Green micellar factorial design optimized first derivative synchronous spectrofluorimetric method for tripelennamine and diphenhydramine determination in pharmaceutical gel.

A green micellar synchronous spectrofluorimetric method was developed and validated for simultaneous determination of tripelennamine hydrochloride and diphenhydramine in bulk and combined pharmaceutical formulation. Synchronous fluorescence of tripelennamine hydrochloride and diphenhydramine was determined using Δλ = 60 nm. The first derivative of synchronous fluorescence was computed to resolve overlap in the synchronous fluorescence spectra. Tripelennamine hydrochloride was quantified at 375 nm, whereas diphenhydramine was quantified at 293 nm; each is the zero-crossing point of the other. As diphenhydramine exhibited weak native fluorescence, micelle enhancement upon incorporation of sodium dodecyl sulfate was considered. Two-level full factorial design was carried out to optimize experimental parameters. Optimum conditions involved using SDS (2% w/v) along with Teorell and Stenhagen buffer (pH 9). The method was found to be linear over the range 0.2-4.5 and 0.2-5 µg/mL for tripelennamine and diphenhydramine, respectively, with limits of detection 0.211 and 0.159 µg/mL. The method was successfully applied for simultaneous determination of tripelennamine hydrochloride and diphenhydramine in laboratory-prepared gel containing all possible excipients with mean percent recoveries ±SD 100.59 ± 0.79 and 98.99 ± 0.98 for tripelennamine hydrochloride and diphenhydramine, respectively. The proposed method was proved to be eco-friendly using different greenness assessment tools.

A nose for tau.

Nasal delivery of an oligomeric tau antibody loaded into micelles reduces pathology and ameliorates cognition in a mouse model of tauopathy.

Nanoparticles that Distinguish Chemical and Supramolecular Contexts of Lysine for Single-Site Functionalization of Protein.

Lysine is one of the most abundant residues on the surface of proteins and its site-selective functionalization is extremely challenging. The existing methods of functionalization rely on differential reactivities of lysine on a protein, making it impossible to label less reactive lysines selectively. We here report polymeric nanoparticles that mimic enzymes involved in the posttranslational modifications of proteins that distinguish the chemical and supramolecular contexts of a lysine and deliver the labeling reagent precisely to its ε amino group. The nanoparticles are prepared through molecular imprinting of cross-linkable surfactant micelles, plus an in situ, on-micelle derivatization of the peptide template prior to the imprinting. The procedures encode the polymeric nanoparticles with all the supramolecular information needed for sequence identification and precise labeling, allowing single-site functionalization of a predetermined lysine on the target protein in a mixture.

Multifunctional Nanoparticle-Loaded Injectable Alginate Hydrogels with Deep Tumor Penetration for Enhanced Chemo-Immunotherapy of Cancer.

Chemo-immunotherapy has become a promising strategy for cancer treatment. However, the inability of the drugs to penetrate deeply into the tumor and form potent tumor vaccines in vivo severely restricts the antitumor effect of chemo-immunotherapy. In this work, an injectable sodium alginate platform is reported to promote penetration of the chemotherapeutic doxorubicin (DOX) and delivery of personalized tumor vaccines. The injectable multifunctional sodium alginate platform cross-links rapidly in the presence of physiological concentrations of Ca2+, forming a hydrogel that acts as a drug depot and releases loaded hyaluronidase (HAase), DOX, and micelles (IP-NPs) slowly and sustainedly. By degrading hyaluronic acid (HA) overexpressed in tumor tissue, HAase can make tumor tissue "loose" and favor other components to penetrate deeply. DOX induces potent immunogenic cell death (ICD) and produces tumor-associated antigens (TAAs), which could be effectively captured by polyethylenimine (PEI) coated IP-NPs micelles and form personalized tumor vaccines. The vaccines efficaciously facilitate the maturation of dendritic cells (DCs) and activation of T lymphocytes, thus producing long-term immune memory. Imiquimod (IMQ) loaded in the core could further activate the immune system and trigger a more robust antitumor immune effect. Hence, the research proposes a multifunctional drug delivery platform for the effective treatment of colorectal cancer.

Polymer Conjugate as the New Promising Drug Delivery System for Combination Therapy against Cancer.

