Recent Progress in Stimuli-Responsive Antimicrobial Electrospun Nanofibers.

Electrospun nanofibrous membranes have garnered significant attention in antimicrobial applications, owing to their intricate three-dimensional network that confers an interconnected porous structure, high specific surface area, and tunable physicochemical properties, as well as their notable capacity for loading and sustained release of antimicrobial agents. Tailoring polymer or hybrid-based nanofibrous membranes with stimuli-responsive characteristics further enhances their versatility, enabling them to exhibit broad-spectrum or specific activity against diverse microorganisms. In this review, we elucidate the pivotal advancements achieved in the realm of stimuli-responsive antimicrobial electrospun nanofibers operating by light, temperature, pH, humidity, and electric field, among others. We provide a concise introduction to the strategies employed to design smart electrospun nanofibers with antimicrobial properties. The core section of our review spotlights recent progress in electrospun nanofiber-based systems triggered by single- and multi-stimuli. Within each stimulus category, we explore recent examples of nanofibers based on different polymers and antimicrobial agents. Finally, we delve into the constraints and future directions of stimuli-responsive nanofibrous materials, paving the way for their wider application spectrum and catalyzing progress toward industrial utilization.

Effective intracellular release of ibuprofen triggered by thermosensitive magnetic nanocarriers.

Stimuli-responsive nanocarriers are being widely applied in the development of new strategies for the diagnosis and treatment of diseases. An inherent difficulty in general drug therapy is the lack of precision with respect to a specific pathological site, which can lead to toxicity, excessive drug consumption, or premature degradation. In this work, the controlled drug delivery is achieved by using magnetite nanoparticles coated with mesoporous silica with core-shell structure (MMS) and grafted with the thermoresponsive polymer poly [N-isopropylacrylamide-co-3-(trimethoxysilyl)propyl methacrylate] (MMS-P). The efficiency of MMS-P as a temperature-controlled drug delivery system was evaluated by in vitro release experiments using ibuprofen (IBU) in various mammalian cell models. Further, the effects of IBU as a photoprotectant in cells exposed to photodynamic therapy (PDT) in a carbaryl-induced neurodegenerative model were evaluated. The results showed that MMS-P nanocarriers do not exhibit cytotoxicity in HepG2 cells at high doses such as 7600 µg mL-1. Pre-incubation of MMS-P charged with IBU showed no effect on the PDT in N2A cells; however, it produced a further decrease in the viability of HepG2 cells, leading to a reduction to PDT resistance. On the other hand, a cytoprotective effect against carbaryl toxicity in N2A cells was observed in IBU administrated by MMS-P, which confirms the effective intracellular IBU uptake by means of MMS-P. These results encourage the potential application of MMS-P as a drug delivery system and confirm the effect of IBU as a cytoprotective agent in a neurodegenerative model.

Thermosensitive gel based on cellulose derivative for topical delivery of propolis in acne treatment.

Thermosensitive bioadhesive formulations can display increased retention time, skin permeation, and improve the topical therapy of many drugs. Acne is an inflammatory process triggered by several factors like the proliferation of the bacteria Propionibacterium acnes. Aiming for a new alternative treatment with a natural source, propolis displays great potential due to its antibiotic, anti-inflammatory, and healing properties. This study describes the development of bioadhesive thermoresponsive platform with cellulose derivatives and poloxamer 407 for propolis skin delivery. Propolis ethanolic extract (PES) was added to the formulations with sodium carboxymethylcellulose (CMC) or hydroxypropyl methylcellulose (HPMC) and poloxamer 407 (Polox). The formulations were characterized as rheology, bioadhesion, and mechanical analysis. The selected formulations were investigated as in vitro propolis release, cytotoxicity, ex vivo skin permeation by Fourier Transform Infrared Photoacoustic Spectroscopy, and the activity against P. acnes. Formulations showed suitable sol-gel transition temperature, shear-thinning behavior, and texture profile. CMC presence decreased the cohesiveness and adhesiveness of formulations. Polox/HPMC/PES system displayed less cytotoxicity, modified propolis release governed by anomalous transport, skin permeation, and activity against P. acnes. These results indicate important advantages in the topical treatment of acne and suggest a potential formulation for clinical evaluation.

