Targeted Polymeric Nanoparticles Based on Mangiferin for Enhanced Protection of Pancreatic ß-Cells and Type 1 Diabetes Mellitus Efficacy.

Mangiferin (MGF) is found in many natural plants, such as Rhizoma Anemarrhenae, and has anti-diabetes effects. However, its clinical applications and development are limited by poor solubility and low-concentration enrichment in pancreatic islets. In this paper, targeted polymeric nanoparticles were constructed for MGF delivery with the desired drug loading content (6.86 ± 0.60%), excellent blood circulation, and missile-like delivery to the pancreas. Briefly, Glucagon-like peptide 1 (GLP-1) as an active targeting agent to the pancreas was immobilized on the block copolymer polyethyleneglycol-polycaprolactone (PEG-PCL) to obtain final GLP-1-PEG-PCL amphiphiles. Spherical MGF-loaded polymeric nanoparticles were acquired from the self-assembly of the targeted GDPP nanoparticles and MGF with a homogeneous size of 158.9 ± 1.7 nm and a negative potential for a good steady state in circulation. In this drug vehicle, GLP-1 acts as the missile vanguard via the GLP-1 receptor on the surface of the pancreas for improving the accumulation and efficiency of MGF in the pancreas, the hypoglycemic effect of MGF, and the restorative effect on pancreatic islets, which were investigated. As compared to free MGF, MGF/GDPP nanoparticles appeared to be more concentrated in the pancreas, with better blood glucose and glucose tolerance, enhanced insulin levels, increased ß-cell proliferation, reduced ß-cell apoptosis, and islet repair in vivo. This targeted drug delivery system provided a novel strategy and hope for enhancing MGF delivery and anti-diabetes efficacy.

CNSL, a Promising Building Blocks for Sustainable Molecular Design of Surfactants: A Critical Review.

Surfactants are crystallizing a certain focus for consumer interest, and their market is still expected to grow by 4 to 5% each year. Most of the time these surfactants are of petroleum origin and are not often biodegradable. Cashew Nut Shell Liquid (CNSL) is a promising non-edible renewable resource, directly extracted from the shell of the cashew nut. The interesting structure of CNSL and its components (cardanol, anacardic acid and cardol) lead to the synthesis of biobased surfactants. Indeed, non-ionic, anionic, cationic and zwitterionic surfactants based on CNSL have been reported in the literature. Even now, CNSL is absent or barely mentioned in specialized review or chapters talking about synthetic biobased surfactants. Thus, this review focuses on CNSL as a building block for the synthesis of surfactants. In the first part, it describes and criticizes the synthesis of molecules and in the second part, it compares the efficiency and the properties (CMC, surface tension, kraft temperature, biodegradability) of the obtained products with each other and with commercial ones.

Cationic amphiphilic dendrons with effective antibacterial performance.

Bacterial infections and antibiotic resistance have become a global healthcare crisis. Herein, we designed and synthesized a series of cationic amphiphilic dendrons with cationic dendrons and hydrophobic alkyl chains for potential antibacterial applications. Our results showed that the antimicrobial activities of the cationic amphiphilic dendrons were highly dependent upon the length of the hydrophobic alkyl chain, whereas the number of cationic charges was less important. Among these cationic amphiphilic dendrons, a prime candidate was identified, which possessed excellent antimicrobial activity against various pathogens (minimum inhibitory concentrations of 9, 3, and 3 µg mL-1 for Escherichia coli, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus, respectively). Scanning electron microscopy and fluorescence microscopy analyses showed that it could disrupt the integrity of a pathogen's membrane, leading to cell lysis and death. In addition, in vitro bacteria-killing kinetics showed that it had rapid bactericidal efficiency. It also had excellent antimicrobial activities against MRSA in vivo and promoted wound healing. In general, the synthesized cationic amphiphilic dendrons, which exhibited rapid and broad-spectrum bactericidal activity, may have great potential in antimicrobial applications.

Surfactant Effect on the Physicochemical Characteristics of Solid Lipid Nanoparticles Based on Pillar[5]arenes.

Novel monosubstituted pillar[5]arenes containing both amide and carboxyl functional groups were synthesized. Solid lipid nanoparticles based on the synthesized macrocycles were obtained. Formation of spherical particles with an average hydrodynamic diameter of 250 nm was shown for pillar[5]arenes containing N-(amidoalkyl)amide fragments regardless of their concentration. It was established that pillar[5]arene containing N-alkylamide fragments can form spherical particles with two different sizes (88 and 223 nm) depending on its concentration. Mixed solid lipid nanoparticles based on monosubstituted pillar[5]arenes and surfactant (dodecyltrimethylammonium chloride) were obtained for the first time. The surfactant made it possible to level the effect of the macrocycle concentration. It was found that various types of aggregates are formed depending on the macrocycle/surfactant ratio. Changing the macrocycle/surfactant ratio allows to control the charge of the particles surface. This controlled property will lead to the creation of molecular-scale porous materials that selectively interact with various types of substrates, including biopolymers.

