Facial Amphiphiles Research Articles

Bile Acid Nanoparticles - An Emerging Approach for Site Specific Drug Targeting

Abstract: Bile acids, a group of steroidal acids present in the bile act as biological surfactants and ligands for bile acid transporter proteins for signalling molecules to perform various paracrine and endocrine functions. The enterohepatic circulation of bile acids can be exploited to develop at-tractive drug delivery approaches with improved targetability of facial amphiphiles and enhanced drug bioavailability by improving absorption and metabolic stability. The effectiveness, safety and targetability of nanoparticles conjugated with bile acids and salts have been discussed in the present review. Various modifications of bile acids promoting absorption and oral bioavailability of drugs for treatment of various disease conditions such as cancer, diabetes and psychosis has al-so been discussed. Additionally, neuroprotective effect of bile acids and salts has demonstrated utility in various neurodegenerative disorders. Nanoparticles based on bile acids and salts repre-sent an area of emergent interest due to their unique and modifiable properties for improving ef-fectiveness of drugs.

Facial Amphiphile-Modified Lipids Highly Sensitize Liposomes toward Secretory Phospholipase A2.

Upregulated secretory phospholipase A2 (sPLA2) in tumors has been proposed as a stimulus to trigger drug release from liposomes for therapeutic effects. However, the current strategy for developing sPLA2-responsive liposomes merely considering substrate preference suffers from limited membrane disruptive effects induced by enzymatic hydrolysis and safety issues resulting from the overuse of sPLA2-preferred lipids. Here, a membrane-destabilizing mechanism based on enzymatic extraction and the transition of facial amphiphiles (FAs) within lipid membranes was introduced. Enzymatic degradation of FA-modified lipids, a process involving substrate extraction of lipids from membranes and cleavage of sn-2 ester bonds by sPLA2, rotation, and interface settling of detached FAs, caused tremendous efflux of payloads from liposomes, termed the SECRIS effect. In the presence of sPLA2, oxaliplatin (L-OHP) loaded liposomes containing FA-modified lipids showed enhanced drug release, comparable in vitro cytotoxicity, and excellent in vivo antitumor efficacy and reduced adverse syndromes in Colo205-bearing mice compared to conventional sPLA2-labile formulations. The discovery of the SECRIS effect creates a new pathway to engineer liposome platforms for the treatment of sPLA2-positive tumors.

Reshaping the aggregation landscape of benzothiadiazole employing steroidal scaffolds and conformationally free alkyne tethers

In this study, we target the introduction of conformational freedom to BTD, aiming to unlock new solid-state arrangements that were previously inaccessible, while striving to maintain its high fluorescence quantum yield. Our approach is grounded in a detailed exploration of the conformational space of designed molecules, employing molecular mechanics to predict and evaluate the impact of structural modifications on solubility and solid-state behavior. By strategically flanking the BTD core with steroidal fragments through alkyne bridges, we not only introduce bulky elements that disrupt the native crystal-packing landscape of pristine BTD, but also ensure significant rotational freedom around the carbon-carbon triple bonds. This design strategy allows the molecules to explore a wide range of conformations, potentially facilitating the formation of novel solid-state supramolecular arrangements.The synthesis of these compounds revealed that they exhibit adequate processability in solution and form solids that prove crystalline by powder X-ray diffraction, but do not readily form macroscopic crystals as BTD normally does. The steroid fragments play a crucial role in determining the supramolecular organization of these compounds. Depending on the specific functional groups present on the steroid skeleton, primary interactions such as hydrogen bonding and secondary interactions related to facial amphiphilicity dictate the overall arrangement of molecules in the solid state.Remarkably, the modifications successfully preserve the intrinsic high fluorescence quantum yield of the BTD core. This achievement underscores the potential of incorporating conformational flexibility into molecular design to access new material properties while retaining desirable photophysical characteristics.