This review highlights the advantages of combination therapy using polymer conjugates as drug delivery systems for cancer treatment. In this review, the specific structures and materials of polymer conjugates, as well as the different types of combination chemotherapy strategies, are discussed. Specific targeting strategies, such as monoclonal antibody therapy and small molecule ligands, are also explored. Additionally, self-assembled polymer micelles and overcoming multidrug resistance are described as potential strategies for combination therapy. The assessment of combinational therapeutic efficacy and the challenges associated with polymer conjugates are also addressed. The future outlook aims to overcome these challenges and improve the effectiveness of drug delivery systems for combination therapy. The conclusion emphasizes the potential of polymer conjugates in combination therapy while acknowledging the need for further research and development in this field.

Enhanced drug resistance suppression by serum-stable micelles from multi-arm amphiphilic block copolymers and tocopheryl polyethylene glycol 1000 succinate.

Aim: To develop a robust drug-delivery system using multi-arm amphiphilic block copolymers for enhanced efficacy in cancer therapy. Materials & methods: Two series of amphiphilic polymer micelles, PEG-b-PCLm and PEG-b-PCLm/TPGS, were synthesized. Doxorubicin (DOX) loading into the micelles was achieved via solvent dialysis. Results: The micelles displayed excellent biocompatibility, narrow size distribution, and uniform morphology. DOX-loaded micelles exhibited enhanced antitumor efficacy and increased drug accumulation at tumor sites compared with free DOX. Additionally, 4A-PEG47-b-PCL21/TPGS micelles effectively suppressed drug-resistant MCF-7/ADR cells. Conclusion: This study introduces a novel micelle formulation with exceptional serum stability and efficacy against drug resistance, promising for cancer therapy. It highlights innovative strategies for refining clinical translation and ensuring sustained efficacy and safety in vivo.

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Posaconazole-hemp seed oil loaded nanomicelles for invasive fungal disease.

Invasive fungal infections (IFI) pose a significant health burden, leading to high morbidity, mortality, and treatment costs. This study aims to develop and characterize nanomicelles for the codelivery of posaconazole and hemp seed oil for IFI via the oral route. The nanomicelles were prepared using a nanoprecipitation method and optimized through the Box Behnken design. The optimized nanomicelles resulted in satisfactory results for zeta potential, size, PDI, entrapment efficiency, TEM, and stability studies. FTIR and DSC results confirm the compatibility and amorphous state of the prepared nanomicelles. Confocal laser scanning microscopy showed that the optimized nanomicelles penetrated the tissue more deeply (44.9µm) than the suspension (25µm). The drug-loaded nanomicelles exhibited sustained cumulative drug release of 95.48 ± 3.27% for 24 h. The nanomicelles showed significant inhibition against Aspergillus niger and Candida albicans (22.4 ± 0.21 and 32.2 ± 0.46 mm, respectively). The pharmacokinetic study on Wistar rats exhibited a 1.8-fold increase in relative bioavailability for the nanomicelles compared to the suspension. These results confirm their therapeutic efficacy and lay the groundwork for future research and clinical applications, providing a promising synergistic antifungal nanomicelles approach for treating IFIs.

Ecofriendly micellar mediated spectrofluorimetric method for ultrasensitive quantification of the antiparkinsonian drug safinamide in pharmaceutical formulation and spiked human plasma.

A novel, highly sensitive and eco-friendly micellar-mediated spectrofluorimetric method was developed and validated for the determination of the novel antiparkinsonian drug safinamide mesylate in the presence of its related precursor impurity, 4-hydroxybenzaldehyde. The proposed approach relies on increasing the inherent fluorescence emission at 296 nm of safinamide, by forming hydrogen bonds between the mentioned drug and sodium dodecyl sulfate in the micellar system using 0.1 N HCl as a solvent, following excitation at 226 nm. A thorough investigation was conducted into the experimental factors affecting spectrofluorimetric behavior of the studied drug. A linearity plot of safinamide over the concentration range of 10.0-1000.0 ng/mL against the relative fluorescence intensities was established. The proposed method demonstrated excellent sensitivity down to the nano-gram level with detection and quantitation limits of 1.91 and 5.79 ng/mL, respectively. The studied drug was effectively determined in Parkimedine® Tablets. Furthermore, the proposed method allows for ultrasensitive quantification of safinamide in spiked human plasma, with satisfactory percentage recovery (98.97-102.28%). Additionally, the greenness assessment using the advanced green certificate classification approach, the complementary green analytical procedure index (Complex-GAPI), and the analytical GREEness metric approach (AGREE), along with the practicality check using the Blue Applicability Grade Index in addition to the all-inclusive overall whiteness evaluation using the RGB-12 model were carried out. The outcomes demonstrated the effectiveness and whiteness of the proposed technique. Clearly, the suggested approach has the advantages of being simple, requiring no pretreatment steps, and relying solely on direct measuring procedures.

