Hydrophilic Hyaluronic Acid Research Articles

Phenylboronic Acid‐Functionalized Hyaluronic Acid as Polysaccharide Carriers for Diol‐Containing Drugs Delivery

Packaging hydrophobic drugs into polysaccharide carriers can improve their aqueous solubility, biocompatibility, tumor‐specific accumulation, and therapeutic effect. In this work, phenylboronic acid (PBA) was anchored onto the chain of biocompatible polysaccharide hyaluronic acid (HA) by an amide condensation reaction, which could be used to fabricate stimuli‐responsive targeted drug delivery systems. A series of pH‐responsive conjugated hyaluronic acid nanoparticles composed of a hydrophobic drug core and hydrophilic hyaluronic acid shell were prepared by the boronate‐crosslink of the PBA with diol‐containing anticancer drugs such as capecitabine (CAPE) and aloin (Al). Satisfactory targeted drug release behavior at acidic pH, lower cytotoxicity, and higher anticancer effect were realized by using this polysaccharide carrier. It is believed that this strategy has great potential for polysaccharide modification and anticancer‐associated applications.

Effect of protein adsorption on hyaluronic acid/curcumin/multi-walled carbon nanotube based electrochemical sensor for detection of dopamine

Resisting protein adsorption on electrode surfaces is one of pivotal challenges in the electrochemical analysis of small bioactive molecules. In this work, we constructed a novel electrochemical sensing electrode modified with hydrophilic hyaluronic acid (HA) and curcumin/multi-walled carbon nanotube (CM/MWCNTs). The modified electrodes were comprehensively characterized for dopamine detection including the sensing sensitivity, selectivity and stability. The constructed electrochemical sensor for dopamine detection exhibited remarkable resistance to protein adsorption because of the inherent hydrophilicity of HA, and synergistically, the superior electrochemical behavior of the CM/MWCNTs composite (quinone/hydroquinone redox couples enabled superior electrochemical behavior). The HA/CM/MWCNTs/GCE performed about 5.0 folds, 3.5 folds and 2.4 folds higher electrocatalytic current for dopamine than that revealed at bare GCE, MWCNTs/GCE, and CM/MWCNTs/GCE, respectively. In addition, the HA/CM/MWCNTs-based sensor demonstrated excellent sensing performance with a low detection limit of 0.009 μM (S/N = 3) within the concentration range from 50 to 200 μM. The constructed HA/CM/MWCNTs-modified glassy carbon electrodes offered a reliable platform for the real-time monitoring of dopamine with no protein absorption.

Hyaluronic acid modified nanocarriers for aerosolized delivery of verteporfin in the treatment of acute lung injury

Verteporfin (VER), a photosensitizer used in macular degeneration therapy, has shown promise in controlling macrophage polarization and alleviating inflammation in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). However, its hydrophobicity, limited bioavailability, and side effects hinder its therapeutic potential. In this study, we aimed to enhance the therapeutic potential of VER through pulmonary nebulized drug delivery for ALI/ARDS treatment. We combined hydrophilic hyaluronic acid (HA) with an oil-in-water system containing a poly(lactic acid-co-glycolic acid) (PLGA) copolymer of VER to synthesize HA@PLGA-VER (PHV) nanoparticles with favorable surface characteristics to improve the bioavailability and targeting ability of VER. PHV possesses suitable electrical properties, a narrow size distribution (approximately 200 nm), and favorable stability. In vitro and in vivo studies demonstrated the excellent biocompatibility, safety, and anti-inflammatory responses of the PHV by suppressing M1 macrophage polarization while inducing M2 polarization. The in vivo experiments indicated that the treatment with aerosolized nano-VER (PHV) allowed more drugs to accumulate and penetrate into the lungs, improved the pulmonary function and attenuated lung injury, and mortality of ALI mice, achieving improved therapeutic outcomes. These findings highlight the potential of PHV as a promising delivery system via nebulization for enhancing the therapeutic effects of VER in ALI/ARDS.

