Layer-by-layer assembly of quercetin-loaded zein/γPGA/low-molecular-weight chitosan/fucoidan nanosystem for targeting inflamed blood vessels.

Chitosan acts as a versatile carrier in polymeric nanoparticle (NP) for diverse drug administration routes. Delivery of antioxidants, such as quercetin (Qu) showcases potent antioxidant and anti-inflammatory properties for reduction of various cardiovascular diseases, but low water solubility limits uptake. To address this, we developed a novel layer-by-layer zein/gamma-polyglutamic acid (γPGA)/low-molecular-weight chitosan (LC)/fucoidan NP for encapsulating Qu and targeting inflamed vessel endothelial cells. We used zein (Z) and γPGA (r) to encapsulate Qu (Qu-Zr NP) exhibited notably higher encapsulation efficiency compared to zein alone. Qu-Zr NP coated with LC (Qu-ZrLC2 NP) shows a lower particle size (193.2 ± 2.9 nm), and a higher zeta potential value (35.2 ± 0.4 mV) by zeta potential and transmission electron microscopy analysis. After coating Qu-ZrLC2 NP with fucoidan, Qu-ZrLC2Fa NP presented particle size (225.16 ± 0.92 nm), zeta potential (-25.66 ± 0.51 mV) and maintained antioxidant activity. Further analysis revealed that Qu-ZrLC2Fa NP were targeted and taken up by HUVEC cells and EA.hy926 endothelial cells. Notably, we observed Qu-ZrLC2Fa NP targeting zebrafish vessels and isoproterenol-induced inflamed vessels of rat. Our layer-by-layer formulated zein/γPGA/LC/fucoidan NP show promise as a targeted delivery system for water-insoluble drugs. Qu-ZrLC2Fa NP exhibit potential as an anti-inflammatory therapeutic for blood vessels.

Sequential removal of phosphate and copper(II) ions using sustainable chitosan biosorbent.

Although adsorbents are good candidates for removing phosphorus and heavy metals from wastewater, the use of biosorbents for the sequential treatment of phosphorus and copper has not yet been studied. Porous chitosan (CS)-based biosorbents (CGBs) were developed to adsorb phytic acid (PA), a major form of organic phosphate. This first adsorbate (PA) further served as an additional ligand (P-type ligand) for the CGBs (N-type ligand) to form a complex with the second adsorbate (copper). After the adsorption of PA (the first adsorbate), the spent CGBs were recycled and used as a new adsorbent to adsorb Cu(II) ions (the second adsorbate), which was expected to have a dual coordination effect through P, N-ligand complexation with copper. The interactions and complexation between CS, PA and Cu(II) ions on the PA-adsorbed CGBs (PACGBs) were investigated by performing FTIR, XPS, XRD, and SEM-EDS analyses. The PACGBs exhibited fast and enhanced adsorption of Cu(II) ions, owing to the synergistic effect of the amino groups of CS (the original ligand, N-type) and the phosphate groups of PA (an additional ligand, P-type) on the adsorption of Cu(II) ions. This is the first time that sequential removal of phosphorus and heavy metals by biosorbents has been performed using biosorbents.

Harnessing HfO2 Nanoparticles for Wearable Tumor Monitoring and Sonodynamic Therapy in Advancing Cancer Care.

Addressing the critical requirement for real-time monitoring of tumor progression in cancer care, this study introduces an innovative wearable platform. This platform employs a thermoplastic polyurethane (TPU) film embedded with hafnium oxide nanoparticles (HfO2 NPs) to facilitate dynamic tracking of tumor growth and regression in real time. Significantly, the synthesized HfO2 NPs exhibit promising characteristics as effective sonosensitizers, holding the potential to efficiently eliminate cancer cells through ultrasound irradiation. The TPU-HfO2 film, acting as a dielectric elastomer (DE) strain sensor, undergoes proportional deformation in response to changes in the tumor volume, thereby influencing its electrical impedance. This distinctive behavior empowers the DE strain sensor to continuously and accurately monitor alterations in tumor volume, determining the optimal timing for initiating HfO2 NP treatment, optimizing dosages, and assessing treatment effectiveness. Seamless integration with a wireless system allows instant transmission of detected electrical impedances to a smartphone for real-time data processing and visualization, enabling immediate patient monitoring and timely intervention by remote medical staff. By combining the dynamic tumor monitoring capabilities of the TPU-HfO2 film with the sonosensitizer potential of HfO2 NPs, this approach propels cancer care into the realm of telemedicine, representing a significant advancement in patient treatment.

