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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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Availability of data and materials. All data used to support the findings of this study are available from the corresponding author upon request., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

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 (HfO 2 NPs) to facilitate dynamic tracking of tumor growth and regression in real time. Significantly, the synthesized HfO 2 NPs exhibit promising characteristics as effective sonosensitizers, holding the potential to efficiently eliminate cancer cells through ultrasound irradiation. The TPU-HfO 2 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 HfO 2 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-HfO 2 film with the sonosensitizer potential of HfO 2 NPs, this approach propels cancer care into the realm of telemedicine, representing a significant advancement in patient treatment.

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 β-chitin (DAC-β-chitin) gels at room temperature through a sequential deacetylation/self-gelation process. The structural transformation of β-chitin to DAC-β-chitin leads to the formation of self-gelling DAC-β-chitin, from which hydrogels and scaffolds were prepared. Gelatin (GLT) accelerated the self-gelation of DAC-β-chitin and increased the pore size and porosity of the DAC-β-chitin scaffold. The DAC-β-chitin scaffolds were then functionalized with a BMP-2-binding sulfate polysaccharide, fucoidan (FD). Compared with β-chitin scaffolds, FD-functionalized DAC-β-chitin scaffolds showed higher BMP-2 loading capacity and more sustainable release of BMP-2, and thus had better osteogenic activity for bone regeneration., Competing Interests: Declaration of competing interest The authors confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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 (Ca 2+ and Zn 2+ -crosslinked films) improved the mechanical strength and water vapor permeability but reduced the swelling degree of the films. Zn 2+ -cross-linked films exhibited significantly higher antibacterial activity than did pristine (non-crosslinked) and Ca 2+ -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., Competing Interests: Declaration of competing interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. We understand that the Corresponding Author is the sole contact for the Editorial process (including Editorial Manager and direct communications with the office). He/she is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the Corresponding Author and which has been configured to accept email from., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

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 ( 1 O 2 ) 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., Competing Interests: Declaration of competing interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2022. Published by Elsevier B.V.)

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 H 2 O 2 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 H 2 O 2 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.

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 Ni 2+ -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., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

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 H 2 O 2 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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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 SiO 2 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financialinterestsor personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

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 β-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., (© 2021 Wiley-VCH GmbH.)

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., (© 2020 Wiley-VCH GmbH.)

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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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 H 2 O 2 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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Galectin-3 (Gal-3) is a 26-kDa lectin that regulates many aspects of inflammatory cell behavior. We assessed the hypothesis that increased levels of Gal-3 contribute to abdominal aortic aneurysm (AAA) progression by enhancing monocyte chemoattraction through macrophage activation. We analyzed the plasma levels of Gal-3 in 76 patients with AAA (AAA group) and 97 controls (CTL group) as well as in angiotensin II (Ang-II)-infused ApoE knockout mice. Additionally, conditioned media (CM) were used to polarize THP-1 monocyte to M1 macrophages with or without Gal-3 inhibition through small interfering RNA targeted deletion to investigate whether Gal-3 inhibition could attenuate macrophage-induced inflammation and smooth muscle cell (SMC) apoptosis. Our results showed a markedly increased expression of Gal-3 in the plasma and aorta in the AAA patients and experimental mice compared with the CTL group. An in vitro study demonstrated that the M1 cells exhibited increased Gal-3 expression. Gal-3 inhibition markedly decreased the quantity of macrophage-induced inflammatory regulators, including IL-8, TNF-α, and IL-1β, as well as messenger RNA expression and MMP-9 activity. Moreover, Gal-3-deficient CM weakened SMC apoptosis through Fas activation. These findings prove that Gal-3 may contribute to AAA progression by the activation of inflammatory macrophages, thereby promoting SMC apoptosis.

