Macrophage-mediated tumor homing of hyaluronic acid nanogels loaded with polypyrrole and anticancer drug for targeted combinational photothermo-chemotherapy.

Rationale: Development of nanosystems that can be integrated with macrophages (MAs), an emerging carrier system, for effective tumor therapy remains to be challenging. We report here the development of MAs specifically loaded with hyaluronic acid (HA) nanogels (NGs) encapsulated with a photothermal agent of polypyrrole (PPy) and anticancer drug doxorubicin (DOX) (HA/DOX@PPy NGs) for tumor homing and combination photothermo-chemotherapy. Methods: Cystamine dihydrochloride-crosslinked HA NGs were first prepared through a double emulsification method, then loaded with PPy via an in-situ oxidization polymerization and physically encapsulated with DOX. The created HA/DOX@PPy NGs were well characterized and subjected to be endocytosed by MAs (MAs-NGs). The MAs-mediated tumor-homing property, phenotype changes and photothermal performance of MAs-NGs were investigated in vitro, and a subcutaneous tumor model was also established to confirm their targeting capability and enhanced antitumor therapy effect in vivo. Results: The generated hybrid NGs possess a size around 77 nm and good colloidal stability, and can be specifically endocytosed by MAs without appreciably affecting their normal biofunctionalities. In particular, NG-loaded MAs display excellent in-vitro cancer cell and in-vivo tumor homing property. Systemic administration of the MAs-NGs leads to the significant inhibition of a subcutaneous tumor model through combination photothermo-chemotherapy under laser irradiation. Conclusions: The developed hybrid HA-based NG nanosystem incorporated with PPy and DOX fully integrates the coordination and heating property of PPy to regulate the optimized DOX release in the tumor region with the assistance of MA-mediated tumor homing, providing a promising cell therapy strategy for enhanced antitumor therapy.

Nanodefensin-encased hydrogel with dual bactericidal and pro-regenerative functions for advanced wound therapy.

Background: Host defense peptides (HDPs) have emerged as a novel therapeutic paradigm for wound management; however, their clinical applications remain a challenge owing to their poor pharmacological properties and lack of suitable pharmaceutical formulations. Nanodefensin (ND), a nanoengineered human α-defensin 5 (HD5), has shown improved pharmacological properties relative to the parent compound. In this study, we engineered a nanodefensin-encased hydrogel (NDEFgel), investigated the effects of NDEFgel on wound healing, and elucidated underlying mechanisms. Method: ND was chemically synthesized and tested functions by in vitro antimicrobial and scratch assays and western blotting. Different NDEFgels were evaluated by in vitro characterizations including degradation, drug release and antimicrobial activity. In full-thickness excisional murine models, the optimal NDEFgel was directly applied onto wound sites, and the efficacy was assessed. Moreover, the underlying mechanisms of pro-regenerative effect developed by NDEFgel were also explored. Results: Apart from bactericidal effects, ND modulated fibroblast behaviors by promoting migration and differentiation. Among the tested hydrogels, the Pluronic F127 (Plu) hydrogel represented the most desirable carrier for ND delivery owing to its favorable controlled release and compatibility with ND. Local treatment of NDEFgel on the wound bed resulted in accelerated wound regeneration and attenuated bacterial burden. We further demonstrated that NDEFgel therapy significantly upregulated genes related to collagen deposition and fibroblasts, and increased the expression of myofibroblasts and Rac1. We therefore found that Rac1 is a critical factor in the ND-induced modulation of fibroblast behaviors in vitro through a Rac1-dependent cytoskeletal rearrangement. Conclusion: Our results indicate that NDEFgel may be a promising dual-action therapeutic option for advanced wound management in the future.

Green and stable piezoresistive pressure sensor based on lignin-silver hybrid nanoparticles/polyvinyl alcohol hydrogel.