Sequential deacetylation/self-gelling chitin hydrogels and scaffolds functionalized with fucoidan for enhanced BMP-2 loading and sustained release.

Bone morphogenetic protein 2 (BMP-2) is a potent osteoinductive factor that promotes bone formation. A major obstacle to the clinical application of BMP-2 is its inherent instability and complications caused by its rapid release from implants. Chitin based materials have excellent biocompatibility and mechanical properties, making them ideal for bone tissue engineering applications. In this study, a simple and easy method was developed to spontaneously form deacetylated ß-chitin (DAC-ß-chitin) gels at room temperature through a sequential deacetylation/self-gelation process. The structural transformation of ß-chitin to DAC-ß-chitin leads to the formation of self-gelling DAC-ß-chitin, from which hydrogels and scaffolds were prepared. Gelatin (GLT) accelerated the self-gelation of DAC-ß-chitin and increased the pore size and porosity of the DAC-ß-chitin scaffold. The DAC-ß-chitin scaffolds were then functionalized with a BMP-2-binding sulfate polysaccharide, fucoidan (FD). Compared with ß-chitin scaffolds, FD-functionalized DAC-ß-chitin scaffolds showed higher BMP-2 loading capacity and more sustainable release of BMP-2, and thus had better osteogenic activity for bone regeneration.

Intelligent films of marine polysaccharides and purple cauliflower extract for food packaging and spoilage monitoring.

In this study, metalloanthocyanin-inspired, biodegradable packaging films were developed by incorporating purple cauliflower extracted (PCE) anthocyanins into alginate (AL)/carboxymethyl chitosan (CCS) hybrid polymer matrices based on complexation of metal ions with these marine polysaccharides and anthocyanins. PCE anthocyanins-incorporated AL/CCS films were further modified with fucoidan (FD) because this sulfated polysaccharide can form strong interactions with anthocyanins. Metals-involved complexation (Ca2+ and Zn2+-crosslinked films) improved the mechanical strength and water vapor permeability but reduced the swelling degree of the films. Zn2+-cross-linked films exhibited significantly higher antibacterial activity than did pristine (non-crosslinked) and Ca2+-cross-linked films. The metal ion/polysaccharide-involved complexation with anthocyanin reduced the release rate of anthocyanins, increased the storage stability and antioxidant capability, and improved the sensitivity of the colorimetric response of the indicator films for monitoring the freshness of shrimp. The anthocyanin-metal-polysaccharide complex film showed great potential as active and intelligent packaging of food products.

A low-molecular-weight chitosan fluorometric-based assay for evaluating antiangiogenic drugs.

Low-molecular-weight chitosan (LMWCS) damaged cell membranes in zebrafish showed its possibility to release reporter proteins for detection. In this study, we developed a simple fluorometric-based assay for the evaluation of clinical antiangiogenic drugs using LMWCS and Tg(fli1:EGFP) transgenic zebrafish, which expressed green-fluorescence protein (GFP) in the endothelial cells of blood vessel. In vitro stable and transiently transfected cell lines was released luciferase and green fluorescent protein (GFP) for intensity evaluation upon LMWCS fluorometric-based assay. In vivo Tg(fli1:EGFP) transgenic zebrafish was also released GFP from endothelial cells of blood vessels and show an increase of fluorescent intensity upon LMWCS fluorometric-based assay. Treatment with the clinical antiangiogenic drug sorafenib and analyzed by LMWCS fluorometric-based assay showed significantly reduction of angiogenesis. Furthermore, treatment with 2 µM sorafenib showed a significant reduction in angiogenesis of the intersegmental vein (ISV) and dorsal longitudinal anastomotic vessels (DLAV) in Tg(fli1:EGFP) transgenic zebrafish. Fluorescence intensity reduction from 2 µM sorafenib was used as a factor in the LMWCS fluorescence-based assay for relative antiangiogenic evaluation. Relative angiogenesis evaluation of the clinical drugs axitinib, cabozantinib, and regorafenib showed a significant reduction. Collectively, this study provided a simple, convenient, and rapid LMWCS fluorometric-based assay for evaluating angiogenic drugs using transgenic zebrafish.