Influence of the enzymatic treatment and pH on the interfacial and emulsifying properties of sunflower and olive protein hydrolysates

This work investigates the influence of the enzymatic treatment (Alcalase or trypsin, degree of hydrolysis 5%) and pH (pH 7 or 4) on the interfacial and emulsifying properties of sunflower and olive protein hydrolysates. Independently of the enzymatic treatment, short peptides (1–3 kDa) were the most abundant in sunflower protein hydrolysates, whereas olive protein hydrolysates were richer in large peptides (>10 kDa). Peptides present in all hydrolysates gained in structure when adsorbing at the oil-water interface due to their facial amphiphilicity, with sunflower peptides presenting a more marked β-sheet conformation than olive peptides. Tryptic hydrolysates of both substrates showed higher interfacial adsorption compared to hydrolysates produced with Alcalase, especially at pH 4. All hydrolysates resulted in elastic interfaces, with generally higher values of dilatational complex modulus at pH 7 compared to pH 4. These findings correlated well with the higher emulsifying activity of all hydrolysates at pH 7 than pH 4. Particularly, sunflower protein hydrolysates led to stiffer and more solid-like viscoelastic interfacial layers than olive peptides due to increased interactions between β-sheet peptides at the interface. Indeed, the use of sunflower protein hydrolysates as emulsifiers resulted in 5 wt% oil-in-water emulsions with higher physical stability at both pH 7 and 4 when compared to olive protein hydrolysates.

Facial amphiphilic naphthoic acid-derived antimicrobial polymers against multi-drug resistant gram-negative bacteria and biofilms

Inspired by the facial amphiphilic nature and antimicrobial efficacy of many antimicrobial peptides, this work reported facial amphiphilic bicyclic naphthoic acid derivatives with different ratios of charges to rings that were installed onto side chains of poly(glycidyl methacrylate). Six quaternary ammonium-charged (QAC) polymers were prepared to investigate the structure-activity relationship. These QAC polymers displayed potent antibacterial activity against various multi-drug resistant (MDR) gram-negative pathogens such as Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. Polymers demonstrated low hemolysis and high antimicrobial selectivity. Additionally, they were able to eradicate established biofilms and kill metabolically inactive dormant cells. The membrane permeabilization and depolarization results indicated a mechanism of action through membrane disruption. Two lead polymers showed no resistance from MDR-P. aeruginosa and MDR-K. pneumoniae. These facial amphiphiles are potentially a new class of potent antimicrobial agents to tackle the antimicrobial resistance for both planktonic and biofilm-related infections.

Main-Chain Cationic Bile Acid Polymers Mimicking Facially Amphiphilic Antimicrobial Peptides.

Antibiotic-resistant bacterial infections have led to an increased demand for antibacterial agents that do not contribute to antimicrobial resistance. Antimicrobial peptides (AMPs) with the facially amphiphilic structures have demonstrated remarkable effectiveness, including the ability to suppress antibiotic resistance during bacterial treatment. Herein, inspired by the facially amphiphilic structure of AMPs, the facially amphiphilic skeletons of bile acids (BAs) are utilized as building blocks to create a main-chain cationic bile acid polymer (MCBAP) with macromolecular facial amphiphilicity via polycondensation and a subsequent quaternization. The optimal MCBAP displays an effective activity against Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative Escherichia coli, fast killing efficacy, superior bactericidal stability in vitro, and potent anti-infectious performance in vivo using the MRSA-infected wound model. MCBAP shows the low possibility to develop drug-resistant bacteria after repeated exposure, which may ascribe to the macromolecular facial amphiphilicity promoting bacterial membrane disruption and the generation of reactive oxygen species. The easy synthesis and low cost of MCBAP, the superior antimicrobial performance, and the therapeutic potential in treating MRSA infection altogether demonstrate that BAs are a promising group of building blocks to mimic the facially amphiphilic structure of AMPs in treating MRSA infection and alleviating antibiotic resistance.

Designing antimicrobial biomembranes via clustering amino-modified cellulose nanocrystals on silk fibroin β-sheets

