon fluorophore core conjugated with triazole-[12]aneN3 via an ester bond afforded an unprecedentedly high transfection efficiency with excellent biocompatibility, which may provide new insights for the design and development of multifunctional nonviral gene vectors for imageable gene delivery.

Zwitterionic micelles efficiently deliver oral insulin without opening tight junctions.

Oral delivery of protein drugs is considered a life-changing solution for patients who require regular needle injections. However, clinical translation of oral protein formulations has been hampered by inefficient penetration of drugs through the intestinal mucus and epithelial cell layer, leading to low absorption and bioavailability, and safety concerns owing to tight junction openings. Here we report a zwitterionic micelle platform featuring a virus-mimetic zwitterionic surface, a betaine side chain and an ultralow critical micelle concentration, enabling drug penetration through the mucus and efficient transporter-mediated epithelial absorption without the need for tight junction opening. This micelle platform was used to fabricate a prototype oral insulin formulation by encapsulating a freeze-dried powder of zwitterionic micelle insulin into an enteric-coated capsule. The biocompatible oral insulin formulation shows a high oral bioavailability of >40%, offers the possibility to fine tune insulin acting profiles and provides long-term safety, enabling the oral delivery of protein drugs.

Amphiphilic Bottlebrush Block Copolymers: Analysis of Aqueous Self-Assembly by Small-Angle Neutron Scattering and Surface Tension Measurements

A systematic series of 16 amphiphilic bottlebrush block copolymers (BCPs) containing polystyrene and poly(N-acryloylmorpholine) (PACMO) side chains were prepared by a combination of atom-transfer radical polymerization (ATRP), photoiniferter polymerization, and ring-opening metathesis polymerization (ROMP). The grafting-through method used to prepare the polymers enabled a high degree of control over backbone and side-chain molar masses for each block. Surface tension measurements on the self-assembled amphiphilic bottlebrush BCPs in water revealed an ultralow critical micelle concentration (cmc), 1–2 orders of magnitude lower than linear BCP analogues on a molar basis, even for micelles with >90% PACMO content. Combined with coarse-grained molecular dynamics simulations, fitting of small-angle neutron scattering traces (SANS) allowed us to evaluate solution conformations for individual bottlebrush BCPs and micellar nanostructures for self-assembled macromolecules. Bottlebrush BCPs showed an increase in a...

Aggregation-Induced Emission (AIE) Polymeric Micelles for Imaging-Guided Photodynamic Cancer Therapy.

Photodynamic therapy (PDT) is a noninvasive treatment for selectively killing malignant tumor cells. The photosensitizer is a necessary component of photodynamic nanomedicine. Many efforts have been made to develop new photosensitizers for efficient cancer photodynamic therapy. In this work, we report a novel nano photosensitizer, polymeric micelles (AIE-M) with aggregation induced emission characteristic, for photodynamic cancer therapy. AIE-M with sub-20 nm particle size is prepared by the self-assembly of salicylaldazine-incorporated amphiphilic polymer (AIE-1), which can produce reactive oxygen species (ROS) with light irradiation in solution. After uptake by cancer cells, AIE-M can specially sojourn in plasma membranes of cancer cells at the early stage and predominantly accumulate in the mitochondria of cancer cell at the late stage. The phototoxicity of AIE-M, resulting from the generation of intracellular ROS with light irradiation, can efficiently cause cancer cells death by apoptosis and necrosis. The advantages of AIE-M as a nano photosensitizer include the small size, highly colloidal stability in the process of preparation and storage, and high cell penetration. The ultra-low Critical Micelle Concentration (CMC) of AIE-1, negligible dark toxicity and super phototoxicity of AIE-M suggest its promising potential for image-guided PDT.