Optimization of micelle-encapsulated extremely small sized iron oxide nanoparticles as a T1 contrast imaging agent: biodistribution and safety profile.

BACKGROUND: Iron oxide nanoparticles (IONPs) have been cleared by the Food and Drug Administration (FDA) for various clinical applications, such as tumor-targeted imaging, hyperthermia therapy, drug delivery, and live-cell tracking. However, the application of IONPs as T1 contrast agents has been restricted due to their high r2 values and r2/r1 ratios, which limit their effectiveness in T1 contrast enhancement. Notably, IONPs with diameters smaller than 5 nm, referred to as extremely small-sized IONPs (ESIONs), have demonstrated potential in overcoming these limitations. To advance the clinical application of ESIONs as T1 contrast agents, we have refined a scale-up process for micelle encapsulation aimed at improving the hydrophilization of ESIONs, and have carried out comprehensive in vivo biodistribution and preclinical toxicity assessments. RESULTS: The optimization of the scale-up micelle-encapsulation process, specifically employing Tween60 at a concentration of 10% v/v, resulted in ESIONs that were uniformly hydrophilized, with an average size of 9.35 nm and a high purification yield. Stability tests showed that these ESIONs maintained consistent size over extended storage periods and dispersed effectively in blood and serum-mimicking environments. Relaxivity measurements indicated an r1 value of 3.43 mM- 1s- 1 and a favorable r2/r1 ratio of 5.36, suggesting their potential as T1 contrast agents. Biodistribution studies revealed that the ESIONs had extended circulation times in the bloodstream and were primarily cleared via the hepatobiliary route, with negligible renal excretion. We monitored blood clearance and organ distribution using positron emission tomography and magnetic resonance imaging (MRI). Additionally, MRI signal variations in a dose-dependent manner highlighted different behaviors at varying ESIONs concentrations, implying that optimal dosages might be specific to the intended imaging application. Preclinical safety evaluations indicated that ESIONs were tolerable in rats at doses up to 25 mg/kg. CONCLUSIONS: This study effectively optimized a scale-up process for the micelle encapsulation of ESIONs, leading to the production of hydrophilic ESIONs at gram-scale levels. These optimized ESIONs showcased properties conducive to T1 contrast imaging, such as elevated r1 relaxivity and a reduced r2/r1 ratio. Biodistribution study underscored their prolonged bloodstream presence and efficient clearance through the liver and bile, without significant renal involvement. The preclinical toxicity tests affirmed the safety of the ESIONs, supporting their potential use as T1 contrast agent with versatile clinical application.

A pH-triggered N-oxide polyzwitterionic nano-drug loaded system for the anti-tumor immunity activation research.

Triple negative breast cancer (TNBC) has the characteristics of low immune cell infiltration, high expression of tumor programmed death ligand 1 (PD-L1), and abundant cancer stem cells. Systemic toxicity of traditional chemotherapy drugs due to poor drug selectivity, and chemotherapy failure due to tumor drug resistance and other problems, so it is particularly important to find new cancer treatment strategies for TNBC with limited treatment options. Both the anti-tumor natural drugs curcumin and ginsenoside Rg3 can exert anti-tumor effects by inducing immunogenic cell death (ICD) of tumor cells, reducing PD-L1 expression, and reducing cancer stem cells. However, they have the disadvantages of poor water solubility, low bioavailability, and weak anti-tumor effect of single agents. We used vinyl ether bonds to link curcumin (Cur) with N-O type zwitterionic polymers and at the same time encapsulated ginsenoside Rg3 to obtain hyperbranched zwitterionic drug-loaded micelles OPDEA-PGED-5HA@Cur@Rg3 (PPH@CR) with pH response. In vitro cell experiments and in vivo animal experiments have proved that PPH@CR could not only promote the maturation of dendritic cells (DCs) and increase the CD4+ T cells and CD8+ T cells by inducing ICD in tumor cells but also reduce the expression of PD-L1 in tumor tissues, and reduce cancer stem cells and showed better anti-tumor effects and good biological safety compared with free double drugs, which is a promising cancer treatment strategy.

A Self-Cascade Penetrating Brain Tumor Immunotherapy Mediated by Near-Infrared II Cell Membrane-Disrupting Nanoflakes via Detained Dendritic Cells.