The continuous rising of infections caused by multidrug-resistant pathogens is becoming a global healthcare concern. Developing new bio-based materials with unique chemical and structural features that allow efficient interaction with bacteria is thus important for fighting this phenomenon. To address this issue, we report an antimicrobial biomaterial that results from clustering local facial amphiphilicity from amino-modified cellulose on silk fibroin β-sheets, by simply blending the two components through casting technology. A simple but effective method for creating a membrane that is antibacterial and non-cytotoxic. Amino-modified cellulose nanocrystals (CNC-NH2) were mixed with proteinaceous silk fibroin (SF) which resulted in a material with improved crystallinity, higher β-sheet content, and exposed amino-groups at its surface features, proven by Fourier transform infrared (FTIR) spectroscopy and X-ray photoelectron spectroscopy (XPS), that does not occur when the components are individually assembled. The resulting material possesses important antibacterial activity inducing >3 CFU log10 reduction of Escherichia coli and Staphylococcus epidermidis, while the pristine membranes show no antibacterial effect. The chemical interactions occurring between SF and CNC-NH2 during casting, exposing the amino moieties at the surface of the material, are proposed as the main reason for this antimicrobial activity. Importantly, the membranes are non-cytotoxic, showing their potential to be used as a new bioinspired material with intrinsic antibacterial activity for biomedical applications. Those may include coatings for medical devices for the control of healthcare-associated infections, with no need for including external antimicrobial agents in the material.

Facially Amphiphilic Skeleton-Derived Antibacterial Cationic Dendrimers.

It is urgent to develop biocompatible and high-efficiency antimicrobial agents since microbial infections have always posed serious challenges to human health. Herein, through the marriage of facially amphiphilic skeletons and cationic dendrimers, high-density positively charged dendrimers D-CA6-N+ (G2) and D-CA2-N+ (G1) were designed and synthesized using the "branch" of facially amphiphilic bile acids, followed by their modification with quaternary ammonium charges. Both dendrimers could self-assemble into nanostructured micelles in aqueous solution. D-CA6-N+ displays potent antibacterial activity against Staphylococcus aureus and Escherichia coli, with minimum inhibitory concentrations (MICs) as low as 7.50 and 7.79 μM, respectively, and has an evidently stronger antibacterial activity than D-CA2-N+. Moreover, D-CA6-N+ can kill S. aureus faster than E. coli. The facial amphiphilicity of the bile acid skeleton facilitates the selective destruction of bacterial membranes and endows dendrimers with negligible hemolysis and cytotoxicity even under a high concentration of 16× MIC. In vivo studies show that D-CA6-N+ is much more effective and safer than penicillin G in treating S. aureus infection and promoting wound healing, which suggests facially amphiphilic skeleton-derived cationic dendrimers can be a promising approach to effectively enhance antibacterial activity and biocompatibility of antibacterial agent, simultaneously.

Interfacial behavior and emulsion stability of lipid delivery system regulated by two-dimensional facial amphiphiles bile salts

Bile salts as two-dimension facial amphiphile effectively emulsify lipids at low concentrations to promote gut digestion. Hence, we select various bile salts sodium cholate (NaC), sodium glycocholate (NaGC) and sodium taurocholate (NaTC) to study the interfacial tension and rheological dilational modulus to illustrate the interfacial adsorption mechanism and interface film strength, which is closely related to emulsion stability. Unlike linear surfactant molecules, the interfacial behavior of bile salts contains into two stages. At the low concentration for the first stage, the rigid facial molecules adsorb at the lipid-water interface with the hydrophilic concave and hydrophobic convex surface. And the interfacial relaxation is mainly dominated by intermolecular interaction and diffusion exchange, resulting in that the adsorption layer is especially an elastic film. During the second stage, aggregates are gradually generated at the interface as the concentration increases, and the interfacial relaxation is mainly dominated by the rapid diffusion exchange between the adsorption film and the sublayer, leading to the faster formation of the adsorption film. The mechanism of facial amphiphile adsorbed at lipid-water interface indicates soft molecular membrane established at interfaces on account of intermolecular interaction, revealing that higher interfacial strength benefits emulsion stability. We also found that NaTC with excellent adsorption capacity can stabilize edible oil for 8 h to facilitate lipid digestion. Compared with linear surfactant, bile salts with great biocompatibility can form two-dimension adsorption layer to emulsify and stabilize lipids, which can be widely used in lipid delivery system.

Facial amphiphilicity index correlating chemical structures with antimicrobial efficacy.