Micelles with ultralow critical micelle concentration as carriers for drug delivery

Conventional micellar carriers disassemble into free surfactants when diluted at concentrations below the critical micelle concentration (CMC). This limits the bioavailability in vivo of injected hydrophobic drugs encapsulated in micellar systems. Here, we show that a micelle comprising a superhydrophilic zwitterionic polymer domain and a superhydrophobic lipid domain has an undetectable CMC below 10-6 mM-a value that is orders of magnitude lower than the CMCs (>10-3 mM) of typical micellar systems. We also show that zwitterionic moieties or zwitterionic polymers added to a micelle solution stabilize the micelles at concentrations below their inherent CMC. In a mouse model of melanoma, ultralow-CMC micelles encapsulating docetaxel led to the complete eradication of tumours, whereas conventional docetaxel micellar formulations did not reverse tumour growth. Ultralow-CMC micelles might become next-generation carriers for drug delivery.

Surfactant-assisted algal flocculationviaaggregation-induced emission with an ultralow critical micelle concentration

Algal flocculation was induced by an aggregation-induced emission surfactant with an ultralow critical micelle concentration.

Tetraphenylethylene-based gemini surfactant as nonviral gene delivery system: DNA complexation, gene transfection and cellular tracking

Gemini surfactant (GS) has been proved to be a powerful system for nonviral gene delivery. Herein, a family of tetraphenylethylene (TPE)-based GS possessing different lengths of hydrophobic tails and different linkages between the TPE and [12]aneN3 moieties (1a, 2a, 1b and 2b) were synthesized for facilitating DNA condensation, promoting gene transfection and tracing cellular fate of GS/DNA complex. These GS can readily self-assemble into micelles in aqueous solution with ultralow critical micelle concentrations (CMC, 1.2−1.3μM), and have good pH-/photo-stabilities and strong DNA binding capacities. DNA nanoparticles condensed by the above GSs are in a range of 90−110nm and in the form of spherical morphology showing great stability in the absence and presence of fetal bovine serum. Biological activities including cytotoxicity, cell transfection and cellular internalization were systematically investigated. Resultsrevealed that good biocompatibility (e.g., all the tested cells showed more than 80% of cell viabilities at 30μM) and high transfection efficiency (e.g., 2a/DOPE showed 4.5-fold TE of Lipo2000 in HeLa cell line) were conferred to these GSs. Moreover, the spatiotemporal messages regarding the cellular uptake, location and release of the DNA condensates were clearly captured by the fluorescence changes. Particularly, the impacts of the hydrophobic length and linkage on the physicochemical properties and biological activities were discussed in detail, shedding light on the corresponding structure-activity relationship. The results have demonstrated that TPE-based GSs are very promising as new gene delivery carrier and instructive for rational expansion of novel nonviral gene system.

Fabrication and biological imaging of polyhedral oligomeric silsesquioxane cross-linked fluorescent polymeric nanoparticles with aggregation-induced emission feature

Aggregation-induced emission (AIE) dyes based fluorescent polymeric nanoparticles (FNPs) have been intensively explored for biomedical applications. However, many of these AIE-active FNPs are relied on the self-assembly of amphiphilic copolymers, which are not stable in diluted solution. Therefore, the introduction of cross-linkages into these micelles has demonstrated to be an efficient route to overcome this stability problem and endow ultra-low critical micelle concentrations (CMC) of these AIE-active FNPs. In this work, we reported the fabrication of cross-linked AIE-active FNPs through controllable reversible addition fragmentation chain transfer polymerization by using commercially available octavinyl-T8-silsesquioxane (8-vinyl POSS) as the cross-linkage for the first time. The resultant cross-linked amphiphilic copolymers (named as PEG-POSS-PhE) are prone to self-assemble into stable core–shell nanoparticles with well water dispersity, strong red fluorescence and low CMC (0.0069mgmL−1) in aqueous solution. More importantly, PEG-POSS-PhE FNPs possess some other properties such as high water dispersity, uniform morphology and small size, excellent biocompatibility and cellular internalization, providing great potential of PEG-POSS-PhE FNPs for biological imaging application.

Gemini-Type Tetraphenylethylene Amphiphiles Containing [12]aneN3 and Long Hydrocarbon Chains as Nonviral Gene Vectors and Gene Delivery Monitors.