Thermo-responsive cascade antimicrobial platform for precise biofilm removal and enhanced wound healing.

Bacterial infection, tissue hypoxia and inflammatory response can hinder infected wound repair. This study aimed to develop a multifunctional specific therapeutic photo-activated release nanosystem [HMPB@MB@AuNPs@PMB@HA (HMAPH)] by loading photosensitizer methylene blue (MB) into hollow mesoporous Prussian blue nanostructures and modifying the surface with gold particles, polymyxin B (PMB) and hydrophilic hyaluronic acid. The HMAPH was characterized using transmission electron microscopy, UV-vis, Fourier-transform infrared spectroscopy, X-ray diffraction and X-ray photon spectroscopy. The photothermal performance, iron ion release and free radical generation of the HMAPH were measured under different conditions to investigate its thermo-responsive cascade reaction. The antibacterial ability of HMAPH was investigated using live/dead fluorescence tests. The morphology and membrane integrity of Pseudomonas aeruginosa (P. aeruginosa) were investigated using transmission electron microscopy. The anti-biofilm activity of HMAPH was evaluated using crystal violet and SYBR Green I staining. Finally, we established a mouse model of a skin wound infected by P. aeruginosa to confirm the in vivo effectiveness of HMAPH. We used immunofluorescent staining, hematoxylin-eosin staining, Masson staining and enzyme-linked immunosorbent assay to examine whether HMAPH promoted wound healing and reduced inflammatory damage. In this study, hyaluronic acid was decomposed under the action of hyaluronidase. Also, the exposed nanomaterials specifically bound to the outer membrane of P. aeruginosa through PMB to increase the membrane sensitivity to photodynamic treatment. Under dual-light irradiation, a large amount of iron ions released by HMAPH underwent a Fenton reaction with H2O2 in bacteria to generate hydroxyl radicals (•OH), enabling direct killing of cells by hyperthermia. Additionally, the photodynamic activity of MB released by photo-induced activation led to the generation of reactive oxygen species, achieving synergistic and effective inhibition of P. aeruginosa. HMAPH also inhibited biofilm formation and downregulated the expression of virulence factors. In vivo experiments revealed that HMAPH accelerated the healing of P. aeruginosa-infected wounds by promoting angiogenesis and skin regeneration, inhibiting the inflammatory response and promoting M1 to M2 polarization. Our study proposed a strategy against bacteria and biofilms through a synergistic photothermal-photodynamic-Fenton reaction, opening up new prospects for combating biofilm-associated infections.

Coating Methods of Carbon Nonwovens with Cross-Linked Hyaluronic Acid and Its Conjugates with BMP Fragments.

The cross-linking of polysaccharides is a universal approach to affect their structure and physical properties. Both physical and chemical methods are used for this purpose. Although chemical cross-linking provides good thermal and mechanical stability for the final products, the compounds used as stabilizers can affect the integrity of the cross-linked substances or have toxic properties that limit the applicability of the final products. These risks might be mitigated by using physically cross-linked gels. In the present study, we attempted to obtain hybrid materials based on carbon nonwovens with a layer of cross-linked hyaluronan and peptides that are fragments of bone morphogenetic proteins (BMPs). A variety of cross-linking procedures and cross-linking agents (1,4-butanediamine, citric acid, and BDDE) were tested to find the most optimal method to coat the hydrophobic carbon nonwovens with a hydrophilic hyaluronic acid (HA) layer. Both the use of hyaluronic acid chemically modified with BMP fragments and a physical modification approach (layer-by-layer method) were proposed. The obtained hybrid materials were tested with the spectrometric (MALDI-TOF MS) and spectroscopic methods (IR and 1H-NMR). It was found that the chemical cross-linking of polysaccharides is an effective method for the deposition of a polar active substance on the surface of a hydrophobic carbon nonwoven fabric and that the final material is highly biocompatible.