Hydrogel-based piezoresistive sensors have high practical value in many revolutionary applications, such as intelligent and electronic devices. However, with existing hydrogels, it is very difficult to achieve a combination of good mechanical properties, stable conductivity, and simple/green fabrication method. In this study, hybrid organic-inorganic nanoparticles (lignin-silver hybrid nanoparticles, Lig-Ag NPs) were synthesized by using alkaline lignin as the organic component and silver nanoparticle (Ag NPs) as the inorganic component. Interaction between the lignin and Ag NPs leads to the composite of hybrid nanoparticles that not only decreased the release of Ag NPs but also generated dynamically stable semi-quinone radicals in lignin. After compositing with polyvinyl alcohol (PVA) matrix, Lig-Ag NPs provided strong sacrificial hydrogen bonds and facilitated the delivery of electronic. Benefiting from these structural features and the pore-forming effect of ammonia (from Lig-Ag NPs solution), the PVA/Lig-Ag NPs hydrogel exhibits outstanding compressibility, pressure sensitivity, and stability of signal response. This study provides a green and simple design strategy for piezoresistive pressure sensors based on nanocomposite hydrogel.

Nonsolvent-induced phase separation of poly(3-hydroxybutyrate) and poly(hydroxybutyrate-co-hydroxyvalerate) blend as a facile platform to fabricate versatile nanofiber gels: Aero-, hydro-, and oleogels.

We demonstrated a strategy to prepare different types of 3-D nanofibrous polymeric gels, including hydro-, aero-, and oleogels by nonsolvent-induced phase separation (NIPS). NIPS-derived gel monoliths of poly(3-hydroxybutyrate) (PHB) and poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) blends were converted into hydrogels and aerogels by solvent exchange and freeze-drying, respectively. The high hydrophobicity and porosity of the nanofibrous PHB/PHBV aerogels enabled them to absorb various oils and swell to 20-30 times their own weight. The pseudo-second-order model was successfully used to describe the oil absorption behavior, and the obtained absorption rate constant increased with increasing PHBV content. The oil-swollen aerogels were highly elastic, thereby indicating that NIPS-derived aerogels are an excellent template for the fabrication of oleogels. With an increase in the PHBV ratio, the gels exhibited reduced modulus and collapse strength but increased collapse strain, thereby revealing higher ductility by compression. The rapid separation and re-binding of the liquid phase entrapped in the nanofiber network resulted in the unique thixotropic properties of the hydro- and oleogels. Indomethacin, a hydrophobic model drug, was successfully incorporated into injectable self-healing oleogels containing soybean oil and aerogels. These gels exhibited excellent cytocompatibility, and a better sustained drug release was observed for the oleogels compared to the aerogels.

pH-Responsive Fluorescence Enhanced Nanogel for Targeted Delivery of AUR and CDDP Against Breast Cancer.

INTRODUCTION: Auraptene (AUR), a natural bioactive prenyloxy coumarin, is a highly pleiotropic molecule that can bind to the MT1 receptor and can effectively reduce the proliferation and migration of breast cancer cells. Cisplatin (CDDP), as the first synthetic platinum-based anticancer drug, is widely used in the clinic due to its definite mechanism and therapeutic effect on diverse tumors. However, both of AUR and CDDP exhibit some disadvantages when used alone, including poor solubility, low bioavailability, lack of selectivity and systemic toxicity when they are used singly. METHODS: Therefore, the biodegradable materials hyaluronic acid (HA) and ß-cyclodextrin derivative (mono-(6-amino-mono-6-deoxy)-ß-CD, CD) were employed as carriers to load AUR and CDDP to form nanogel (CDDPHA-CD@AUR) capable of dual-targeted delivery and synergistic therapy for breast cancer and cell imaging. RESULTS: With the help of the CDDP-crosslinked CD-loaded structure, the newly synthesized nanogel exhibited excellent physiological stability and fluorescence effects. The release of AUR and CDDP was affected by the pH value, which was beneficial to the selective release in the tumor microenvironment. Cell experiments in vitro demonstrated that the nanogel could be selectively internalized by MCF-7 cells and exhibited low cytotoxicity to HK-2 cells. Antitumor experiments in vivo showed that the nanogel have better antitumor effects and lower systemic toxicity. CONCLUSION: Based on these, the nanogel loaded with AUR and CDDP have the potential for targeted delivery against breast cancer.