Drug Delivery Platforms Containing Thermoresponsive Polymers and Mucoadhesive Cellulose Derivatives: A Review of Patents.

Nowadays, the development of mucoadhesive systems for drug delivery has gained keen interest, with enormous potential in applications through different routes. Mucoadhesion characterizes an attractive interaction between the pharmaceutical dosage form and the mucosal surface. Many polymers have shown the ability to interact with mucus, increasing the residence time of local and/or systemic administered preparations, such as tablets, patches, semi-solids, and micro and nanoparticles. Cellulose is the most abundant polymer on the earth. It is widely used in the pharmaceutical industry as an inert pharmaceutical ingredient, mainly in its covalently modified forms: methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and carboxymethylcellulose salts. Aiming to overcome the drawbacks of oral, ocular, nasal, vaginal, and rectal routes and thereby maintaining patient compliance, innovative polymer blends have gained the interest of the pharmaceutical industry. Combining mucoadhesive and thermoresponsive polymers allows for simultaneous in situ gelation and mucoadhesion, thus enhancing the retention of the system at the site of administration and drug availability. Thermoresponsive polymers have the ability to change physicochemical properties triggered by temperature, which is particularly interesting considering the physiological temperature. The present review provides an analysis of the main characteristics and applications of cellulose derivatives as mucoadhesive polymers and their use in blends together with thermoresponsive polymers, aiming at platforms for drug delivery. Patents were reviewed, categorized, and discussed, focusing on the applications and pharmaceutical dosage forms using this innovative strategy. This review manuscript also provides a detailed introduction to the topic and a perspective on further developments.

Development of "on-demand" thermo-responsive hydrogels for anti-cancer drugs sustained release: Rational design, in silico prediction and in vitro validation in colon cancer models.

A rational design accurate based on the use of Statistical Design of the Experiments (DoE) and Molecular Dynamics Simulations Studies allows the prediction and the understanding of thermo-responsive hydrogels prepared regarding their gelation temperature and anti-cancer drug release rate. N-isopropylacrilamide (NIPAM) modified with specific co-monomers and crosslinkers, can be used to prepare "on-demand" thermo-responsive hydrogels with the ideal properties for clinical applications in which local sustained release of drugs is crucial. Two preferential formulations resulting from the predictive studies of DoE and In Silico methods were synthesized by radical polymerization, fully characterized, and loaded with the anticancer drug Doxorubicin (Dox). The hydrogel formulations were characterized by swelling rate, turbidity, FTIR, 1H NMR, SEM, gelation time, rheology, and biocompatibility assays. Both formulations demonstrated adequate morphologic, rheological, and biocompatibility properties; however, important differences in terms of drug retention were detected. As demonstrated by a Dox cumulative release study and posteriorly confirmed by an efficacy assay in an in vitro colorectal cancer model, the formulation composed by NIPAM and 4-penten-1-ol crosslinked with poly(ethylene glycol) diacrylate (PEGDA) (PNiPenPH) present a slow release over the time, presenting ideal properties to become and ideal depot system for the local sustained release of anticancer drugs as adjuvant therapy or in the case of non-resectable tumors.

Nanocomposite gels of poloxamine and Laponite for ß-Lapachone release in anticancer therapy.