Immunotherapy can potentially suppress the highly aggressive glioblastoma (GBM) by promoting T lymphocyte infiltration. Nevertheless, the immune privilege phenomenon, coupled with the generally low immunogenicity of vaccines, frequently hampers the presence of lymphocytes within brain tumors, particularly in brain tumors. In this study, the membrane-disrupted polymer-wrapped CuS nanoflakes that can penetrate delivery to deep brain tumors via releasing the cell-cell interactions, facilitating the near-infrared II (NIR II) photothermal therapy, and detaining dendritic cells for a self-cascading immunotherapy are developed. By convection-enhanced delivery, membrane-disrupted amphiphilic polymer micelles (poly(methoxypoly(ethylene glycol)-benzoic imine-octadecane, mPEG-b-C18) with CuS nanoflakes enhances tumor permeability and resides in deep brain tumors. Under low-power NIR II irradiation (0.8 W/cm2), the intense heat generated by well-distributed CuS nanoflakes actuates the thermolytic efficacy, facilitating cell apoptosis and the subsequent antigen release. Then, the positively charged polymer after hydrolysis of the benzoic-imine bond serves as an antigen depot, detaining autologous tumor-associated antigens and presenting them to dendritic cells, ensuring sustained immune stimulation. This self-cascading penetrative immunotherapy amplifies the immune response to postoperative brain tumors but also enhances survival outcomes through effective brain immunotherapy.

The Aggregated and Micellar Forms of ß-Casein Purified from Donkey and Bovine Milk Present Potential as Carriers for Bioactive Nutritional Compounds.

In recent years, there has been a growing interest in the pure casein fraction of milk protein, particularly ß-casein due to its physicochemical properties as well as its bio- and techno-functional properties. The utilization of self-assembled ß-caseins from bovine origin as nanocarriers for the delivery of nutraceutical compounds or drugs has increased dramatically. Concerning ß-caseins from other milk sources, the use of hypoallergenic donkey ß-caseins as a potential delivery vehicle for nutraceutical hydrophobic compounds is beginning to generate interest. The present review deals with casein micelles models, bovine and donkey ß-casein molecular structures, as well as their physical-chemical properties that account for their exploitation in nutraceutics and pharmaceutics. This review work suggests the possibility of developing delivery systems for hydrophobic bioactive compounds using ß-casein purified from hypoallergenic donkey milk, highlighting the potential of this protein as an innovative and promising vehicle for enhancing the enrichment and bioavailability of various bioactive substances in food products.

High-Throughput Fluorometric Assay For Quantifying Polysorbate In Biopharmaceutical Products Using Micelle Activated Fluorescence Probe N-Phenyl-1-Naphthylamine.

PURPOSE: Polysorbates are among the most used surfactants in biopharmaceutical products containing proteins. Our work aims to develop a high-throughput fluorometric assay to further diversify the analytical toolbox for quantification of PSs. METHOD: The assay leverages the micelle activated fluorescence signal from N-Phenyl-1-Naphthylamine (NPN). The development and optimization of assay parameters were guided by the pre-defined analytical target profile. Furthermore, NMR was used to probe the interaction between protein, PS80 and NPN in the measurement system and understand protein interference. RESULTS: All assay parameters including excitation and emission wavelengths, standard curve, NPN concentration, and incubation time have been optimized and adapted to a microplate format, making it compatible with automated solutions that will be pursued in the near future to drive consistency and efficiency in our workflows. The specificity, accuracy, and precision of the assay have been demonstrated through a case study. Furthermore, NMR results provided additional insight into the change of the interaction dynamics between PS80 and NPN as the protein concentration increases. The results indicate minimal interaction between the protein and PS80 at lower concentration. However, when the concentration exceeds 75 mg/mL, there is a significant interaction between the protein and PS-80 micelle and monomer. CONCLUSION: A high-throughput fluorometric assay has been developed for quantification of polysorbates in biopharmaceutical samples including in-process samples, drug substance and drug product. The assay reported herein could serve as a powerful analytical tool for polysorbate quantification and control, complementing the widely used liquid chromatography with charged aerosol detection method.

Poly(Photosensitizer-Prodrug) Unimolecular Micelles for Chemo-Photodynamic Synergistic Therapy of Antitumor and Antibacteria.