Severe Acute Respiratory Syndrome Coronavirus-2 Spike Protein Nanogel as a Pro-Antigen Strategy with Enhanced Protective Immune Responses.

Prevention and intervention methods are urgently needed to curb the global pandemic of coronavirus disease-19 caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Herein, a general pro-antigen strategy for subunit vaccine development based on the reversibly formulated receptor binding domain of SARS-CoV-2 spike protein (S-RBD) is reported. Since the poor lymph node targeting and uptake of S-RBD by antigen-presenting cells prevent effective immune responses, S-RBD protein is formulated into a reversible nanogel (S-RBD-NG), which serves as a pro-antigen with enhanced lymph node targeting and dendritic cell and macrophage accumulation. Synchronized release of S-RBD monomers from the internalized S-RBD-NG pro-antigen triggers more potent immune responses in vivo. In addition, by optimizing the adjuvant used, the potency of S-RBD-NG is further improved, which may provide a generally applicable, safer, and more effective strategy for subunit vaccine development against SARS-CoV-2 as well as other viruses.

Designing, structural determination and biological effects of rifaximin loaded chitosan- carboxymethyl chitosan nanogel.

Due to the poor solubility and permeability of rifaximin (RFX), it is not effective against intracellular pathogens although it shows strong activity against most bacteria. To develop an effective mucoadhesive drug delivery system with a targeted release in bacterial infection site, RFX-loaded chitosan (CS)/carboxymethyl-chitosan (CMCS) nanogel was designed and systematically evaluated. FTIR, DSC, and XRD demonstrated that the nanogel was formed by interactions between the positively charged NH3+ on CS and CMCS, and the negatively charged COO on CMCS. RFX was encapsulated into the optimized nanogel in amorphous form. The nanogel was a uniform spherical shape with a mean diameter of 171.07 nm. It had excellent sustained release, strong mucin binding ability, and pH-responsive properties of quicker swelling and release at acidic pH. It showed low hemolytic ratio and high antioxidant activity. The present investigation indicated that the CS-nanogel could be potentially used as a promising bacterial responsiveness drug delivery system.

Green, in situ fabrication of silver/poly(3-aminophenyl boronic acid)/sodium alginate nanogel and hydrogen peroxide sensing capacity.

The silver/poly(3-aminophenyl boronic acid)/sodium alginate nanogel (Ag@PABA-SA) was fabricated through green, in situ chemical oxidative polymerization method. 3-Aminophenyl boronic acid (APBA) served as the room temperature reductant of AgNO3 which acted as an oxidant towards the polymerization of APBA to its conducting polymeric form (PABA). Importantly with SA present, PABA will bind to hydroxyl groups of SA through covalent bonding to generate PABA-SA semi-interpenetrating network, on which AgNPs were concomitantly deposited. This results highly stable, dispersed polymer based AgNPs. The morphology, size, surface charge, composition and thermal stability of nanogel was characterized by UV-vis, Raman and FTIR spectroscopy, TEM, FESEM, EDX, XRD, DLS and zeta potential analysis, TGA and DTG. The Ag@PABA-SA nanogel was investigated as colorimetric probe towards H2O2 detection. Wide linearity from 5 to 1000 µM H2O2, with low limit of detection of 1.0 µM in addition to satisfactory precision (< 3.5 %) and recovery (95-105 %) and high selectivity was achieved.

NIR-responsive multi-healing HMPAM/dextran/AgNWs hydrogel sensor with recoverable mechanics and conductivity for human-machine interaction.

Conductive and self-healing hydrogel sensor is perspective in human-machine interaction applications. However, the design of ideal self-healing hydrogels are always challenging. Herein, by introducing disulfide modified Ag nanowires (AgNWs), we show a novel self-healing hydrogel strain sensor with superior mechanics, conductivity, antibacterial property, and firstly realizing of self-healing with both recovery of mechanics and sensing properties. We demonstrate that the covalent and reversible non-covalent hydrophobic blocks in hydrophobic modified polyacrylamide (HMPAM) achieves the basic self-healing network; dextran with plentiful hydroxyl groups synergistic helps the self-healing by hydrogen bonds; disulfide on the AgNWs surface forms a NIR-responsive and dynamic Ag-S coordination bridge between HMPAM and AgNWs. The resulted hydrogel sensor exhibits comprehensive electromechanical properties, and precisely monitors human motion and subtle electromyography (EMG) signals. Importantly, we firstly achieved the recovery of sensing properties on human motion detection and EMG signal detection after self-healing. This work provides a promising exploration to manufacture bionic strain sensors for potential applications in wearable electronics.