Hybrid Networks of Hyaluronic Acid and Poly(trimethylene carbonate) for Tissue Regeneration.

To improve the mechanical performance of hyaluronic acid (HA)-based hydrogels, we prepared novel hybrid hydrogels consisting of hydrophilic HA and hydrophobic poly(trimethylene carbonate) (PTMC). Both polymers were functionalized with methacrylic anhydride, yielding HAMA and PTMC-tMA. Hybrid networks with different ratios of PTMC-tMA:HAMA were prepared by photo-cross-linking, using DMSO pH 2.7 as a common solvent for both macromers. The hybrid networks had high gel contents. The hydrophilicity of the networks increased with increasing HAMA content. The networks consisted of the intended amounts of both macromers. The suture retention strength and compression modulus of the networks increased with increasing PTMC-tMA content. While the 100% HAMA network could not be sutured, the 50:50 PTMC-tMA:HAMA network had a suture retention strength of 5.3 N/mm. This is comparable to that of natural vascular tissues. Also the compression modulus (867 kPa) was significantly higher than that of the 100% HAMA network (13 kPa). Moreover, the networks were compatible with human mesenchymal stem cells. In conclusion, these resilient PTMC-tMA:HAMA networks are promising new biomaterials for tissue regeneration.

Mucus-permeable polymyxin B-hyaluronic acid/ poly (lactic-co-glycolic acid) nanoparticle platform for the nebulized treatment of lung infections

The aim of this study was to improve the bioavailability of polymyxin B (PMB) in pulmonary nebulized drug delivery. To this end, we developed a nano-delivery system that penetrates the mucus barrier of the lung. Hydrophilic hyaluronic acid (HA) was combined with a water-in-oil system containing a poly (lactic acid)-glycolic acid copolymer of PMB to prepare HA@PLGA-PMB nanoparticles (NPs) with good surface properties. HA@PLGA-PMB NPs with suitable electrical properties, particle size, and good hydrophilicity prevented strong interactions between the NPs and mucus, thereby allowing more drugs to enter deeper into the lung. Compared to the free drug PMB, NPs had more than 2-fold higher mucus penetration efficiency in vitro and better delivery to infected alveolar cells during in vivo nebulization. NPs had better biocompatibility, which further reduced the drug toxicity. More importantly, NPs showed better antimicrobial therapeutic efficacy in the treatment of lung infections in mice. These findings may provide support for the clinical application of nebulized pulmonary antibiotics.

PH-Responsive Hyaluronic Acid Nanoparticles for Enhanced Triple Negative Breast Cancer Therapy.

PurposeThis study emphasized that dasatinib (DAS) and olaparib (OLA) have synergistic effects on triple negative breast cancer, by inducing DNA damage and inhibiting DNA damage repair. However, poor water solubility, short half-life of drugs, and low drug concentration in tumor tissue limit the clinical application.MethodsIn this research, acid-sensitive ester bonds were used to connect hydrophobic DAS and hydrophilic hyaluronic acid (HA) to form the amphiphilic polymer prodrug HA-DAS, and then OLA was added as the core, the HA-DAS was used as the carrier to form nanomicelles (HDO-NPs) in aqueous. The characterization and drug release of HDO-NPs were studied, and the cytotoxicity, targeting effect, and intracellular transport behavior of HDO-NPs were evaluated in MDA-MB-231. In addition, the pharmacokinetic and therapeutic effect of HDO-NPs were further verified in vivo.ResultsIn vitro characterizations showed that HDO-NPs were spherical with uniform particle size, good stability and anti-dilution ability, and displayed favorable pH-responsive drug release behavior. In addition, the cell experiments showed that HDO-NPs could be effectively taken up by binding to the overexpressed CD44 proteins of MDA-MB-231 cells, resulting in increased intracellular drug concentration. In vivo experiments showed that HDO-NPs can effectively target tumor tissues, have excellent therapeutic effects on tumor, significantly prolong the circulation time of drugs in vivo, and effectively improved the bioavailability of drugs.ConclusionDAS and OLA were designed into micelles, the efficacy of HDO-NPs was higher than that of free drugs. Therefore, HDO-NPs have good application prospects in the treatment of triple negative breast cancer.