Nano-hybrid systems have been shown to be an attractive platform for drug delivery. Laponite® RD (LAP), a biocompatible synthetic clay, has been exploited for its ability to establish of strong secondary interactions with guest compounds and hybridization with polymers or small molecules that improves, for instance, cell adhesion, proliferation, and differentiation or facilitates drug attachment to their surfaces through charge interaction. In this work, LAP was combined with Tetronics, X-shaped amphiphilic PPO-PEO (poly (propylene oxide)-poly (ethylene oxide) block copolymers. ß-Lapachone (BLPC) was selected for its anticancer activity and its limited bioavailability due to very low aqueous solubility, with the aim to improve this by using LAP/Tetronic nano-hybrid systems. The nanocarriers were prepared over a range of Tetronic 1304 concentrations (1 to 20% w/w) and LAP (0 to 3% w/w). A combination of physicochemical methods was employed to characterize the hybrid systems, including rheology, particle size and shape (DLS, TEM), thermal analysis (TG and DSC), FTIR, solubility studies and drug release experiments. In vitro cytotoxicity assays were performed with BALB/3T3 and MCF-7 cell lines. In hybrid systems, a sol-gel transition can occur below physiological temperature. BLPC exhibits the most significant increase in solubility in formulations with a high concentration of T1304 (over 10% w/w) and 1.5% w/w LAP, or systems with only LAP (1.5%), with a 50 and 100-fold increase in solubilisation, respectively. TEM images showed spherical micelles of T1304, which elongated into wormlike micelles with concentration (20%) and in the presence of LAP, a finding that has not been reported before. A sustained release of BLPC over 140 hours was achieved in one of the formulations (10% T1304 with 1.5% laponite), which also showed the best selectivity index towards cancer cells (MCF-7) over BALB/3T3 cell lines. In conclusion, BLPC-loaded T1304/LAP nano-hybrid systems proved safe and highly effective and are thus a promising formulation for anticancer therapy.

Thermoresponsive Hydrogel Containing Viscum album Extract for Topic and Transdermal Use: Development, Stability and Cytotoxicity Activity.

Viscum album L. (Santalaceae), also known as European mistletoe, is a semi-parasitic plant that grows on different host trees. Our group recently demonstrated the antitumoral activity of ethanolic V. album extracts in vitro, depending on the dose and the host tree, V. album ssp abietis from Abies alba being the most active extract. The goal of this work focused on the development of a new topical formulation containing V. album extracts, evaluation of in vitro toxicity and ex vivo skin permeation assays. The Poloxamer 407 hydrogel containing 5% of dry (VA_DEH) or aqueous (VA_AEH) extract presented dermal compatible pH and microbiological stability for 180 days. The hydrogels flow curve presented a non-linear relation, characteristic of non-Newtonian fluids, and the mean viscosity for the VA_DEH and VA_AEH was 372.5 ± 7.78 and 331.0 ± 2.83 Pa.s, respectively, being statistically different (Welch's t test; p < 0.01). Additionally, WST-1 in vitro assays revealed a dose-dependent toxicity for both formulations and VA_DEH presented a higher activity than the VA_AEH. The promising cytotoxic potential of VA_DEH lead to the ex vivo skin permeation assay with 2.73 ± 0.19 µg/cm2 of chlorogenic acid, which permeated at 8 h, showing a transdermal potential. These in vitro results support the idea that VA_DEH is a novel promising candidate for mistletoe therapy. Therefore, further in vivo and pre-clinical experiments should be performed to evaluate the safety and efficacy of this new dermic delivery system.

Different Strategies for the Preparation of Galactose-Functionalized Thermo-Responsive Nanogels with Potential as Smart Drug Delivery Systems.