The therapeutic outcome of pancreatic cancer remains unsatisfactory, despite many attempts to improve it. To address this challenge, an oral drug delivery system that spontaneously initiates an effervescent reaction to form gas-bubble carriers is proposed. These carriers concurrently deliver lipophilic paclitaxel (PTX) and hydrophilic gemcitabine (GEM) in the small intestine. The bursting of the bubbles promotes the intestinal absorption of the drugs. The antitumor efficacy of this proposed oral drug delivery system is evaluated in rats with experimentally created orthotopic pancreatic tumors. The combined administration of equivalent amounts of PTX and GEM via the intravenous (i.v.) route, which is clinically used for treating pancreatic cancer, serves as a control. Following oral administration, the lipophilic PTX is initially absorbed through the intestinal lymphatic system and then enters systemic circulation, whereas the hydrophilic GEM is directly taken up into the blood circulation, ultimately accumulating in the tumorous pancreatic tissues. A pharmacokinetic study reveals that the orally delivered formulation has none of the toxic side-effects that are associated with the i.v. injected formulation; changes the pharmacokinetic profiles of the drugs; and increases the bioavailability of PTX. The oral formulation has a greater impact than the i.v. formulation on tumor-specific stromal depletion, resulting in greater inhibition of tumor growth with no evidence of metastatic spread. As well as enhancing the therapeutic efficacy, this unique approach of oral chemotherapy has potential for use on outpatients, greatly improving their quality of life., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The polysaccharides from Ophiopogon japonicus (OJPs) were known to have protective effects against diabetes, and cardiovascular and chronic inflammatory diseases. However, OJPs were poorly absorbed after oral administration, resulting in limited efficacy because of the low bioavailability. In this study, OJPs extracted and fractionated from Ophiopogon japonicus were used to prepare OJPs/chitosan (CS)/whey protein (WP) co-assembled nanoparticles. The OJPs/CS/WP nanoparticles showed high biocompatibility and inhibited the cytotoxicity of RAW264.7 cells induced by nickel. With the assistance of CS and WP, the anti-inflammatory and antioxidant activities of OJPs were enhanced because the nanoparticles improved OJPs uptake by RAW264.7 macrophage cells as evidenced by efficient scavenging of DPPH and ABTS free radicals and effective inhibition of NO production and the gene expressions of iNOS, COX2, TNF-α, CCL2, and CXCL2 inflammatory signals. Determining the transepithelial electrical resistance and paracellular permeability of Caco-2 monolayer/macrophage co-cultured system suggested that the OJPs-loaded nanoparticles effectively protected the intestinal epithelial barrier integrity against the damage caused by LPS-stimulated macrophage inflammation and attenuated the defects of intestinal epithelial TJ barrier and permeability. These findings suggest that the OJPs/CS/WP nanoparticles may be potential carriers for oral delivery of OJPs to treat intestinal barrier defects, such as inflammatory bowel disease (IBD)., (Copyright © 2020. Published by Elsevier B.V.)

Multifunctional nanoplatforms combined with photodynamic therapy (PDT) and anticancer drugs have shown great promising in cancer therapy. However, their efficacy is limited by the low specificity, low oxygen levels, and a tolerant tumor immune microenvironment. Herein, we developed a biocompatible theranostic nanoplatform (FM@VP) based on co-assembly of a nanocomplex formed by a functional polysaccharide fucoidan and a bioreducible polyamidoamine (PAMAM) dendrimer, a photosensitizer verteporfin (VP), and MnO 2 nanoparticles (a tumor microenvironment responsive oxygen evolving nanomaterial) into a multifunctional nanoparticle cluster. The dendrimer-fucoidan polyionic nanocomplex (DFPN) specifically targeted P-selectin-overexpressed triple-negative breast cancer (TNBC) and the tumor-associated vasculature, and was sensitive to glutathione (GSH) in tumor. More importantly, this FM@VP nanocomplex simultaneously overcame tumor hypoxia, suppressed oncogenic signaling, and attenuated tumor-mediated immunosuppression, resulting in improving therapeutic efficacy of PDT while enhancing antitumor immunity and anti-metastasis. This discovery provides a powerful strategy for synergetic cancer targeting/photodynamic/immunotherapy and could serve as a safe clinical translational approach., (Copyright © 2020. Published by Elsevier Ltd.)