Thiolated hyaluronic acid and catalase-enhanced CD44-targeting and oxygen self-supplying nanoplatforms with photothermal/photodynamic effects against hypoxic breast cancer cells.

Photothermal and photodynamic therapies (PTT/PDT) have been widely accepted as noninvasive therapeutic methods for cancer treatment. However, tumor hypoxia and insufficient delivery of photoactive compounds to cancer cells can reduce the efficacy of phototherapy. Herein, we first synthesized thiolated hyaluronic acid (THA) and then conjugated it with catalase (CAT) onto chlorin e6 (Ce6)-adsorbed small gold nanorods (Ce6@sAuNRs) with near-infrared (NIR)/visible light activated photothermal/photodynamic effects. The conjugation of THA and CAT on Ce6@sAuNRs resulted in a red-shift of the longitudinal LSPR absorption band of sAuNRs up to 1000 nm and maintained the excellent enzymatic activity of catalase. Modification of Ce6@sAuNRs with THA resulted in efficient internalization of the nanocomposite into MCF-7/ADR multidrug-resistant (MDR) breast cancer cells (CD44+), thereby significantly enhancing the intracellular accumulation of the photosensitizer Ce6. CAT endows Ce6@sAuNRs with self-supporting oxygen production, which enables them to efficiently generate singlet oxygen (1O2) under 660 nm laser irradiation and enhances the photodynamic effect against hypoxic breast cancer cells. The results highlight the prospect of this novel multi-functional nanoplatform integrating active biological macromolecules (THA and CAT) into photosensitizer/photothermal gold nanocomposites in overcoming the limitations of hypoxic MDR breast cancer cell treatment.

Ultrasound-Activated, Tumor-Specific In Situ Synthesis of a Chemotherapeutic Agent Using ZIF-8 Nanoreactors for Precision Cancer Therapy.

The in situ transformation of low-toxicity precursors into a chemotherapeutic agent at a tumor site to enhance the efficacy of its treatment has long been an elusive goal. In this work, a zinc-based zeolitic imidazolate framework that incorporates pharmaceutically acceptable precursors is prepared as a nanoreactor (NR) system for the localized synthesis of an antitumor drug. The as-prepared NRs are administered intratumorally in a tumor-bearing mouse model and then irradiated with ultrasound (US) to activate the chemical synthesis. The US promotes the penetration of the administered NRs into the tumor tissue to cover the lesion entirely, although some NRs leak into the surrounding normal tissue. Nevertheless, only the tumor tissue, where the H2O2 concentration is high, is adequately exposed to the as-synthesized antitumor drug, which markedly impedes development of the tumor. No significant chemical synthesis is detected in the surrounding normal tissue, where the local H2O2 concentration is negligible and the US irradiation is not directly applied. The as-proposed tumor-specific in situ synthesis of therapeutic molecules induces hardly any significant in vivo toxicity and, thus, is potentially a potent biocompatible approach to precision chemotherapy.

Biodegradable Nanoparticles Prepared from Chitosan and Casein for Delivery of Bioactive Polysaccharides.