Four gemini amphiphiles decorated with triazole-[12]aneN3 as the hydrophilic moiety and various long hydrocarbons as hydrophobic moieties, 1-4, were designed to form micelles possessing the aggregation-induced emission (AIE) property for gene delivery and tracing. All four amphiphiles give ultralow critical micelle concentrations, are pH-/photostable and biocompatible, and completely retard the migration of plasmid DNAs at low concentrations. The DNA-binding abilities of the micelles were fully assessed. The coaggregated nanoparticles of 1-4 with DNAs could convert back into AIE micelles. In vitro transfections indicated that lipids 1 and 2 and their originated liposomes bearing decent delivering abilities have great potentials as nonviral vectors. Finally, on the basis of the transfection and the transitions between condensates and micelles, lipid 2 was singled out as the first example for real-time tracing of the intracellular deliveries of nonlabeled DNA, which provides spatiotemporal messages about the processes of condensate uptake and DNA release.

Polymerizable aggregation-induced emission dye for preparation of cross-linkable fluorescent nanoprobes with ultra-low critical micelle concentrations

In recent years, aggregation-induced emission (AIE) dyes based fluorescent organic nanoparticles (FONs) have achieved significant progress in various biomedical applications. In this work, we developed a covalent strategy to prepare biocompatible AIE-active dyes based cross-linked copolymers (MPC-POSS-PhE) via controllable reversible addition fragmentation chain transfer (RAFT) polymerization using zwitterionic 2-methacryloyloxyethyl phosphorylcholine (MPC), polymerizable AIE dye (named as PhE) and 8-vinyl polyoctahedral silsesquioxanes (POSS) as monomers. Due to the existence of hydrophilic MPC and hydrophobic PhE, the resultant copolymers will self-assemble into core-shell nanoparticles in aqueous solution with ultra-low critical micelle concentration (CMC). This could effectively overcome the drawbacks of non-crosslinked micelles and show more attractive properties and better performance for biomedical applications. Furthermore, the characterization results and biological assays demonstrated that the final MPC-POSS-PhE FONs show stable aqueous stability, uniform size and morphology, high water dispersity, desirable optical properties and low cytotoxicity. These remarkable properties make the resultant AIE-active nanoprobes great potential for biomedical applications.

Facile Fabrication of AIE-Active Fluorescent Polymeric Nanoparticles with Ultra-Low Critical Micelle Concentration Based on Ce(IV) Redox Polymerization for Biological Imaging Applications

Fluorescent polymeric nanoparticles (FPNs) with aggregation-induced emission (AIE) property have received increasing attention and possess promising biomedical application potential in the recent years. Many efforts have been devoted to the fabrication methodologies of FPNs and significant advance has been achieved. In this contribution, a novel strategy for the fabrication of AIE-active amphiphilic copolymers is reported for the first time based on the Ce(IV) redox polymerization. As an example, ene group containing AIE-active dye (named as Phe-alc) is directly grafted onto a water soluble polymer polyethylene glycol (PEG) in H2 O/THF system under low temperature. Thus-obtained amphiphilic fluorescent polymers will self-assemble into FPNs with ultra-low critical micelle concentration, ultra-brightness, and great water dispersibility. Biological evaluation results suggest that the PEG-poly(Phe-alc) possess excellent biocompatibility and can be used for tracing their behavior in cells using confocal laser scanning microscope. These features make PEG-poly(Phe-alc) FPNs promising candidates for many biomedical applications, such as cell imaging, drug delivery vehicles, and targeted tracing. More importantly, many other functional groups can also be incorporated into these AIE-active FPNs through the redox polymerization. Therefore, the redox polymerization should be a facile and effective strategy for fabrication of AIE-active FPNs.