Dynamic Covalent Chemistry Enables Reconfigurable All-Polysaccharide Nanogels.

Dynamic covalent bonds are established upon molecular recognition of sugar derivatives by boronic acid molecules. These reversible links can be used in a cross-linking method to fabricate polymer-based responsive nanosystems. Herein, the design of the first dynamic nanogels made entirely of polysaccharides (PS) is reported. Based on PS chains alternately modified with phenyl boronic acid groups and sugar moieties, these colloids self-assemble in physiological conditions and combine the biocompatible nature of their PS backbone with the reconfiguration capacities of their cross-linking chemistry. These dynamic nanogels are easily prepared, stable for a long time, pH responsive, and efficiently internalized by cancer cells.

Binder-free CuS/ZnS/sodium alginate/rGO nanocomposite hydrogel electrodes for enhanced performance supercapacitors.

CuS/ZnS/sodium alginate/reduced graphene oxide nanocomposites (CZSrG) were prepared by physical crosslinking followed by one-step reduction and were justified as green binder-free hydrogel high-capacitance electrodes. The physical crosslinking was realized simply through the hydrogen-bond interaction between sodium alginate (SA) and graphene oxide (GO), avoiding the usage of traditional Ca2+ crosslinking agent. The hydrogel structure made of CZSrG possessed the most beneficial effect of avoiding large volume change and increasing cycle stability for supercapacitors. When used as electrode, the specific capacitance of CZSrG was 992 F·g-1 (10 mV·s-1) in a three-electrode system. Furthermore, the fabricated supercapacitors had a specific capacitance of 252.1 F·g-1 (5 mV·s-1), and a power density of 1800 Wh·kg-1 at the energy density of 2.05 Wh·kg-1. Thus, the CZSrG has a favorable electrochemical performance and wide application prospects in supercapacitors.

Green and facile synthesis of carboxymethylcellulose/ZnO nanocomposite hydrogels crosslinked with Zn2+ ions.

A green method was used for the preparation of functional carboxymethyl cellulose (CMC) hydrogel crosslinked by divalent zinc ions and incorporated with zinc oxide nanoparticles (ZnO) without using alkaline reagents. In the process, sodium carboxymethyl cellulose was used not only as a hydrogel matrix but also for the release of free hydroxyl groups, which increases the pH of the reaction mixture, consequently leading to the formation of ZnO. The chemical structure and morphology of the hydrogels were characterized using FTIR and FE-SEM analysis, respectively. The water absorption capacity of the hydrogels was studied as a function of temperature and pH. The results of FE-SEM showed the formation of ZnO particles in the hydrogel, while the water absorption capacity results supported the formation of zinc ion cross-linking within the carboxymethylcellulose chains. The CMC/ZnO nanocomposite hydrogel exhibited strong antimicrobial activity against pathogenic bacteria E. coli and L. monocytogenes.

Size-controlled clustering of iron oxide nanoparticles within fluorescent nanogels using LCST-driven self-assembly.

Size-controlled clustering of iron oxide nanoparticles (IONPs) within the fluorescent polymer nanogels was achieved using the lower critical solution temperature (LCST) driven self-assembly and cross-linking of grafted polymer on the IONPs. The grafted polymer was comprised of oligoethyleneglycol methacrylate (OEGMA) and a novel dichloromaleimide functional methacrylate monomer as building blocks. As a result of the temperature responsive behavior of OEGMA, polymer grafted IONPs clustered to form larger nano-sized aggregates when heated above the LCST of the polymer. When these nano-sized aggregates were cross-linked using an amine-dichloromaleimide reaction, well-defined fluorescent hybrid nanogels could be fabricated. Moreover, the size of these hybrid nanogels was effectively controlled by varying the initial concentration of the polymer grafted IONPs in water.