Polysaccharide-Based Bilayer Coatings for Biofilm-Inhibiting Surfaces of Medical Devices.

Chitosan (Chi) and 77KS, a lysine-derived surfactant, form polyelectrolyte complexes that reverse their charge from positive to negative at higher 77KS concentrations, forming aggregates that have been embedded with amoxicillin (AMOX). Dispersion of this complex was used to coat polydimethylsiloxane (PDMS) films, with an additional layer of anionic and hydrophilic hyaluronic acid (HA) as an outer adsorbate layer to enhance protein repulsion in addition to antimicrobial activity by forming a highly hydrated layer in combination with steric hindrance. The formed polysaccharide-based bilayer on PDMS was analyzed by water contact angle measurements, X-ray photoelectron spectroscopy (XPS), and surface zeta (ζ)-potential. All measurements show the existence and adhesion of the two layers on the PDMS surface. Part of this study was devoted to understanding the underlying protein adsorption phenomena and identifying the mechanisms associated with biofouling. Thus, the adsorption of a mixed-protein solution (bovine serum albumin, fibrinogen, γ-globulin) on PDMS surfaces was studied to test the antifouling properties. The adsorption experiments were performed using a quartz crystal microbalance with dissipation monitoring (QCM-D) and showed improved antifouling properties by these polysaccharide-based bilayer coatings compared to a reference or for only one layer, i.e., the complex. This proves the benefit of a second hyaluronic acid layer. Microbiological and biocompatibility tests were also performed on real samples, i.e., silicone discs, showing the perspective of the prepared bilayer coating for medical devices such as prostheses, catheters (balloon angioplasty, intravascular), delivery systems (sheaths, implants), and stents.

On-Demand Antimicrobial Agent Release from Functionalized Conjugated Oligomer-Hyaluronic Acid Nanoparticles for Tackling Antimicrobial Resistance.

Controllable drug release is promising for fighting against antimicrobial resistance, which is a critical threat to human health worldwide. Herein, new hyaluronidase-responsive conjugated oligo(thiophene ethynylene) (OTE)-covalently modified hyaluronic acid (OTE-HA) nanoparticles for on-demand release of antimicrobial agents are reported. The synthesis of amphiphilic OTE-HA was carried out by esterification reaction. The resulting macromolecules were self-assembled in water to form nanoparticles, in which the hydrophobic OTE section, as bactericides, formed "cores" and the hydrophilic hyaluronic acid (HA) formed "shells". The OTE-HA nanoparticles avoid bactericide premature leakage and effectively block the dark cytotoxicity of the OTE section, possessing excellent biocompatibility. Using methicillin-resistant Staphylococcus aureus (MRSA) as an example, hyaluronidase, largely secreted by MRSA, can in situ trigger the release of OTE via hydrolyzing OTE-HA nanoparticles into fragments, even disaccharides linked with OTE. Importantly, the OTE section could effectively break cell membranes, leading to bacterial death. The half-maximal inhibitory concentration of the nanoparticles against MRSA is 3.3 μg/mL. The great antibacterial activity of OTE-HA nanoparticles against Gram-positive bacteria Streptococcus pneumoniae further confirms the controllable bactericide delivery mechanism. OTE-HA nanoparticles coated on a surface can also effectively inhibit the growth of bacteria, which holds a remarkable promise in biomedical applications. Therefore, this work provides a favorable strategy of on-demand and in situ drug release for sterilization and defeating antimicrobial resistance.