Amphiphilic quaternized chitosan: Synthesis, characterization, and anti-cariogenic biofilm property.

Hydrophobized chitosan derivatives, hexyl chitosan (HCS), dodecyl chitosan (DCS), and phthaloyl chitosan (PhCS) of approximately 30 and 50% degree of substitution (%DS) reacted with glycidyltrimethylammonium chloride (GTMAC) to incorporate hydrophilic positively charged groups of N-[(2-hydroxyl-3-trimethylammonium)propyl] and yielded amphiphilic quaternized chitosan derivatives. They can assemble into spherical nanoparticles with a hydrodynamic diameter of ~100-300 nm and positive ζ-potential values (+15 to +56). Their anti-biofilm efficacy was evaluated against the dental caries pathogen, Streptococcus mutans. Among all derivatives, the one having 30%DS of hexyl group and prepared by reacting with 1 mol equivalent of GTMAC (H30CS-GTMAC) showed the best performance in terms of its aqueous solubility, the lowest minimum inhibitory concentration (138 µg/mL) and the minimum bactericidal concentration (275 µg/mL) which are superior to the unmodified chitosan. Its equivalent anti-biofilm efficacy to that of chlorhexidine suggests that it can be a greener antibacterial agent for oral care formulations.

Antimicrobial Properties and Cytotoxic Effect of Imidazolium Geminis with Tunable Hydrophobicity.

Antimicrobial, membranotropic and cytotoxic properties of dicationic imidazolium surfactants of n-s-n (Im) series with variable length of alkyl group (n = 8, 10, 12, 14, 16) and spacer fragment (s = 2, 3, 4) were explored and compared with monocationic analogues. Their activity against a representative range of Gram-positive and Gram-negative bacteria, and also fungi, is characterized. The relationship between the biological activity and the structural features of these compounds is revealed, with the hydrophobicity emphasized as a key factor. Among dicationic surfactants, decyl derivatives showed highest antimicrobial effect, while for monocationic analogues, the maximum activity is observed in the case of tetradecyl tail. The leading compounds are 2-4 times higher in activity compared to reference antibiotics and prove effective against resistant strains. It has been shown that the antimicrobial effect is not associated with the destruction of the cell membrane, but is due to specific interactions of surfactants and cell components. Importantly, they show strong selectivity for microorganism cells while being of low harm to healthy human cells, with a SI ranging from 30 to 100.

Phosphonodithioester-Amine Coupling as a Key Reaction Step for the Design of Cationic Amphiphiles Used for Gene Delivery.

A convergent synthesis of cationic amphiphilic compounds is reported here with the use of the phosphonodithioester-amine coupling (PAC) reaction. This versatile reaction occurs at room temperature without any catalyst, allowing binding of the lipid moiety to a polar head group. This strategy is illustrated with the use of two lipid units featuring either two oleyl chains or two-branched saturated lipid chains. The final cationic amphiphiles were evaluated as carriers for plasmid DNA delivery in four cell lines (A549, Calu3, CFBE and 16HBE) and were compared to standards (BSV36 and KLN47). These new amphiphilic derivatives, which were formulated with DOPE or DOPE-cholesterol as helper lipids, feature high transfection efficacies when associated with DOPE. The highest transfection efficacies were observed in the four cell lines at low charge ratios (CR = 0.7, 1 or 2). At these CRs, no toxic effects were detected. Altogether, this new synthesis scheme using the PAC reaction opens up new possibilities for investigating the effects of lipid or polar head groups on transfection efficacies.

Supramolecular Drug Delivery System from Macrocycle-Based Self-Assembled Amphiphiles for Effective Tumor Therapy.