Injectable in Situ Forming Hydrogels of Thermosensitive Polypyrrole Nanoplatforms for Precisely Synergistic Photothermo-Chemotherapy.

The combination of photothermal therapy (PTT) with chemotherapy has great potential to maximize the synergistic effect of thermo-induced chemosensitization and improve treatment performance. To achieve high drug-loading capacity as well as precise synchronization between the controllable release of chemotherapeutics and the duration of near-infrared PTT, in this work, a facile one-step method was first developed to fabricate a novel injectable in situ forming photothermal modulated hydrogel drug delivery platform (D-PPy@PNAs), in which a PNIPAM-based temperature-sensitive acidic triblock polymer [poly(acrylic acid-b-N-isopropylamide-b-acrylic acid (PNA)] was utilized as the stabilizing agent in the polymerization of polypyrrole (PPy). The in situ forming hydrogels showed a sensitive temperature-responsive sol-gel phase-transition behavior, as well as an excellent photothermal property. The strong interaction of ionic bonds together with π-π stacking interactions resulted in high doxorubicin (DOX) loading capacity and controlled/sustained drug release behavior. In addition, D-PPy@PNAs also displayed enhanced cellular uptake and promoted intratumoral penetration of DOX upon NIR laser irradiation. The synergistic photothermal therapy-chemotherapy of D-PPy@PNA hydrogels greatly improved the antitumor efficacy in vivo. Therefore, thermosensitive polypyrrole-based D-PPy@PNA hydrogels may be powerful drug delivery nanoplatforms for precisely synergistic photothermo-chemotherapy of tumors.

Preparation and characterization of hydrogel nanocomposite based on nanocellulose and acrylic acid in the presence of urea.

In this study, acrylic acid (AA) and cellulose nanofibers (CNFs) were used as main materials to synthesize an acrylic-nanocellulose hybrid hydrogel nanocomposite in the presence of urea. The interpenetrating polymer networks were obtained by radical polymerization in different urea: AA ratios (0:10, 1:10, 3:10, 5:10, 10:10). Fourier transform infrared spectroscopy (FTIR) combined with X-ray diffraction (XRD) and elemental analysis techniques confirmed the chemical interaction of urea in the network structure. Free absorption and water absorption under load (AUL) of the synthesized hydrogels varying in urea: acrylic acid weight ratios were measured in distilled water and saline (0.9 wt%) solution for hybrid (5 wt% CNFs) and pure polyacrylic acid (0 wt% CNFs) hydrogels. It was found that incorporation of urea and CNFs in the hybrid structure generating compact hydrogel networks with high crosslink density leading to lower absorption with and without pressure, whereas incorporation of urea in the structure resulted in a more extended network with higher absorption capacity (about 3×) than hybrid structure.

Examination of Adsorption Orientation of Amyloidogenic Peptides Over Nano-Gold Colloidal Particle Surfaces.

The adsorption of amyloidogenic peptides, amyloid beta 1-40 (Aß1-40), alpha-synuclein (α-syn), and beta 2 microglobulin (ß2m), was attempted over the surface of nano-gold colloidal particles, ranging from d = 10 to 100 nm in diameter (d). The spectroscopic inspection between pH 2 and pH 12 successfully extracted the critical pH point (pHo) at which the color change of the amyloidogenic peptide-coated nano-gold colloids occurred due to aggregation of the nano-gold colloids. The change in surface property caused by the degree of peptide coverage was hypothesized to reflect the ΔpHo, which is the difference in pHo between bare gold colloids and peptide coated gold colloids. The coverage ratio (Θ) for all amyloidogenic peptides over gold colloid of different sizes was extracted by assuming Θ = 0 at ΔpHo = 0. Remarkably, Θ was found to have a nano-gold colloidal size dependence, however, this nano-size dependence was not simply correlated with d. The geometric analysis and simulation of reproducing Θ was conducted by assuming a prolate shape of all amyloidogenic peptides. The simulation concluded that a spiking-out orientation of a prolate was required in order to reproduce the extracted Θ. The involvement of a secondary layer was suggested; this secondary layer was considered to be due to the networking of the peptides. An extracted average distance of networking between adjacent gold colloids supports the binding of peptides as if they are "entangled" and enclosed in an interfacial distance that was found to be approximately 2 nm. The complex nano-size dependence of Θ was explained by available spacing between adjacent prolates. When the secondary layer was formed, Aß1-40 and α-syn possessed a higher affinity to a partially negative nano-gold colloidal surface. However, ß2m peptides tend to interact with each other. This difference was explained by the difference in partial charge distribution over a monomer. Both Aß1-40 and α-syn are considered to have a partial charge (especially δ+) distribution centering around the prolate axis. The ß2m, however, possesses a distorted charge distribution. For a lower Θ (i.e., Θ <0.5), a prolate was assumed to conduct a gyration motion, maintaining the spiking-out orientation to fill in the unoccupied space with a tilting angle ranging between 5° and 58° depending on the nano-scale and peptide coated to the gold colloid.