PH-responsive hyaluronic acid-based nanoparticles for targeted curcumin delivery and enhanced cancer therapy

Curcumin (CUR) display promising antitumor effects, however, the poor water solubility severely limited its clinical application. To overcome this problem, polymeric nanocarriers have been adopted for targeted CUR delivery and enhanced cancer therapy. In this paper, utilizing an acid-labile hydrazone linkage, hydrophobic CUR was conjugated with hydrophilic hyaluronic acid (HA) to form amphiphilic HA-ADH-CUR conjugates, which could subsequently self-assemble to form nanoparticles (HA@CUR NPs) in aqueous. The in vitro drug release experiments showed that HA@CUR NPs exhibited a pH-responsive CUR release behavior, and the release rate of CUR was 73.5 % in pH 5.0. Further, in vitro cell experiments showed HA@CUR NPs could be efficiently internalized by 4T1 and MCF-7 cancer cells through CD44 receptor mediated endocytosis and successfully release CUR in acidic lysosome environment for chemotherapy. In vivo antitumor experiments showed that, compared to free CUR, HA@CUR NPs could efficiently cumulate in tumor site via EPR effect and CD44 mediated endocytosis, achieve superior therapeutic effect for tumor growth suppression. Therefore, HA@CUR NPs were a highly promising nanocarrier for hydrophobic CUR to realize enhanced cancer therapy with good biosafety.

Curcumin/Usnic Acid-Loaded Electrospun Nanofibers Based on Hyaluronic Acid.

Hyaluronic acid, curcumin, and usnic acid are separately utilized as effective biological agents in medicine, and materials based on its blend are considered to have wider therapeutic effects than individual ones. In this study, for the first time, native hyaluronic acid-based fibers containing curcumin and usnic acid with an average diameter of 298 nm were successfully prepared by the electrospinning technique and characterized. Additionally, unstable and hydrophobic curcumin and usnic acid were loaded into the hydrophilic hyaluronic acid matrix without utilizing the activating (catalyzing) agents, resulting in the formation of an electrospinnable solution. Only the binary mixture deionized water—dimethyl sulfoxide (50:50)—was used as solvent. The presence of small amounts of dimethyl sulfoxide in the fibrous materials was expected to provide the materials with local anesthetic and antiseptic activity. The effect of electric voltage on the electrospinning process, diameter, and morphology of hyaluronic acid/curcumin/usnic acid fibers was investigated in detail. The impact of curcumin and usnic acid on the stability of fiber formation was observed. The investigation of fibers based on pure hyaluronic acid without additional polymers and with active pharmaceutical ingredients will lay the groundwork for the development of highly effective wound dressings and new drug delivery scaffolds.

Physical Properties of High Functional Contact Lenses with Hydrophilic Substance and Graphene Oxide Nanocolloids.

The purpose of this experiment is to evaluate the physical properties of contact lenses made by adding hydrophilic Hyaluronic acid (HA) and Methacrylic acid (MA) as additives and Graphene oxide nanocolloids. As a contact lens, AIBN (Azobisisobutyronitrile) was used as an initiator with HEMA (2-hydroxy methyl methacrylate) and EGDMA (ethylene glycol dimethacrylate) as a cross-linker. Hyaluronic acid (HA) and methacrylic acid (MA) were added at 5%, respectively. Graphene oxide nanocolloids were added at 0.1%, 0.3% and 0.5%, respectively. Each prepared contact lens was hydrated in 99% NaCl saline solution for 24 hours. And the basic physical properties of contact lenses were evaluated and compared. The refractive index of the sample with hyaluronic acid and MA added was 1.4390, which was not significantly different from that of the basic combination contact lens sample. When Graphene oxide nanocolloids, a nanomaterial, were added, the refractive index decreased with increasing amount of Graphene oxide nanocolloids from 1.4209 to 13959. In the case of water content, the sample with 5% Hyaluronic acid and MA added slightly increased to 41.01%. In the case of Graphene oxide nanocolloids added, 48.76%~53.56% of Graphene oxide nanocolloids were added. Especially, it was observed that the water content increased sharply in the 0.1% sample of Graphene oxide nanocolloids. When the amount of graphene oxide nanocolloids added to the contact lens material was increased, the refractive index, which is a basic physical property, gradually decreased as the contact lens material was added together with Hyaluronic acid, MA, and Graphene oxide nanocolloids added as a nanomaterial. The water content tended to increase gradually. Therefore, the combination of Graphene oxide and hydrophilicmaterials shows a synergistic effect of physical properties, which is considered to be suitable as a material for contact lenses.