Ophiopogon japonicus polysaccharides (OJPs) have great anti-inflammation and immunomodulatory abilities. However, the low bioavailability of OJPs reduces its applicability in the biomedical and pharmaceutical fields. Chitosan (CS) has excellent mucoadhesive properties and absorption-enhancing ability in oral administration. Casein hydrolysate (CL) has good interfacial diffusivity and emulsifying ability, and can interact with polysaccharides to form complexes combining the individual properties of both. Therefore, chitosan and casein hydrolysate are good candidates for developing nanoformulations for oral delivery. In this study, bioactive polysaccharides (OJPs), CS and CL, were combined to prepare CS/OJPs/CL co-assembled biodegradable nanoparticles. The interactions between polysaccharides (CS and OJPs) and peptide (CL) resulted in the formation of nanoparticles with an average particle size of 198 nm and high OJPs loading efficiency. The colloidal properties of the nanoparticles were pH-dependent, which were changed significantly in simulated digestive fluid at different pH values. OJPs released from the CS/OJPs/CL nanoparticles were greatly affected by pH and enzymatic degradation (trypsin and lysozyme). The nanoparticles were easily internalized by macrophages, thereby enhancing the OJPs' inhibitory ability against Ni2+-induced cytotoxicity and LPS-induced nitric oxide production. This study demonstrates that prepared polysaccharide/protein co-assembled nanoparticles can be potential nanocarriers for the oral delivery of bioactive polysaccharides with anti-inflammatory functions.

Modification of chitosan nanofibers with CuS and fucoidan for antibacterial and bone tissue engineering applications.

Chitosan (CS) electrospun nanofiber (ENF) membranes were modified with fucoidan (Fu) and CuS NPs through polyelectrolyte complexation and genipin (GP)-involved cross-linking reaction. The formation of Fu/CS complex and cross-linking of CS with GP increased the acid resistance and reduced the swelling rate of CS ENF, while the covalent conjugation of CuS NPs provided CS ENF with durable Fenton-like catalytic activity. The CuS@ENF composite (ENFC) effectively adsorbed H2O2 and near-infrared (NIR) light, enabling it to kill bacteria by photothermal and photocatalytic bactericidal effects. Fu and copper ions were able to release from the ENFC in a pH-dependent manner, and promoted the alkaline phosphatase activity of osteoblast cells and capillary tube formation of endothelial cells. This study provides a new approach to modify CS ENF with antibacterial and osteoblast differentiation activities, which may be available for bone infection prevention and tissue regeneration.

A novel low-molecular-weight chitosan/gamma-polyglutamic acid polyplexes for nucleic acid delivery into zebrafish larvae.

Many challenges, such as virus infection, extreme weather and long cultivation periods, during the development of fish larvae have been observed, especially in aquaculture. Gene delivery is a useful method to express functional genes to defend against these challengers. However, the methods for fish larvae are insufficient. In our earlier report, low-molecular-weight chitosan (LMWCS) showed a strong positive charge and may be useful for polyplex formulation. Herein, we present a simple self-assembly of LMWCS polyplexes (LMWCSrNPs) for gene delivery into zebrafish larvae. Different weight ratios of LMWCS/gamma-polyglutamic acid (γ-PGA)/plasmid DNA were analyzed by gel mobility assay. Delivery efficiency determined by green fluorescent protein (GFP) expression in zebrafish liver (ZFL) cells showed that delivery efficiency at a weight ratio of 20:8:1 was higher than others. Zeta potential and transmission electron microscopy (TEM) analysis showed that the round shape of the particle size varied. In our earlier reports, IRF9S2C could induce interferon-stimulated gene (ISG) expression to induce innate immunity in zebrafish and pufferfish. Further delivery of pcDNA3-IRF9S2C-HA plasmid DNA into ZFL cells and zebrafish larvae by LMWCSrNP successfully induced ISG expression. Collectively, LMWCSrNP could be a novel gene delivery system for zebrafish larvae and might be used to improve applications in aquaculture.

Thrombus-specific theranostic nanocomposite for codelivery of thrombolytic drug, algae-derived anticoagulant and NIR fluorescent contrast agent.