It is crucial to use simple methods to prepare stable polymeric micelles with multiple functions for cancer treatment. Herein, via a "bottom-up" strategy, we reported the fabrication of ß-CD-(PEOSMA-PCPTMA-PPEGMA)21 (ßPECP) unimolecular micelles that could simultaneously treat tumors and bacteria with chemotherapy and photodynamic therapy (PDT). The unimolecular micelles consisted of a 21-arm ß-cyclodextrin (ß-CD) core as a macromolecular initiator, photosensitizer eosin Y (EOS-Y) monomer EOSMA, anticancer drug camptothecin (CPT) monomer, and a hydrophilic shell PEGMA. Camptothecin monomer (CPTMA) could achieve controlled release of the CPT due to the presence of responsively broken disulfide bonds. PEGMA enhanced the biocompatibility of micelles as a hydrophilic shell. Two ßPECP with different lengths were synthesized by modulating reaction conditions and the proportion of monomers, which both were self-assembled to unimolecular micelles in water. ßPECP unimolecular micelles with higher EOS-Y/CPT content exhibited more excellent 1O2 production, in vitro drug release efficiency, higher cytotoxicity, and superior antibacterial activity. Also, we carried out simulations of the self-assembly and CPT release process of micelles, which agreed with the experiments. This nanosystem, which combines antimicrobial and antitumor functions, provides new ideas for bacteria-mediated tumor clinical chemoresistance.

Ready, Set, Grow: From Micelles to Giant Vesicles via Biocatalytic Activation.

Controlling physicochemical processes that drive changes in supramolecular aggregates is an important objective toward creating artificial soft micro- and nanomachines. Previous research explored the morphology control of membrane-based materials subjected to externally imposed chemical stimuli. Here, we modulate the microscale morphology of pH-responsive assemblies by using biocatalysis to internally generate changes in global pH. Catalytic reactions offer flexibility in the mechanism and rate at which stimuli are introduced to responsive assemblies, ultimately enabling precision and control over size and morphology. We observed, by dynamic light scattering and fluorescence microscopy, substantial microscale differences between assemblies subjected to manually titrated pH changes compared to biocatalytically activated pH changes, including the growth of giant vesicles from micelles. Coarse-grained molecular dynamics simulations of these metastable self-assembled structures provided insight into the thermodynamics and kinetics of the preferred structures. These results demonstrate the feasibility of using biocatalytic reactions to modulate the size and morphology of supramolecular assemblies, from micelles to giant vesicles.

Hierarchical Self-Aggregation of Multifunctional Steviol Glycosides in Aqueous Solutions.

Steviol glycosides (SGs) are a natural sweetener widely used in the food and beverage industry, but the low solubility and stability of SG aqueous solutions greatly limit their application performance, especially in liquid formulations. In this work, we explore the solubility behavior of rebaudioside A (Reb A) in water, a major component of SGs, with the aim of clarifying the underlying mechanisms of the solubility and stability constraints of SGs, as well as the impact on their multifunctional properties. We demonstrate for the first time that Reb A exhibits hierarchical self-assembly in solutions, forming spherical micelles first when the concentration exceeds its critical micelle concentration (5.071 mg/mL), which then further assemble into large rod-like aggregates. The formation of such large Reb A aggregates is mainly dominated by hydrogen bonding and short-range Coulomb interaction energy, thus leading to the low solubility and precipitation of Reb A solutions. Surprisingly, aggregated Reb A structures display significantly improved organoleptic properties, revealing that self-aggregation can be developed as a simple, efficient, and green strategy for improving the taste profile of SGs. Additionally, the self-aggregation of Reb A at high concentrations impairs active encapsulation and also affects its interfacial and emulsifying properties.

Succinyl Curcumin Conjugated Chitosan Polymer-Prodrug Nanomicelles: A Potential Treatment for Type-II Diabetes in Diabetic Balb/C Mice.

Diabetes mellitus is a chronic metabolic disorder marked by elevated blood sugar levels, leading to organ dysfunction. Curcumin, derived from turmeric, exhibits promise in managing type II diabetes. Nanomicelles were created by conjugating curcumin with chitosan through succinic anhydride. Succinyl-curcumin, the resultant compound, was esterified with chitosan to form a polymer prodrug conjugate. Nanomicelles, formed via dialysis, were spherical with a hydrodynamic size of 49.37 nm. In vitro release studies revealed 97% curcumin release at pH 5 in 7 days. A 21-day experiment on diabetic mice compared nanomicelles, standard drug, and free curcumin's impact on fasting blood glucose. The study showcased gradual, controlled curcumin release from nanomicelles, suggesting their potential in type II diabetes treatment.