Overcoming Multiple Absorption Barrier for Insulin Oral Delivery Using Multifunctional Nanoparticles Based on Chitosan Derivatives and Hyaluronic Acid.

BackgroundAlthough dynamics and uses of modified nanoparticles (NPs) as orally administered macromolecular drugs have been researched for many years, measures of molecule stability and aspects related to important transport-related mechanisms which have been assessed in vivo remain as relatively under characterized. Thus, our aim was to develop a novel type of oral-based delivery system for insulin and to overcome barriers to studying the stability, transport mechanisms, and efficacy in vivo of the delivery system.MethodsNPs we developed and tested were composed of insulin (INS), dicyandiamide-modified chitosan (DCDA-CS), cell-penetrating octaarginine (r8), and hydrophilic hyaluronic acid (HA) and were physically constructed by electrostatic self-assembly techniques.ResultsCompared to free-insulin, levels of HA-DCDA-CS-r8-INS NPs were retained at more desirable measures of biological activity in our study. Further, our assessments of the mechanisms for NPs suggested that there were high measures of cellular uptake that mainly achieved through active transport via lipid rafts and the macropinocytosis pathway. Furthermore, investigations of NPs indicated their involvement in caveolae-mediated transport and in the DCDA-CS-mediated paracellular pathway, which contributed to increasing the efficiency of sequential transportation from the apical to basolateral areas. Accordingly, high efficiency of absorption of NPs in situ for intestinal loop models was realized. Consequently, there was a strong induction of a hypoglycemic effect in diabetic rats of NPs via orally based administrations when compared with measures related to free insulin.ConclusionOverall, the dynamics underlying and influenced by HA-DCDA-CS-r8-INS may hold great promise for stability of insulin and could help overcome interference by the epithelial barrier, and thus showing a great potential to improve the efficacy of orally related treatments.

Hydrogen peroxide-response nanoprobe for CD44-targeted circulating tumor cell detection and H2O2 analysis

Circulating tumor cells (CTCs) represent the most common way of tumor metastasis and has been considered as a significant index for tumor diagnosis, staging and prognosis. However, CTC detection and analysis are always limited by the scarcity of CTC in the peripheral blood and the interference of blood cells. Therefore, here we presented with a hydrogen peroxide (H2O2)–response nanoprobes with CD44-targeted ability to reduce the interference of blood cells and improve the detection efficiency and accuracy and the pancreatic cancer cell was used to evaluate the feasibility of our probe. Shortly, hydrophobic H2O2-response naphthalimide-borate fluorophore was introduced onto the hydrophilic hyaluronic acid to form an amphiphilic complex, which could self-assemble into fluorescent nanoprobes in water. Our studies demonstrated that the nanoprobes were not only able to specifically recognize the pancreatic cancer cells with overexpressed CD44 proteins and reduce the influence of white blood cells in the peripheral blood, but also capable of semi-quantifying H2O2 content in CTCs, Which could be further used as a significant index for tumor clinical evaluation and therapy.

Hyaluronic Acid-Coated Camptothecin Nanocrystals for Targeted Drug Delivery to Enhance Anticancer Efficacy.