Mixtures of Anionic/Cationic Surfactants: A New Approach for Enhanced Oil Recovery in Low-Salinity, High-Temperature Sandstone Reservoir

Summary Test results indicate that a lipophilic surfactant can be designed by mixing both hydrophilic anionic and cationic surfactants, which broaden the design of novel surfactant methodology and application scope for conventional chemical enhanced-oil-recovery (EOR) methods. These mixtures produced ultralow critical micelle concentrations (CMCs), ultralow interfacial tension (IFT), and high oil solubilization that promote high tertiary oil recovery. Mixtures of anionic and cationic surfactants with molar excess of anionic surfactant for EOR applications in sandstone reservoirs are described in this study. Physical chemistry properties, such as surface tension, CMC, surface excess, and area per molecule of individual surfactants and their mixtures, were measured by the Wilhelmy (1863) plate method. Morphologies of surfactant solutions, both surfactant/polymer (SP) and alkaline/surfactant/polymer (ASP), were studied by cryogenic-transmission electron microscopy (Cryo-TEM). Phase behaviors were recorded by visual inspection including crossed polarizers at different surfactant concentrations and different temperatures. IFTs between normal octane, crude oil, and surfactant solution were measured by the spinning-drop-tensiometer method. Properties of IFT, viscosity, and thermal stability of surfactant, SP, and ASP solutions were also tested. Static adsorption on sandstone was measured at reservoir temperature. IFT was measured before and after multiple contact adsorptions to recognize the influence of adsorption on interfacial properties. Forced displacements were conducted by flooding with water, SP, and ASP. The coreflooding experiments were conducted with synthetic brine with approximately 5,000 ppm of total dissolved solids (TDS), and with a crude oil from a Sinopec reservoir.

Aggregation induced emission amphiphile with an ultra low critical micelle concentration: fabrication, self assembling, and cell imaging.

A novel aggregation induced emission amphiphile is constructed, containing a tetraphenylethene hydrophobic moiety connected to a hydrophilic quarternary ammonium salt. Owing to an ultra low critical micelle concentration in water, the amphiphile tends to self assemble into well-defined organic nanoaggregates that exhibit intense fluorescence, stable dispersibility in dilute solutions, and excellent biocompatibility for cell imaging.

Designing an Optimized Surfactant Flood in the Bakken

This article, written by JPT Technology Editor Chris Carpenter, contains highlights of paper SPE 175937, “Designing an Optimized Surfactant Flood in the Bakken,” by Matthew Dawson, Statoil; Duy Nguyen, Nalco Champion; and Huina Li, Statoil, prepared for the 2015 SPE/CSUR Unconventional Resources Conference, Calgary, 20–22 October. The paper has not been peer reviewed. The Bakken is one of the most prolific plays in North America, but, even with the deployment of horizontal wells and hydraulic fracturing, anticipated recovery factors under primary depletion are usually in the range of 10 to 20%. Waterflooding has been a commonly deployed technology in conventional reservoirs to enhance recovery beyond primary depletion. However, the Bakken’s ultratight, largely oil-wet nature limits the potential of waterflooding. As an alternative, an optimally spaced well-to- well surfactant-flooding technology is proposed. Introduction Recent studies focusing on wettability alteration by use of surfactant in the Bakken have shown strong potential. Spontaneous-imbibition tests in Bakken cores show recovery factors that can exceed 30% and sometimes achieve up to 60%. However, in an ultralow-permeability system, the rate of surfactant imbibition is perhaps more important than the ultimate recovery factor. Initial studies show potential, but to achieve an economical surfactant recovery process, ultrahigh imbibition rates must be achieved. In addition to the technical challenges associated with stability, compatibility, and injectivity, economical deployment of surfactant in a marginally profitable play such as the Bakken is another major challenge. To minimize the surfactant required for a successful process, a surfactant would ideally have an ultralow critical micelle concentration (CMC) and low adsorption while maintaining key performance indicators that are discussed in the complete paper.

Fabrication of stable and biocompatible red fluorescent glycopolymer nanoparticles for cellular imaging

Glycosylated cross-linked red fluorescent amphiphilic polymer has been facilely synthesized in one pot, which would readily self-assemble into nanoparticles with high water dispersibility in aqueous media. The resulted nanoparticles have surplus carboxyl groups and glycosyl groups on the surface, which can be further functionalized, and they can demonstrate strong bio-favorable red fluorescence with a fluorescence quantum yield of 18% due to the aggregation induced emission (AIE) dyes aggregated in the core. Moreover, the nanoparticles also revealed great photostability and structure stability with an ultralow critical micelle concentration of 0.0018 mg mL−1. Their excellent biocompatibility and cell uptake behavior make them promising for cellular imaging.