Different synthetic strategies were tested for the incorporation of galactose molecules on thermoresponsive nanogels owing to their affinity for receptors expressed in cancer cells. Three families of galactose-functionalized poly(N-vinylcaprolactam) nanogels were prepared with the aim to control the introduction of galactose-moieties into the core, the core-shell interface and the shell. First and second of the above mentioned, were prepared via surfactant free emulsion polymerization (SFEP) by a free-radical mechanism and the third one, via SFEP/reversible addition-fragmentation chain transfer (RAFT) polymerization. Synthetic recipes for the SFEP/free radical method included besides N-vinylcaprolactam (NVCL), a shell forming poly(ethylene glycol) methyl ether methacrylate (PEGMA), while the galactose (GAL) moiety was introduced via 6-O-acryloyl-1,2,:3,4-bis-O-(1-methyl-ethylidene)-α-D-galactopiranose (6-ABG, protected GAL-monomer): nanogels I, or 2-lactobionamidoethyl methacrylate (LAMA, GAL-monomer): nanogels II. For the SFEP/RAFT methodology poly(2-lactobionamidoethyl methacrylate) as GAL macro-chain transfer agent (PLAMA macro-CTA) was first prepared and on a following stage, the macro-CTA was copolymerized with PEGMA and NVCL, nanogels III. The crosslinker ethylene glycol dimethacrylate (EGDMA) was added in both methodologies for the polymer network construction. Nanogel's sizes obtained resulted between 90 and 370 nm. With higher content of PLAMA macro-CTA or GAL monomer in nanogels, a higher the phase-transition temperature (TVPT) was observed with values ranging from 28 to 46 °C. The ρ-parameter, calculated by the ratio of gyration and hydrodynamic radii from static (SLS) and dynamic (DLS) light scattering measurements, and transmission electron microscopy (TEM) micrographs suggest that core-shell nanogels of flexible chains were obtained; in either spherical (nanogels II and III) or hyperbranched (nanogels I) form.

Stimuli-Responsive Materials for Tissue Engineering and Drug Delivery.

Smart or stimuli-responsive materials are an emerging class of materials used for tissue engineering and drug delivery. A variety of stimuli (including temperature, pH, redox-state, light, and magnet fields) are being investigated for their potential to change a material's properties, interactions, structure, and/or dimensions. The specificity of stimuli response, and ability to respond to endogenous cues inherently present in living systems provide possibilities to develop novel tissue engineering and drug delivery strategies (for example materials composed of stimuli responsive polymers that self-assemble or undergo phase transitions or morphology transformations). Herein, smart materials as controlled drug release vehicles for tissue engineering are described, highlighting their potential for the delivery of precise quantities of drugs at specific locations and times promoting the controlled repair or remodeling of tissues.

An In Situ Gelling System for the Local Treatment of Inflammatory Bowel Disease (IBD). The Loading of Maqui (Aristotelia Chilensis) Berry Extract as an Antioxidant and Anti-Inflammatory Agent.

The aim of the present work was the development of an innovative in situ gelling system, to be applied on the mucosa of the distal colon via rectal route. The system consisted of three polymers having different functions: gellan (GG), able to jellify in presence of ions; methylcellulose (MC), a thermosensitive polymer with a gelation temperature close to 50 °C; and hydroxypropylcellulose (HPC), a mucoadhesive polymer. The three polymers were able to act synergistically, increasing the permanence of the vehicle on the mucosa and forming a protective gel layer. A DoE approach, "simplex centroid mixture design," was used to identify the optimal quantitative composition of the vehicle. The response variables considered were: vehicle viscosity at room temperature; increase in vehicle viscosity on increasing temperature (from room to physiological value) and upon dilution with simulated colonic fluid (SCF); and viscoelastic behavior, thixotropic area, and mucoadhesion properties of the gel formed at 37 °C upon dilution in SCF. The optimized vehicle was loaded with maqui berry extract (MBE), known for its antioxidant and anti-inflammatory properties. MBE loading (0.5% w/w) into the vehicle improved rheological and mucoadhesive properties of the formulation. Both MBE and the optimized vehicle were not cytotoxic towards human fibroblasts and Caco-2 cells. Moreover, the optimized vehicle did not affect MBE antioxidant properties.

Development of Silver Nanoparticles/Gelatin Thermoresponsive Nanocomposites: Characterization and Antimicrobial Activity.