Tumor-targeted drug delivery via chemotherapy is very effective on cancer treatment. For potential anticancer agent such as Camptothecin (CPT), high chemotherapeutic efficacy and accurate tumor targeting are equally crucial. Inspired by special CD44 binding capability from hyaluronic acid (HA), in this study, novel HA-coated CPT nanocrystals were successfully prepared by an antisolvent precipitation method for tumor-targeted delivery of hydrophobic drug CPT. These HA-coated CPT nanocrystals demonstrated high drug loading efficiency, improved aqueous dispersion, prolonged circulation, and enhanced stability resulting from their nanoscaled sizes and hydrophilic HA layer. Moreover, as compared to crude CPT and naked CPT nanocrystals, HA-coated CPT nanocrystals displayed dramatically enhanced in vitro anticancer activity, apoptosis-inducing potency against CD44 overexpressed cancer cells, and lower toxic effect toward normal cells due to pH-responsive drug release behavior and specific HA-CD44 mediated endocytosis. Additionally, HA-coated CPT nanocrystals performed fairly better antimigration activity and biocompatibility. The possible molecular mechanism regarding this novel drug formulation might be linked to intrinsic mitochondria-mediated apoptosis by an increase of Bax to Bcl-2 ratio and upregulation of P53. Consequently, HA-coated CPT nanocrystals are expected to be an effective nanoplatform in drug delivery for cancer therapy.

Developing Body-Components-Based Theranostic Nanoparticles for Targeting Ovarian Cancer.

Ovarian cancer mortality is the highest among gynecologic malignancies. Hence, the major challenges are early diagnosis and efficient targeted therapy. Herein, we devised model theranostic nanoparticles (NPs) for combined diagnostics and delivery of chemotherapeutics, targeted to ovarian cancer cells. These NPs were made of natural biocompatible and biodegradable body components: hyaluronic acid (HA) and serum albumin (SA). The hydrophilic HA served as the targeting ligand for cancer cells overexpressing CD44, the HA receptor. SA, the natural carrier of various ligands through the blood, served as the hydrophobic block of the self-assembling block copolymeric Maillard-conjugates. We show the successful construction of fluorescently-labeled SA-HA conjugate-based theranostic NPs, their loading with paclitaxel (PTX) (association constant (8.6 ± 0.8) × 103 M−1, maximal loading capacity of 4:1 PTX:BSA, and 96% encapsulation efficiency), selective internalization and cytotoxicity to CD44-overexpressing ovarian cancer cells (IC50: 26.4 ± 2.3 nM, compared to 115.0 ± 17.4 of free PTX, and to 58.6 ± 19.7 nM for CD44-lacking cognate ovarian cancer cells). Fluorescein isothiocyanate (FITC) was used for in vitro imaging, whereas long wavelength fluorophores or other suitable tracers would be used for future in vivo diagnostic imaging. Collectively, our findings demonstrate that fluorescent HA-SA NPs harboring a cytotoxic drug cargo can specifically target, label CD44-expressing ovarian cancer cells and efficiently eradicate them.

Electrochemical Co-deposition of Polydopamine/Hyaluronic Acid for Anti-biofouling Bioelectrodes.

Bioelectrodes are key components of electronic devices that efficiently mediate electrical signals in biological systems. However, conventional bioelectrodes often undergo biofouling associated with non-specific proteins and cell adhesion on the electrode surfaces, which leads to seriously degraded electrical and/or electrochemical properties. Hence, a facile and effective method to modify the surface of bioelectrodes is required to introduce anti-biofouling properties and improve performance. Here, we report an electrochemical surface modification of a bioelectrode via co-deposition of hyaluronic acid (HA) and polydopamine (PDA). The electrochemical polymerization and deposition of PDA offered simple and effective incorporation of highly hydrophilic and anti-fouling HA to the electrode surfaces, with no substantial increase in impedance. HA-incorporated PDA (PDA/HA)-modified electrodes displayed significant resistance to non-specific protein adsorption and the adhesion of fibroblasts. In addition, 4-week subcutaneous implantation studies revealed that the modified electrodes attenuated scar tissue formation compared with that induced by unmodified bare electrodes. This simple and effective electrochemical surface modification could be further employed for various implantable bioelectrodes (e.g., prosthetics and biosensors) and could extend their bioelectronic applications.