Facial amphiphilicity is an extraordinary chemical structure feature of a variety of antimicrobial peptides and polymers. Vast efforts have been dedicated to small molecular, macromolecular and dendrimer-like systems to mimic this highly preferred structure or conformation, including local facial amphiphilicity and global amphiphilicity. This work conceptualizes Facial Amphiphilicity Index (FAI) as a numerical value to quantitatively characterize the measure of chemical compositions and structural features in dictating antimicrobial efficacy. FAI is a ratio of numbers of charges to rings, representing both compositions of hydrophilicity and hydrophobicity. Cationic derivatives of multicyclic compounds were evaluated as model systems for testing antimicrobial selectivity against Gram-negative and Gram-positive bacteria. Both monocyclic and bicyclic compounds are non-antimicrobial regardless of FAIs. Antimicrobial efficacy was observed with systems having larger cross-sectional areas including tricyclic abietic acid and tetracyclic bile acid. While low and high FAIs respectively lead to higher and lower antimicrobial efficacy, in consideration of cytotoxicity, the sweet spot is typically suited with intermediate FAIs for each specific system. This can be well explained by the synergistic hydrophobic-hydrophobic and electrostatic interactions with bacterial cell membranes and the difference between bacterial and mammalian cell membranes. The adoption of FAI would pave a new avenue toward the design of next-generation antimicrobial macromolecules and peptides.

Antimicrobial Polymers of Linear and Bottlebrush Architecture: Probing the Membrane Interaction and Physicochemical Properties

Polymeric antimicrobial peptide mimics are a promising alternative for the future management of the daunting problems associated with antimicrobial resistance. However, the development of successful antimicrobial polymers (APs) requires careful control of factors such as amphiphilic balance, molecular weight, dispersity, sequence, and architecture. While most of the earlier developed APs focus on random linear copolymers, the development of APs with advanced architectures proves to be more potent. It is recently developed multivalent bottlebrush APs with improved antibacterial and hemocompatibility profiles, outperforming their linear counterparts. Understanding the rationale behind the outstanding biological activity of these newly developed antimicrobials is vital to further improving their performance. This work investigates the physicochemical properties governing the differences in activity between linear and bottlebrush architectures using various spectroscopic and microscopic techniques. Linear copolymers are more solvated, thermo-responsive, and possess facial amphiphilicity resulting in random aggregations when interacting with liposomes mimicking Escheria coli membranes. The bottlebrush copolymers adopt a more stable secondary conformation in aqueous solution in comparison to linear copolymers, conferring rapid and more specific binding mechanism to membranes. The advantageous physicochemical properties of the bottlebrush topology seem to be a determinant factor in the activity of these promising APs.

Solvent-Driven Transformation of Zn/Cd2+-Deoxycholate Assemblies.

Deoxycholic acid (DOC) is a unique, biologically derived surfactant with facial amphiphilicity that has been exploited, albeit minimally, in supramolecular assembly of materials. Here, we present the synthesis and structural characterization of three hybrid metal (Zn2+ and Cd2+)-DOC compounds. Analysis by single-crystal X-ray diffraction reveals the many interactions that are possible between these facial surfactants and the influence of solvent molecules that drive the assembly of materials. These structures are the first metal-DOC complexes besides those obtained from alkali and alkaline earth metals. We isolated polymeric chains of both Cd and Zn (Znpoly-DOC and Cdpoly-DOC) from water. Major interactions between DOC molecules in these phases are hydrophobic in nature. Cdpoly-DOC exhibits unique P1 symmetry, with complete interdigitation of the amphiphiles between neighboring polymeric chains. Zn4-DOC, obtained from methanol dissolution of Znpoly-DOC, features the OZn4 tetrahedron, widely known in basic zinc acetate and MOF-5 (metal organic framework). We document a solvent-driven, room-temperature transition between Znpoly-DOC and Zn4-DOC (in both directions) by scanning and transmission electron microscopies in addition to small-angle X-ray scattering, powder X-ray diffraction, and infrared spectroscopy. These studies show the methanol-driven transition of Znpoly-DOC to Zn4-DOC occurs via an intermediate with no long-range order of the Zn4 clusters, indicating the strongest interactions driving assembly are intramolecular. On the contrary, water-driven solid-to-solid transformation from Zn4-DOC to Znpoly-DOC exhibits crystal-to-crystal transformation. Znpoly-DOC is robust, easy to synthesize, and comprised of biologically benign components, so we demonstrate dye absorption as a proxy for water treatment applications. It favors absorption of positively charged dyes. These studies advance molecular level knowledge of the supramolecular assembly of facial surfactants that can be exploited in the design of organic-inorganic hybrid materials. This work also highlights the potential of solvent for tuning supramolecular assembly processes, leading to new hybrid materials featuring facial surfactants.