Thrombolysis is a standard treatment for rapidly restoring blood flow. However, the application of urokinase-type plasminogen activator (Uk) in clinical therapy is limited due to its nonspecific distribution and inadequate therapeutic accumulation. Precise thrombus imaging and site-specific drug delivery can enhance the diagnostic and therapeutic efficacy for thrombosis. Accordingly, we developed a P-selectin-specific, photothermal theranostic nanocomposite for thrombus-targeted codelivery of Uk and indocyanine green (ICG, a contrast agent for near-infrared (NIR) fluorescence imaging). We evaluated its capabilities for thrombus imaging and enzyme/hyperthermia combined thrombolytic therapy. Mesoporous silica-coated gold nanorods (Si-AuNRs) were functionalized with an arginine-rich peptide to create an organic template for the adsorption of ICG and fucoidan (Fu), an algae-derived anticoagulant. Uk was loaded into the SiO2 pores of the Si-AuNRs through the formation of a Fu-Uk-ICG complex on the peptide-functionalized template. The Fu-Uk/ICG@SiAu NRs nanocomposite increased the photostability of ICG and improved its targeting/accumulation at blood clot sites with a strong NIR fluorescence intensity for precise thrombus imaging. Furthermore, ICG incorporated into the nanocomposite enhanced the photothermal effect of Si-AuNRs. Fu, as a P-selectin-targeting ligand, enabled the nanocomposite to target a thrombus site where platelets were activated. The nanocomposite enabled a faster release of Uk for rapid clearing of blood clots and a slower release of Fu for longer lasting prevention of thrombosis regeneration. The nanocomposite with multiple functions, including thrombus-targeting drug delivery, photothermal thrombolysis, and NIR fluorescence imaging, is thus an advanced theranostic platform for thrombolytic therapy with reduced hemorrhaging risk and enhanced imaging/thrombolysis efficiency. STATEMENT OF SIGNIFICANCE: Herein, for the first time, a P-selectin specific, photothermal theranostic nanocomposite for thrombus-targeted co-delivery of urokinase and NIR fluorescence contrast agent indocyanine green (ICG) was developed. We evaluated the potential of this theranostic nanocomposite for thrombus imaging and enzyme/hyperthermia combined thrombolytic therapy. The nanocomposite showed multiple functions including thrombus targeting and imaging, and photothermal thrombolysis. Besides, it allowed faster release of the thrombolytic urokinase for rapidly clearing blood clots and slower release of a brown algae-derived anticoagulant fucoidan (also acting as a P-selectin ligand) for prevention of thrombosis regeneration. The nanocomposite is thus a new and advanced theranostic platform for targeted thrombolytic therapy.

A Noninvasive Gut-to-Brain Oral Drug Delivery System for Treating Brain Tumors.

Most orally administered drugs fail to reach the intracerebral regions because of the intestinal epithelial barrier (IEB) and the blood-brain barrier (BBB), which are located between the gut and the brain. Herein, an oral prodrug delivery system that can overcome both the IEB and the BBB noninvasively is developed for treating gliomas. The prodrug is prepared by conjugating an anticancer drug on ß-glucans using a disulfide-containing linker. Following oral administration in glioma-bearing mice, the as-prepared prodrug can specifically target intestinal M cells, transpass the IEB, and be phagocytosed/hitchhiked by local macrophages (Mϕ). The Mϕ-hitchhiked prodrug is transported to the circulatory system via the lymphatic system, crossing the BBB. The tumor-overexpressed glutathione then cleaves the disulfide bond within the prodrug, releasing the active drug, improving its therapeutic efficacy. These findings reveal that the developed prodrug may serve as a gut-to-brain oral drug delivery platform for the well-targeted treatment of gliomas.

Enhanced anticancer effect of ROS-boosted photothermal therapy by using fucoidan-coated polypyrrole nanoparticles.