Micelle-embedded coating with ebselen for nitric oxide generation.

Nitric oxide generation is considered to be a key factor to mimic endothelial function in terms of anti-coagulation and anti-hyperplasia. Herein, ebselen which could play the similar role as glutathion peroxidase-like was loaded into micelles and was further assembled into a layer-by-layer coating. The ability of nitric oxide generation and corresponding biological effect were investigated. Endothelial-mimetic surface has now attracted huge attention in blood-contacting materials, due to its inherent ability of secreting nitric oxide. Among those categories, nitric oxide generation surface is considered to be safe and tunable in the modification of vascular biomedical devices. How to adsorb or immobilize glutathion peroxidase-like catalyst and maintain sustained/safe nitric oxide generation is full of interest. This study aimed at developing a functional coating constructed via layer-by-layer assembly to introduce the catalyst into the coating by pre-loading ebselen in micelles. We firstly introduced phenylboronic acid moiety into the micelle molecule backbone and grafted catechol moiety to chitosan backbone. Then, chitosan, micelles (containing ebselen) and heparin were adopted as polyelectrolytes and then alternatively assembled onto the substrate via layer-by-layer protocol. The catechol was conjugated to the amine groups of chitosan by Schiff base reaction to synthesize chitosan-catechol. The hydrophobic cholesterol was conjugated to the one end of the hydrophilic hyaluronic acid, and the hydroxymethylphenylboronic acid was conjugated to the other end via the esterification of carboxyl (–COOH) and hydroxyl (–OH). The modified hyaluronic acid could spontaneously form micelles in aqueous solution. Ebselen was the loaded into the as-prepared micelles. Chitosan-catechol, heparin, and micelles were alternatively assembled onto the substrate layer by layer to form a micelle-embedded coating. The micelle-embedded coating with ebselen was successfully obtained and the nitric oxide generation ability was in a safe level which was close to healthy endothelial cells. The coating could effectively inhibit platelet adhesion and smooth muscle cell proliferation. The use of ebselen preloaded into micelles could provide a sustained release of catalyst for in situ nitric oxide generation. Besides, this method could also be used to load diverse drugs and regulate desired properties. The study was approved by the Institutional Review Board of the West China Hospital in Sichuan University on March 3, 2018, with approval No. K2018044.

Photocurable Bioinks for the 3D Pharming of Combination Therapies.

Combination therapies mediate drug synergy to improve treatment efficacy and convenience, leading to higher levels of compliance. However, there are challenges with their manufacturing as well as reduced flexibility in dosing options. This study reports on the design and characterization of a polypill fabricated through the combination of material jetting and binder jetting for the treatment of hypertension. The drugs lisinopril and spironolactone were loaded into hydrophilic hyaluronic acid and hydrophobic poly(ethylene glycol) (PEG) photocurable bioinks, respectively, and dispensed through a piezoelectric nozzle onto a blank preform tablet composed of two attachable compartments fabricated via binder jetting 3D printing. The bioinks were photopolymerized and their mechanical properties were assessed via Instron testing. Scanning electron microscopy (SEM) was performed to indicate morphological analysis. The polypill was ensembled and drug release analysis was performed. Droplet formation of bioinks loaded with hydrophilic and hydrophobic active pharmaceutical ingredients (APIs) was achieved and subsequently polymerized after a controlled dosage was dispensed onto preform tablet compartments. High-performance liquid chromatography (HPLC) analysis showed sustained release profiles for each of the loaded compounds. This study confirms the potential of material jetting in conjunction with binder jetting techniques (powder-bed 3D printing), for the production of combination therapy oral dosage forms involving both hydrophilic and hydrophobic drugs.