Intelligent drug delivery systems (DDSs) that can improve therapeutic outcomes of antitumor agents and decrease their side effects are urgently needed to satisfy special requirements of treatment of malignant tumors in clinics. Here, the fabrication of supramolecular self-assembled amphiphiles based on the host-guest recognition between a cationic water-soluble pillar[6]arene (WP6A) host and a sodium decanesulfonate guest (G) is reported. The chemotherapeutic agent doxorubicin hydrochloride (DOX) can be encapsulated into the formed vesicle (G/WP6A) to construct supramolecular DDS (DOX@G/WP6A). WP6A affords strong affinities to G to avoid undesirable off-target leakage during delivery. Nanoscaled DOX@G/WP6A is capable of preferentially accumulating in tumor tissue via enhanced permeability and retention (EPR) effect. After internalization by tumor cells, the abundant adenosine triphosphate (ATP) binds competitively with WP6A to trigger the disintegration of self-assembled vesicles with the ensuing release of DOX. In vitro and in vivo research confirmed that DOX@G/WP6A is not only able to promote antitumor efficacy but also reduce DOX-related systemic toxicity. The above favorable findings are ascribed to the formation of ternary self-assembly, which profits from the combination of the factors of the EPR effect and the ATP-triggered release.

Molecular Insight into the ß-Sheet Twist and Related Morphology of Self-Assembled Peptide Amphiphile Ribbons.

Self-assembly of high-aspect-ratio filaments containing ß-sheets has attracted much attention due to potential use in bioengineering and biomedicine. However, precisely predicting the assembled morphologies remains a grand challenge because of insufficient understanding of the self-assembly process. We employed an atomistic model to study the self-assembly of peptide amphiphiles (PAs) containing valine-glutamic acid (VE) dimeric repeats. By changing of the sequence length, the assembly morphology changes from flat ribbon to left-handed twisted ribbon, implying a relationship between ß-sheet twist and strength of interstrand hydrogen bonds. The calculations are used to quantify this relationship including both magnitude and sign of the ribbon twist angle. Interestingly, a change in chirality is observed when we introduce the RGD epitope into the C-terminal of VE repeats, suggesting arginine and glycine's role in suppressing right-handed ß-sheet formation. This study provides insight into the relationship between ß-sheet twist and self-assembled nanostructures including a possible design rule for PA self-assembly.

Modular amphiphilic poly(aryl ether)-based supramolecular nanomicelles: an efficient endocytic drug carrier.

A rationally designed amphiphilic poly(aryl ether)-based dendrimer self-assembles into nanomicelles and exhibits tunable morphology upon varying the hydrophilic chain length. The 30 nm-sized dendrimer nanomicelles successfully entrapped Doxorubicin, demonstrated the sustained release of Doxorubicin and can successfully penetrate cancer cells through caveolae-dependent endocytosis, compared to the free drug.

Generation and Characterization of a Library of Novel Biologically Active Functional Surfactants (Surfmers) Using Combined High-Throughput Methods.

We report the first successful combination of three distinct high-throughput techniques to deliver the accelerated design, synthesis, and property screening of a library of novel, bio-instructive, polymeric, comb-graft surfactants. These three-dimensional, surface-active materials were successfully used to control the surface properties of particles by forming a unimolecular deep layer on the surface of the particles via microfluidic processing. This strategy deliberately utilizes the surfactant to both create the stable particles and deliver a desired cell-instructive behavior. Therefore, these specifically designed, highly functional surfactants are critical to promoting a desired cell response. This library contained surfactants constructed from 20 molecularly distinct (meth)acrylic monomers, which had been pre-identified by HT screening to exhibit specific, varied, and desirable bacterial biofilm inhibitory responses. The surfactant's self-assembly properties in water were assessed by developing a novel, fully automated, HT method to determine the critical aggregation concentration. These values were used as the input data to a computational-based evaluation of the key molecular descriptors that dictated aggregation behavior. Thus, this combination of HT techniques facilitated the rapid design, generation, and evaluation of further novel, highly functional, cell-instructive surfaces by application of designed surfactants possessing complex molecular architectures.

One-Component Multifunctional Sequence-Defined Ionizable Amphiphilic Janus Dendrimer Delivery Systems for mRNA.

Efficient viral or nonviral delivery of nucleic acids is the key step of genetic nanomedicine. Both viral and synthetic vectors have been successfully employed for genetic delivery with recent examples being DNA, adenoviral, and mRNA-based Covid-19 vaccines. Viral vectors can be target specific and very efficient but can also mediate severe immune response, cell toxicity, and mutations. Four-component lipid nanoparticles (LNPs) containing ionizable lipids, phospholipids, cholesterol for mechanical properties, and PEG-conjugated lipid for stability represent the current leading nonviral vectors for mRNA. However, the segregation of the neutral ionizable lipid as droplets in the core of the LNP, the "PEG dilemma", and the stability at only very low temperatures limit their efficiency. Here, we report the development of a one-component multifunctional ionizable amphiphilic Janus dendrimer (IAJD) delivery system for mRNA that exhibits high activity at a low concentration of ionizable amines organized in a sequence-defined arrangement. Six libraries containing 54 sequence-defined IAJDs were synthesized by an accelerated modular-orthogonal methodology and coassembled with mRNA into dendrimersome nanoparticles (DNPs) by a simple injection method rather than by the complex microfluidic technology often used for LNPs. Forty four (81%) showed activity in vitro and 31 (57%) in vivo. Some, exhibiting organ specificity, are stable at 5 °C and demonstrated higher transfection efficiency than positive control experiments in vitro and in vivo. Aside from practical applications, this proof of concept will help elucidate the mechanisms of packaging and release of mRNA from DNPs as a function of ionizable amine concentration, their sequence, and constitutional isomerism of IAJDs.