Physiology and Physical Chemistry of Bile Acids.

Bile acids (BAs) are facial amphiphiles synthesized in the body of all vertebrates. They undergo the enterohepatic circulation: they are produced in the liver, stored in the gallbladder, released in the intestine, taken into the bloodstream and lastly re-absorbed in the liver. During this pathway, BAs are modified in their molecular structure by the action of enzymes and bacteria. Such transformations allow them to acquire the chemical–physical properties needed for fulling several activities including metabolic regulation, antimicrobial functions and solubilization of lipids in digestion. The versatility of BAs in the physiological functions has inspired their use in many bio-applications, making them important tools for active molecule delivery, metabolic disease treatments and emulsification processes in food and drug industries. Moreover, moving over the borders of the biological field, BAs have been largely investigated as building blocks for the construction of supramolecular aggregates having peculiar structural, mechanical, chemical and optical properties. The review starts with a biological analysis of the BAs functions before progressively switching to a general overview of BAs in pharmacology and medicine applications. Lastly the focus moves to the BAs use in material science.

Improving the Cellular Selectivity of a Membrane-Disrupting Antimicrobial Agent by Monomer Control and by Taming.

Antimicrobial resistance represents a significant world-wide health threat that is looming. To meet this challenge, new classes of antimicrobial agents and the redesign of existing ones will be required. This review summarizes some of the studies that have been carried out in my own laboratories involving membrane-disrupting agents. A major discovery that we made, using a Triton X-100 as a prototypical membrane-disrupting molecule and cholesterol-rich liposomes as model systems, was that membrane disruption can occur by two distinct processes, depending on the state of aggregation of the attacking agent. Specifically, we found that monomers induced leakage, while attack by aggregates resulted in a catastrophic rupture of the membrane. This discovery led us to design of a series of derivatives of the clinically important antifungal agent, Amphotericin B, where we demonstrated the feasibility of separating antifungal from hemolytic activity by decreasing the molecule’s tendency to aggregate, i.e., by controlling its monomer concentration. Using an entirely different approach (i.e., a “taming” strategy), we found that by covalently attaching one or more facial amphiphiles (“floats”) to Amphotericin B, its aggregate forms were much less active in lysing red blood cells while maintaining high antifungal activity. The possibility of applying such “monomer control” and “taming” strategies to other membrane-disrupting antimicrobial agents is briefly discussed.

Site‐Selective Oxidation of Monolayered Liquid‐Exfoliated WS2 by Shielding the Basal Plane through Adsorption of a Facial Amphiphile

AbstractIn recent years, various functionalization strategies for transition‐metal dichalcogenides have been explored to tailor the properties of materials and to provide anchor points for the fabrication of hybrid structures. Herein, new insights into the role of the surfactant in functionalization reactions are described. Using the spontaneous reaction of WS2 with chloroauric acid as a model reaction, the regioselective formation of gold nanoparticles on WS2 is shown to be heavily dependent on the surfactant employed. A simple model is developed to explain the role of the chosen surfactant in this heterogeneous functionalization reaction. The surfactant coverage is identified as the crucial element that governs the dominant reaction pathway and therefore can severely alter the reaction outcome. This study shows the general importance of the surfactant choice and how detrimental or beneficial a certain surfactant can be to the desired functionalization.

Site-Selective Oxidation of Monolayered Liquid-Exfoliated WS2 by Shielding the Basal Plane through Adsorption of a Facial Amphiphile.

In recent years, various functionalization strategies for transition‐metal dichalcogenides have been explored to tailor the properties of materials and to provide anchor points for the fabrication of hybrid structures. Herein, new insights into the role of the surfactant in functionalization reactions are described. Using the spontaneous reaction of WS2 with chloroauric acid as a model reaction, the regioselective formation of gold nanoparticles on WS2 is shown to be heavily dependent on the surfactant employed. A simple model is developed to explain the role of the chosen surfactant in this heterogeneous functionalization reaction. The surfactant coverage is identified as the crucial element that governs the dominant reaction pathway and therefore can severely alter the reaction outcome. This study shows the general importance of the surfactant choice and how detrimental or beneficial a certain surfactant can be to the desired functionalization.