BACKGROUND: Skin and soft tissue infections involve microbial invasion of the skin and underlying soft tissues. To overcome this problem, nanocomposites were obtained using gelatin as a biopolymer scaffold and silver nanoparticles as a wide spectrum antimicrobial agent. Water and glycerol have been used as solvents for the gelatin hydrogel synthesis. This mixture led to a stable and homogeneous biomaterial with improved mechanical properties. METHODS: Silver nanoparticles were characterized using SEM, EDS and TEM. Moreover, the AgNp/gelatin nanocomposite obtained using these nanoparticles was characterized using SEM and FTIR. Moreover, mechanical and swelling properties were studied. RESULTS: The storage modulus was 3000 Pa for gelatin hydrogels and reached 5800 Pa for AgNp/gelatin nanocomposite. Silver nanoparticles have been studied as an alternative to antibiotics. Importantly, the rate of silver release was modulated as a function of the temperature of the nanocomposite. Thus, the silver release from the nanocomposites at 24 °C and 38 °C was analyzed by atomic absorption spectroscopy. The silver release reached 25% after 24 h at 24 °C, while a 75% release was achieved at 38°C in the same period, showing the material thermoresponsive behavior. AgNp/gelatin nanocomposite showed a deleterious effect over 99.99% of Pseudomonas aeruginosa and Staphylococcus aureus, leading to a material with antimicrobial properties. CONCLUSION: AgNp/gelatin nanocomposite with improved mechanical properties and silver nanoparticles as a source of silver ions has been synthesized. The properties of the nanocomposite with controlled silver delivery result in a more efficient topical pharmaceutical form for wound healing applications.

Synthesis and in vitro testing of thermoresponsive polymer-grafted core-shell magnetic mesoporous silica nanoparticles for efficient controlled and targeted drug delivery.

In this work, thermoresponsive polymer grafted magnetic mesoporous silica nanoparticles were prepared, fully characterized and tested as controlled drug delivery systems. For this purpose, iron oxide nanoparticles coated with mesoporous silica shell were grafted with poly(N-isopropylacrylamide-co-3-(methacryloxypropyl)trimethoxysilane) (PNIPAM-co-MPS). The grafting and polymerization on the as-prepared nanoparticles were performed in one-step procedure. Using this methodology, the polymer was successfully grafted mainly onto the silica surface, leaving the mesopores empty for the drug loading. The prepared hybrid nanoparticles (MMSNP-PNIPAM-co-MPS) showed high magnetization saturation (19.5 emu g-1) and high specific surface area (505 m2 g-1) and pore volume (0.29 cm3 g-1). Ibuprofen was used as a model drug to test the performance of the hybrid particles as thermosensitive drug delivery systems. For this, in vitro drug delivery tests were conducted below (25 °C) and above (40 °C) the lower critical solution temperature (LCST) of the polymer (PNIPAM-co-MPS). Considerable difference (80%) in the ibuprofen release at these two temperatures and a fast and complete release of the drug at 40 °C was observed. These results suggest that the thermoresponsive copolymer acts as a gatekeeper for the temperature-controlled release of the drug loaded inside the mesopores. Therefore, MMSNP-PNIPAM-co-MPS are promising magnetic and thermoresponsive nanocarriers for targeted delivery of therapeutic substances.

Triggered release of paclitaxel from magnetic solid lipid nanoparticles by magnetic hyperthermia.

We developed a magnetic solid lipid nanoparticles formulation of paclitaxel (PTX-loaded MSLNs) via emulsification-diffusion method. The physicochemical characterization of PTX-loaded MSLNs was performed by AFM, DLS, determination of entrapment efficiency (EE) and drug loading (DL), DSC, VSM, and physical stability. The in vitro effect of temperature and pulsed magnetic hyperthermia on drug release were studied. PTX-loaded MSLNs had a particle diameter around 250 nm with a narrow size distribution, spherical morphology, EE of 67.3 ±â€¯1.2% and a DL of 17.1 ±â€¯0.4 µg/mg. A decrease of the melting point of the lipid was observed following the preparation of the MSLNs. A threefold increase in the in vitro drug release rate was seen when temperature was raised from 25 to 43 °C. The lipid coating of MPs confer a temperature-dependent drug release and magnetic hyperthermia was used to trigger controlled PTX release from MSLNs.

Assessing Mucoadhesion in Polymer Gels: The Effect of Method Type and Instrument Variables.