A new antibacterial nano-system based on hematoporphyrin-carboxymethyl chitosan conjugate for enhanced photostability and photodynamic activity.

To promote bactericidal activity, improve photostability and safety, novel antibacterial nanoparticle system based on photodynamic action (PDA) was prepared here through conjugation of photosensitizer hematoporphyrin (HP) onto carboxymethyl chitosan (CMCS) via amide linkage and followed by ultrasonic treatment. The system was stable in PBS (pH 7.4) and could effectively inhibit the photodegradation of conjugated HP because of aggregation-caused quenching effect. ROS produced by the conjugated HP under light exposure could change the structure of nanoparticles by oxidizing the CMCS skeleton and thereby significantly promote the photodynamic activity of HP and its photodynamic activity after 6 h was higher than that of HP·2HCl under the same conditions. Antibacterial experiments showed that CMCS-HP nanoparticles had excellent photodynamic antibacterial activity, and the bacterial inhibition rates after 60 min of light exposure were greater than 97%. Safety evaluation exhibited that the nanoparticles were safe to mammalian cells, showing great potential for antibacterial therapy.

Redox-responsive magnetic nanovectors self-assembled from amphiphilic polymer and iron oxide nanoparticles for a remotely targeted delivery of paclitaxel.

To reduce the side effect of paclitaxel and enhance accumulation at the tumor site, a novel redox-responsive nanovector with excellent biocompatibility based on disulfide-linked amphiphilic polymer and magnetic nanoparticle was prepared. The system would realize PTX release due to breakage of the disulfide bond when being targeted to the tumor site by the external magnetic field. The nanovector significantly improved endocytosis and enhanced accumulation at the tumor site, with an effective inhibition of tumor cells in vitro and in vivo.

Design and optimization of curcumin loaded nano lipid carrier system using Box-Behnken design.

Herbal antioxidant like curcumin holds great potential to treat neurodegenerative disease like Alzheimer's disease. However, its therapeutic potency is obstructed due to rapid metabolism, poor solubility, GI susceptibility, enzymatic degradation and lower bioavailability. Thus, the present work aimed to design and optimize curcumin-loaded NLC (CNL) with higher drug entrapment, prolonged release and better stability. CNL was prepared by modified melt emulsification method followed by ultrasonication. The formulation was optimized by 3 factor 3 level Box-Behnken design using solid: liquid lipid, surfactant concentration and ultrasonication time as independent variable while particle size, entrapment efficiency and % drug release as dependant variable. The design suggested 3.092 solid:liquid lipid, 2.131% surfactant and 4.757 min ultrasonication fit best to get the optimized formulation. The size of the optimized CNL was noted 124.37 ± 55.81 nm, which is in the acceptable range for brain delivery. SEM results also comply with this size range (near 150 nm) and demonstrated almost spherical and uniform particles with porous and uneven surface structures. PDI, zeta potential, entrapment efficiency and % drug release were observed as 0.201 ± 0.00, - 17.2 ± 2.35 mV, 93.62 ± 0.68% and 92.73 ± 0.06%, respectively. The NLC demonstrated initial burst release with subsequent prolonged release of drug for 48 h. Weibull kinetic equation with 0.9958 R2, minimum AIC and maximum MSC value was found best fit to explain the release behavior. The ß exponent and diffusional coefficient (n) indicated combined release mechanism with Fickian diffusion as drug release mechanism. Formulation was also found stable at different storage condition.

Amphipathic Barbiturates as Mimics of Antimicrobial Peptides and the Marine Natural Products Eusynstyelamides with Activity against Multi-resistant Clinical Isolates.