Cover Picture: Site‐Selective Oxidation of Monolayered Liquid‐Exfoliated WS2 by Shielding the Basal Plane through Adsorption of a Facial Amphiphile (Angew. Chem. Int. Ed. 33/2020)

Cover Picture: Site‐Selective Oxidation of Monolayered Liquid‐Exfoliated WS₂ by Shielding the Basal Plane through Adsorption of a Facial Amphiphile (Angew. Chem. Int. Ed. 33/2020)

Investigation of the structure-activity relationship in ponericin L1 from Neoponera goeldii.

Naturally derived antimicrobial peptides have been an area of great interest because of high selectivity against bacterial targets over host cells and the limited development of bacterial resistance to these molecules throughout evolution. There are also a significant number of venom-derived peptides that exhibit antimicrobial activity in addition to activity against mammals or other organisms. Many venom peptides share the same net cationic, amphiphilic nature as host-defense peptides, making them an attractive target for development as potential antibacterial agents. The peptide ponericin L1 derived from Neoponera goeldii was used as a model to investigate the role of cationic residues and net charge on peptide activity. Using a combination of spectroscopic and microbiological approaches, the role of cationic residues and net charge on antibacterial activity, lipid bilayer interactions, and bilayer and membrane permeabilization were investigated. The L1 peptide and derivatives all showed enhanced binding to lipid vesicles containing anionic lipids, but still bound to zwitterionic vesicles. None of the derivatives were especially effective at permeabilizing lipid bilayers in model vesicles, in-tact Escherichia coli, or human red blood cells. Taken together the results indicate that the lack of facial amphiphilicity regarding charge segregation may impact the ability of the L1 peptides to effectively permeabilize bilayers despite effective binding. Additionally, increasing the net charge of the peptide by replacing the lone anionic residue with either Gln or Lys dramatically improved efficacy against several bacterial strains without increasing hemolytic activity.

Identification of emulsifier potato peptides by bioinformatics: application to omega-3 delivery emulsions and release from potato industry side streams

In this work, we developed a novel approach combining bioinformatics, testing of functionality and bottom-up proteomics to obtain peptide emulsifiers from potato side-streams. This is a significant advancement in the process to obtain emulsifier peptides and it is applicable to any type of protein. Our results indicated that structure at the interface is the major determining factor of the emulsifying activity of peptide emulsifiers. Fish oil-in-water emulsions with high physical stability were stabilized with peptides to be predicted to have facial amphiphilicity: (i) peptides with predominantly α-helix conformation at the interface and having 18–29 amino acids, and (ii) peptides with predominantly β-strand conformation at the interface and having 13–15 amino acids. In addition, high physically stable emulsions were obtained with peptides that were predicted to have axial hydrophobic/hydrophilic regions. Peptides containing the sequence FCLKVGV showed high in vitro antioxidant activity and led to emulsions with high oxidative stability. Peptide-level proteomics data and sequence analysis revealed the feasibility to obtain the potent emulsifier peptides found in this study (e.g. γ-1) by trypsin-based hydrolysis of different side streams in the potato industry.

Facial Amphiphilicity-Induced Polymer Nanostructures for Antimicrobial Applications.

New antimicrobial agents are needed to address ever-increasing antimicrobial resistance and a growing epidemic of infections caused by multidrug resistant pathogens. We design nanostructured antimicrobial copolymers containing multicyclic natural products that bear facial amphiphilicity. Bile acid based macromolecular architectures of these nanostructures can interact preferentially with bacterial membranes. Incorporation of polyethylene glycol into the copolymers not only improved the colloidal stability of nanostructures but also increased the biocompatibility. This study investigated the effects of facial amphiphilicity, polymer architectures, and self-assembled nanostructures on antimicrobial activity. Advanced nanostructures such as spheres, vesicles, and rod-shaped aggregates are formed in water from the facial amphiphilic cationic copolymers via supramolecular interactions. These aggregates were particularly interactive toward Gram-positive and Gram-negative bacterial cell membranes and showed low hemolysis against mammalian cells.