Nanomaterial mediated cancer/tumor photo driven hyperthermia has obtained great awareness. Nevertheless, it is a challenge for improving the hyperthermic efficacy lacking resistance to stimulated thermal stress. We thus developed a bioinspired nano-platform utilizing inclusion complexation between photosensitive polypyrrole (Ppy) nanoparticles (NP) and fucoidan (FU). This FU-Ppy NP proved to be an excellent P-selectin-mediated, lung cancer-cell/tumor targeting delivery and specific accumulation, could augment cancer/tumor oxidative stress levels through producing cellular reactive oxygen species. Potent ROS/photothermal combinational therapeutic effects were exhibited by the bioinspired FU-Ppy NP through a selective P-selectin cancer/tumor targeting aptitude for the lung cancer cells/tumor compared with other nano-formulations. The usage of FU-Ppy NP also involves the potential mechanism of suppressing the biological expression of tumor vascular endothelial growth factor (VEGF). This FU biological macromolecule-amplified photothermally therapeutic nano-platform has promising potential for future medical translation in eradicating numerous tumors.

A smart and active film with tunable drug release and color change abilities for detection and inhibition of bacterial growth.

Antimicrobial resistance has become a global issue and thus the development of natural products/biomedical materials composites with antibacterial activities is urgently needed. When acute wounds develop into chronic wounds, the wound environments become alkaline. As long as infections occur, the wound pH further increases, making the wounds difficult to heal. Besides, bacterial growth in poultry, meat, fish and seafood products is usually reflected in a marked increase of pH values. Herein, smart, stimuli responsive self-assembled multilayer and complex film were constructed through the formation of hydrogen bonds and hydrophobic interactions between hydroxypropyl methylcellulose (HPMC) and epigallocatechin-3-gallate (EGCG), thereby greatly reducing the hydrophilicity of HPMC and offering enhanced mechanical strength, superior free radical scavenging capability, and improved water vapor and light barrier properties. The EGCG/HPMC complex film was able to control EGCG release by tuning pH or temperature of the release medium. Furthermore, incorporation of CuS nanoparticles into the film allowed it to triggers EGCG release in an on-demand fashion under near-infrared (NIR) exposure. Bacterial growth in glucose-free nutrient broth medium caused pH to rise (near pH 8.0), leading to transformation of EGCG from phenol type to phenolate ion and then quinone, allowing for spontaneous generation of H2O2 to kill bacteria. The complex films changed their color in response to bacterial growth because EGCG transformed from phenol type to quinone type under alkaline condition. The green synthesized EGCG/HPMC complex films can be used as a colorimetric pH indicator and an antibacterial material for wound dressing and food packaging applications.

Conductive Materials for Healing Wounds: Their Incorporation in Electroactive Wound Dressings, Characterization, and Perspectives.

The use of conductive materials to promote the activity of electrically responsive cells is an effective means of accelerating wound healing. This article focuses on recent advancements in conductive materials, with emphasis on overviewing their incorporation with non-conducting polymers to fabricate electroactive wound dressings. The characteristics of these electroactive dressings are deliberated, and the mechanisms on how they accelerate the wound healing process are discussed. Potential directions for the future development of electroactive wound dressings and their potential in monitoring the course of wound healing in vivo concomitantly are also proposed.

Active and intelligent gellan gum-based packaging films for controlling anthocyanins release and monitoring food freshness.

Active and intelligent packaging films with multiple functions including antioxidant, antibacterial and colorimetric pH indicator properties were developed by incorporating Clitoria ternatea (CT) extract into gellan gum (G) film. G enhanced the stability of CT anthocyanins and allowed the anthocyanins to release from G film in a pH-responsive behavior. Heat-treated soy protein isolate (HSPI) was able to interact with G and CT anthocyanins through the formation of electrostatic forces and covalent bonds. G film blended with HSPI greatly reduced the swelling capacity of G/HSPI composite film and controlled the anthocyanins release at pH greater than 6.0. The physical and mechanical properties of G films such as hydrophobicity, water vapor permeability, swelling capacity and tensile strength were also significantly modified by addition of HSPI to G films. The smart films changed their color with the increase of total volatile basic nitrogen (TVBN) values during progressive spoilage of shrimp, revealing their potential application for monitoring seafood freshness.