The process of mucoadhesion has been widely studied using a wide variety of methods, which are influenced by instrumental variables and experiment design, making the comparison between the results of different studies difficult. The aim of this work was to standardize the conditions of the detachment test and the rheological methods of mucoadhesion assessment for semisolids, and introduce a texture profile analysis (TPA) method. A factorial design was developed to suggest standard conditions for performing the detachment force method. To evaluate the method, binary polymeric systems were prepared containing poloxamer 407 and Carbopol 971P®, Carbopol 974P®, or Noveon® Polycarbophil. The mucoadhesion of systems was evaluated, and the reproducibility of these measurements investigated. This detachment force method was demonstrated to be reproduceable, and gave different adhesion when mucin disk or ex vivo oral mucosa was used. The factorial design demonstrated that all evaluated parameters had an effect on measurements of mucoadhesive force, but the same was not observed for the work of adhesion. It was suggested that the work of adhesion is a more appropriate metric for evaluating mucoadhesion. Oscillatory rheology was more capable of investigating adhesive interactions than flow rheology. TPA method was demonstrated to be reproducible and can evaluate the adhesiveness interaction parameter. This investigation demonstrates the need for standardized methods to evaluate mucoadhesion and makes suggestions for a standard study design.

Biocompatible and Antibacterial Nitric Oxide-Releasing Pluronic F-127/Chitosan Hydrogel for Topical Applications.

Nitric oxide (NO) is involved in physiological processes, including vasodilatation, wound healing and antibacterial activities. As NO is a free radical, designing drugs to generate therapeutic amounts of NO in controlled spatial and time manners is still a challenge. In this study, the NO donor S-nitrosoglutathione (GSNO) was incorporated into the thermoresponsive Pluronic F-127 (PL)-chitosan (CS) hydrogel, with an easy and economically feasible methodology. CS is a polysaccharide with known antimicrobial properties. Scanning electron microscopy, rheology and differential scanning calorimetry techniques were used for hydrogel characterization. The results demonstrated that the hydrogel has a smooth surface, thermoresponsive behavior and good mechanical stability. The kinetics of NO release and GSNO diffusion from GSNO-containing PL/CS hydrogel demonstrated a sustained NO/GSNO release, in concentrations suitable for biomedical applications. The GSNO-PL/CS hydrogel demonstrated a concentration-dependent toxicity to Vero cells, and antimicrobial activity to Pseudomonas aeruginosa (minimum inhibitory concentration and minimum bactericidal concentration values of 0.5 µg·mL-1 of hydrogel, which corresponds to 1 mmol·L-1 of GSNO). Interestingly, the concentration range in which the NO-releasing hydrogel demonstrated an antibacterial effect was not found to be toxic to the Vero mammalian cell. Thus, the GSNO-PL/CS hydrogel is a suitable biomaterial for topical NO delivery applications.

Electrochemical preparation and characterization of PNIPAM-HAp scaffolds for bone tissue engineering.

In the last decade, a variety of methods for fabrication of three-dimensional biomimetic scaffolds based on hydrogels have been developed for tissue engineering. However, many methods require the use of catalysts which compromises the biocompatibility of the scaffolds. The electrochemical polymerization (ECP) of acrylic monomers has received an increased attention in recent years due to its versatility in the production of highly biocompatible coatings for the electrodes used in medical devices. The main aim of this work was the use of ECP as scaffold fabrication technique to produce highly porous poly(N-isopropylacrylamide) (PNIPAM)/hydroxyapatite (HAp) composite for bone tissue regeneration. The prepared PNIPAM-HAp porous scaffolds were characterized by SEM, FTIR, water swelling, porosity measurements and X-ray diffraction (XRD) techniques. FTIR indicates that ECP promotes a successful conversion of NIPAM to PNIPAM. The water swelling and porosity were shown to be controlled by the HAp content in PNIPAM-HAp scaffolds. The PNIPAM-HAp scaffolds exhibited no cytotoxicity to MG63 cells, showing that ECP are potentially useful for the production of PNIPAM-HAp scaffolds. To address the osteomyelitis, a significant complication in orthopedic surgeries, PNIPAM-HAp scaffolds were loaded with the antibiotic oxacillin. The oxacillin release and the bacterial killing activity of the released oxacillin from PNIPAM-HAp against S. aureus and P. aeruginosa were demonstrated. These observations demonstrate that ECP are promising technique for the production of non-toxic, biocompatible PNIPAM-HAp scaffolds for tissue engineering.