Insight into the interaction of quinizarin with SDS micelles - effects of additives.

Association behavior between quinizarin (1,4-dihydroxyanthraquinone), an analogue of the chromophore of anthracycline anticancer drugs and sodium dodecyl sulfate (SDS) micelles in the presence of glucose, NaCl and urea additives was studied using absorption spectroscopy and conductometric techniques. The spectral results indicate an increase of binding constant and partition coefficient values in the presence of glucose and NaCl whereas the addition of urea leads to a decrease of binding strength and quinizarin partitioning into SDS micelles. Thus, the rise of NaCl and glucose concentrations is favorable for the quinizarin distribution into SDS micelles. From electrical conductivity measurements it was found that the critical micelle concentration (CMC) of SDS/quinizarin system decreases by adding NaCl and glucose whereas urea has not influence on the micelization process at the concentrations used in the present study. Since biologically compounds like glucose, NaCl and urea are found in the human body, the attained outcomes can be important in finding of effective drug delivery systems.

Nanostructured lipopeptide-based membranomimetics for stabilizing bacteriorhodopsin.

Nanostructured 7-9-residue cyclic and unstructured lipopeptide-based facial detergents have been engineered to stabilize the model integral membrane protein, bacteriorhodopsin. Formation of a cylindrical-type micelle assembly induced by facial amphipathic lipopeptides resembles a biological membrane more effectively than conventional micelles. The hydrophobic face of this cylindrical-type micelle provides extended stability to the membrane protein and the hydrophilic surface interacts with an aqueous environment. In our present study, we have demonstrated experimentally and computationally that lipopeptide-based facial detergents having an unstructured or ß-turn conformation can stabilize membrane proteins. However, constrained peptide detergents can provide enhanced stability to bacteriorhodopsin. In this study, we have computationally examined the structural stability of bacteriorhodopsin in the presence of helical, beta-strand, and cyclic unstructured peptide detergents, and conventional detergent-like peptides. Our study demonstrates that optimal membranomimetics (detergents) for stabilizing a specific membrane protein can be screened based on the following criteria: (i) hydrodynamic radii of the self-assembled peptide detergents, (ii) stability assay of detergent-encased membrane proteins, (iii) percentage covered area of detergent-encased membrane proteins obtained computationally and (iv) protein-detergent interaction energy.

Rigid Cyclic Fluorinated Detergents: Fine-Tuning the Hydrophilic-Lipophilic Balance Controls Self-Assembling and Biochemical Properties.

We report herein the synthesis of three detergents bearing a perfluorinated cyclohexyl group connected through a short, hydrogenated spacer (i.e., propyl, butyl, or pentyl) to a ß-maltoside polar head that are, respectively, called FCymal-3, FCymal-4, and FCymal-5. Increasing the length of the spacer decreased the critical micellar concentration (CMC), as demonstrated by surface tension (SFT) and isothermal titration calorimetry (ITC), from 5 mM for FCymal-3 to 0.7 mM for FCymal-5. The morphology of the micelles was studied by dynamic light scattering (DLS), analytical ultracentrifugation (AUC), and small-angle X-ray scattering (SAXS), indicating heterogeneous rod-like shapes. While micelles of FCymal-3 and -4 have similar hydrodynamic diameters of ∼10 nm, those of FCymal-5 were twice as large. We also investigated the ability of the detergents to solubilize lipid membranes made of 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine (POPC). Molecular modeling indicated that the FCymal detergents generate disorder in lipid bilayers, with FCymal-3 being inserted more deeply into bilayers than FCymal-4 and -5. This was experimentally confirmed using POPC vesicles that were completely solubilized within 2 h with FCymal-3, whereas FCymal-5 required >8 h. A similar trend was noticed for the direct extraction of membrane proteins from E. coli membranes, with FCymal-3 being more potent than FCymal-5. An opposite trend was observed in terms of stabilization of the two model membrane proteins bacteriorhodopsin (bR) and SpNOX. In all three FCymal detergents, bR was stable for at least 2 months with no signs of aggregation. However, while the structural integrity of bR was fully preserved in FCymal-4 and -5, minor bleaching was observed in FCymal-3. Similarly, SpNOX exhibited the least activity in FCymal-3 and the highest activity in FCymal-5. By combining solubilizing and stabilizing potency, FCymal detergents push forward our expectations of the usefulness of fluorinated detergents for handling and investigating membrane proteins.