A Paclitaxel-Based Mucoadhesive Nanogel with Multivalent Interactions for Cervical Cancer Therapy.

Cervical cancer treatment is subject to limited drug access to locally diseased targets and generally resistant to chemotherapy, thus it is essential to develop a local drug delivery system to overcome these problems, premised on guaranteeing drug efficacy. With this goal in mind, a multivalent interactions-based mucoadhesive nanogel for vaginal delivery is proposed. Briefly, the nanogel is constructed with mucoadhesive poly(acrylic acid) as the backbone and multiple inclusions between ß-cyclodextrin and paclitaxel as the crosslinking points. The in vitro experiments demonstrate that nanogel exerts high cytotoxicity to cancer cells, reverses multidrug resistance effectively, and successfully promotes the permeation of drugs. More to the point, as proved in the in vivo experiments, the retention time in the vagina is prolonged and the tumor growth is effectively suppressed by the nanogel without any side effects in the orthotopic cervical cancer model. As mentioned above, this novel mucoadhesive nanogel is believed to be a useful tool toward designing drug delivery systems for cervical cancer treatment.

Glucose and pH Dual-Responsive Nanogels for Efficient Protein Delivery.

Direct delivery of protein suffers from their in vitro and in vivo instability, immunogenicity, and a relatively short half-life within the body. To overcome these challenges, pH and glucose dual-responsive biodegradable nanogels comprised of dextran and poly(L-glutamic acid)-g-methoxy poly-(ethylene glycol)/phenyl boronic acid (PLG-g-mPEG/PBA) are designed. The cross-linked network imparted drug-loading efficacy of α-amylase up to 55.6% and hyaluronidase up to 29.1%. In vitro protein release profiles reveal that the release of protein is highly dependent on the pH or glucose concentrations, that is, less amount of protein is released at pH 7.4 or healthy blood glucose level (1 mg mL-1 glucose), while quicker release of protein occurs at pH 5.5 or diabetic blood glucose level (above 3 mg mL-1 glucose). Circular dichroism spectra show that the secondary structure of released protein is maintained compared to naive protein. Overall, the nanogels have provided a simple and effective strategy to deliver protein.

Hyaluronic acid-based nanogels improve in vivo compatibility of the anti-biofilm peptide DJK-5.

Anti-biofilm peptides are a subset of antimicrobial peptides and represent promising broad-spectrum agents for the treatment of bacterial biofilms, though some display host toxicity in vivo. Here we evaluated nanogels composed of modified hyaluronic acid for the encapsulation of the anti-biofilm peptide DJK-5 in vivo. Nanogels of 174 to 194 nm encapsulating 33-60% of peptide were created. Efficacy and toxicity of the nanogels were tested in vivo employing a murine abscess model of a Pseudomonas aeruginosa LESB58 high bacterial density infection. The dose of DJK-5 that could be administered intravenously to mice without inducing toxicity was more than doubled after encapsulation in nanogels. Upon subcutaneous administration, the toxicity of the DJK-5 in nanogels was decreased four-fold compared to non-formulated peptide, without compromising the anti-abscess effect of DJK-5. These findings support the use of nanogels to increase the safety of antimicrobial and anti-biofilm peptides after intravenous and subcutaneous administration.