We report a series of synthetic cationic amphipathic barbiturates inspired by the pharmacophore model of small antimicrobial peptides (AMPs) and the marine antimicrobials eusynstyelamides. These N,N'-dialkylated-5,5-disubstituted barbiturates consist of an achiral barbiturate scaffold with two cationic groups and two lipophilic side chains. Minimum inhibitory concentrations of 2-8 µg/mL were achieved against 30 multi-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including isolates with extended spectrum ß-lactamase-carbapenemase production. The guanidine barbiturate 7e (3,5-di-Br) demonstrated promising in vivo antibiotic efficacy in mice infected with clinical isolates of Escherichia coli and Klebsiella pneumoniae using a neutropenic peritonitis model. Mode of action studies showed a strong membrane disrupting effect and was supported by nuclear magnetic resonance and molecular dynamics simulations. The results express how the pharmacophore model of small AMPs and the structure of the marine eusynstyelamides can be used to design highly potent lead peptidomimetics against multi-resistant bacteria.

Sweet surfactants I: Fatty acid esters of sucralose.

Surface active agents derived from the non-toxic sweetener sucralose and fatty acids of different chain length were synthesized. Obtained compounds were characterized chemically and with regard to their properties as emulsifying agents, antimicrobial preservatives and fat-soluble sweeteners. Results show that sucralose-fatty acid esters are possible multi-purpose additives, compatible with both cosmetic and edible emulsions, as well as purely oil-based, waterless formulations. Their relative effectiveness in those applications varies, and is highly dependent on the fatty acid chain length, with hydrophobic/hydrophilic character strongly impacting both emulsifying and antimicrobial properties. While the structural differences between sucrose and sucralose proved to be enough to push all of the newly synthesized compounds out of the detergent/solubilizer category of surfactants, the retention of the substrate's high sweetness is an indication that non-bitter compounds with washing capabilities are possible to obtain.

Enzymatic Hydrolysis-Responsive Supramolecular Hydrogels Composed of Maltose-Coupled Amphiphilic Ureas.

Maltose is a ubiquitous disaccharide produced by the hydrolysis of starch. Amphiphilic ureas bearing hydrophilic maltose moiety were synthesized via the following three steps: I) construction of urea derivatives by the condensation of 4-nitrophenyl isocyanate and alkylamines, II) reduction of the nitro group by hydrogenation, and III) an aminoglycosylation reaction of the amino group and the unprotected maltose. These amphiphilic ureas functioned as low molecular weight hydrogelators, and the mixtures of the amphipathic ureas and water formed supramolecular hydrogels. The gelation ability largely depended on the chain length of the alkyl group of the amphiphilic urea; amphipathic urea having a decyl group had the highest gelation ability (minimum gelation concentration=0.4 mM). The physical properties of the supramolecular hydrogels were evaluated by measuring their thermal stability and dynamic viscoelasticity. These supramolecular hydrogels underwent gel-to-sol phase transition upon the addition of α-glucosidase as a result of the α-glucosidase-catalyzed hydrolysis of the maltose moiety of the amphipathic urea.

Solvent-tailored ordered self-assembly of oligopeptide amphiphiles to create an anisotropic meso-matrix.

Herein, we have developed a solvent-tailored ordered self-assembly strategy to create anisotropic nanomaterials. A trace amount of water has been found to be a predominant factor to direct peptide self-assembly into an anisotropic meso-matrix in DMSO. The obtained meso-matrix was applied to measure the anisotropic RDC parameter of organic molecules for structural elucidation.

Critical Tools in Tableting Research: Using Compaction Simulator and Quality by Design (QbD) to Evaluate Lubricants' Effect in Direct Compressible Formulation.

As commonly known, the product development stage is quite complex, requires intensive knowledge, and is time-consuming. The selection of the excipients with the proper functionality and their corresponding levels is critical to drug product performance. The objective of this study was to apply quality by design (QbD) principles for formulation development and to define the desired product quality profile (QTPP) and critical quality attributes (CQA) of a product. QbD is a risk- and science-based holistic approach for upgraded pharmaceutical development. In this study, Ibuprofen DC 85W was used as a model drug, Cellactose® 80 along with MicroceLac® 100 as a filler, and magnesium stearate, stearic acid, and sodium stearyl fumarate as lubricants. By applying different formulation parameters to the filler and lubricants, the QbD approach furthers the understanding of the effect of critical formulation and process parameters on CQAs and the contribution to the overall quality of the drug product. An experimental design study was conducted to determine the changes of the obtained outputs of the formulations, which were evaluated using the Modde Pro 12.1 statistical computer program that enables optimization by modeling complex relationships. The results of the optimum formulation revealed that MicroceLac® 100 was the superior filler, while magnesium stearate at 1% was the optimum lubricant. A design space that indicates the safety operation limits for the process and formulation variables was also created. This study enriches the understanding of the effect of excipients in formulation and assists in enhancing formulation design using experimental design and mathematical modeling methods in the frame of the QbD approach.