Evaluation of the methylene blue addition in binary polymeric systems composed by poloxamer 407 and Carbopol 934P using quality by design: rheological, textural, and mucoadhesive analysis.

This study describes the investigation about the physicochemical behavior of methylene blue (Mb) addition to systems containing poloxamer 407 (Polox), Carbopol 934P (Carb), intended to be locally used by photodynamic therapy. A factorial design 23 (plus center point) was used to analyze the rheological, mucoadhesive and textural properties of the preparations. Systems containing the lower concentrations of Polox (15 and 17.5%, w/w) exhibited pseudoplastic flow and low degrees of rheopexy. On the other hand, at higher Polox concentration (20%, w/w) the systems display plastic flow and thixotropy. Carb and Mb exhibited a negative influence for the consistency and flow behavior index, due to the interaction between them. For most of the formulations, the increase of Polox and Mb content significantly increased storage modulus, loss modulus and dynamic viscosity. The systems display a sol-gel transition temperature, existing as a liquid at room temperature and gel at 29-37 °C. Increasing the temperature and the polymer concentration, the compressional properties of systems significantly increased. The mucoadhesion was noted to all formulations, except to systems composed by 15% (w/w) of Polox. The analyses enabled to understand and predict the performance of formulations and the polymer-Mb interactions, tailoring to the suit systems (Polox/Carb/Mb): 17.5/0.50/0.20 and 20/0.15/0.25.

Thermoregulated Coacervation, Metal-Encapsulation and Nanoparticle Synthesis in Novel Triazine Dendrimers.

The synthesis and solubility behaviors of four generation five (G5) triazine dendrimers are studied. While the underivatized cationic dendrimer is soluble in water, the acetylated and propanoylated derivatives undergo coacervation in water upon increasing temperature. Occurring around room temperature, this behavior is related to a liquid-liquid phase transition with a lower critical solution temperature (LCST) and is explained by differences in composition, notably, the hydrophobic nature of the terminal groups. Interestingly, the water solubility of the acetylated dendrimer is affected by the addition of selected metal ions. Titrating solutions of acetylated dendrimer at temperatures below the LCST with gold or palladium ions promoted precipitation, but platinum, iridium, and copper did not. Gold nanoparticles having diameters of 2.5 ± 0.8 nm can be obtained from solutions of the acetylated dendrimer at concentrations of gold less than that required to induce precipitation by treating the solution with sodium borohydride.

Thermoresponsive hyaluronic acid nanogels as hydrophobic drug carrier to macrophages.

Delivery systems for macrophages are particularly attractive since these phagocytic cells play a important role in immunological and inflammatory responses, also acting as host cells for microorganisms that are involved in deadly infectious diseases, such as leishmaniasis. Hyaluronic acid (HA) is specifically recognized by macrophages that are known to express HA receptors. Therefore, in this study, we focused on HA-based nanogels as drug carriers for these cells. The drug delivery was validated in an in vivo study on mice using intravital two-photon laser scanning microscopy. HA derivatives were modified with a biocompatible oligo(ethylene glycol)-based thermoresponsive polymer to form nanogels. These HA conjugates were readily prepared by varying the molar mass of initial HA and the degree of substitution via radical-mediated thiol-ene chemistry in aqueous solution. The derivatives were shown to self-assemble into spherical gel particles with diameters ranging from 150 to 214 nm above 37 °C. A poorly water-soluble two-photon dye was successfully loaded into the nanogels during this self-assembly process. In vitro cellular uptake tests using a RAW 264.7 murine macrophage cell line showed successful intracellular delivery of the hydrophobic dye. After intravenous injection in mice, the nanogels circulated freely in the blood but were rapidly phagocytized within 13 min by circulating macrophages and stored in the liver and spleen, as observed by two-photon microscopy. Benefit can be thus expected in using such a delivery system for the liver and spleen macrophage-associated diseases.