P-selectin overexpressed on activated endothelial cells and platelets is a new target for treatment of cancers and cardiovascular diseases such as atherosclerosis and thrombosis. In this study, depolymerized low molecular weight fucoidan (LMWF 8775 ) and a thermolysin-hydrolyzed protamine peptide (TPP 1880 ) were prepared. TPP 1880 and LMWF 8775 were able to form self-assembled complex nanoparticles (CNPs). The formation of TPP 1880 /LMWF 8775 CNPs was characterized by Fourier-transform infrared spectra, circular dichroism spectra and isothermal titration calorimetry. The CNPs selectively targeted PMA-stimulated, inflamed endothelial cells (HUVECs) with high expression of P-selectin. Gd-DTPA MRI contrast agent was successfully loaded in the CNPs with better T 1 relaxivity and selectively accumulated in the activated HUVECs with increased MRI intensity and reduced cytotoxicity as compared to free Gd-DTPA. Our results suggest that the TPP 1880 /LMWF 8775 CNPs may have potential in future for early diagnosis of cardiovascular diseases and cancers in which the endothelium is inflamed or activated., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Epigallocatechin gallate (EGCG) has many biological functions; however, the use of EGCG in biomedical and food industries was limited due to its poor oral absorption and high susceptibility to degradation. In this study, a mucoadhesive quaternary chitosan was synthesized and combined with fucoidan (FD) (or depolymerized lower molecular weight fucoidan, LMWF) to prepare EGCG-loaded nanoparticles, which extended EGCG release over 300 min and enhanced the transepithelial permeation of EGCG using Caco-2 cells as a model for intestinal absorption. The nanoparticls protected EGCG against degradation in phosphate buffer (pH 6.8) and the remaining EGCG was 1.7-folds higher than the control (EGCG alone). The additive effects of EGCG combined with FD or LMWF in the nanoparticles increased the DPPH radical scavenging activity and the enzyme inhibitory activity against α-amylase (2.82-4.92 fold increase) and α-glucosidase (1.35-1.67 fold increase), while quaternary chitosan helped to enhance the antibacterial effect of EGCG., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Chitosan is suggested as no or low toxicity and biocompatible biomaterial. Digestion of chitosan to reduce molecular weight and formulate nanoparticle was generally used to improve efficiency for DNA or protein delivery. However, the toxicity of low-molecular-weight chitosan (LMWCS) towards freshwater fishes has not been well evaluated. Here, we reported the toxic mechanism of LMWCS using zebrafish (Danio rerio) liver (ZFL) cell line, zebrafish larvae, and adult fish. LMWCS rapidly induced cytotoxicity of ZFL cells and death of zebrafish. Cell membrane damaged by LMWCS reduced cell viability. Damaged membrane of epithelial cell in zebrafish larvae induced breakage of the yolk. Adult fish exhibited hypoxia before death due to multiple damages induced by LMWCS. Although the toxicity of LMWCS was revealed in zebrafish model, the toxicity was only present in pH < 7 and easy be neutralized by other negative ions. Collectively, these data improved a new understanding of LMWCS properties., (Copyright © 2020. Published by Elsevier Ltd.)

Fucoidan is a fucose-rich polysaccharide that has gained attention for its various anticancer properties. However, the effect and underlying mechanism of fucoidan on triple-negative breast cancer (TNBC) are still unknown. Herein, we investigated the anticancer potential of fucoidan from Laminaria japonica. We found that fucoidan showed modest antiproliferative activity against TNBC cells, while it effectively reduced migratory and invasive capacities. Mechanistically, fucoidan suppressed activation of MAPK and PI3K followed by inhibition of AP-1 and NF-κB signaling in TNBC. Additionally, fucoidan downregulated expressions of proangiogenic factors in TNBC cells, and fucoidan blocked tumor-elicited tube formation by human umbilical vascular endothelial cells (HUVECs). We also observed that fucoidan blocked tumor adhesion and invasion towards HUVECs. Surprisingly, fucoidan robustly suppressed tube formation on HUVECs. Moreover, fucoidan inhibited in vivo angiogenesis and micrometastasis in a transgenic zebrafish model. Together, L. japonica fucoidan exhibits potent antitumor effects by its attenuation of invasiveness and proangiogenesis in TNBC., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Erythropoietin-producing hepatomocellular receptors and their receptor-interacting proteins (Eph/ephrin) can participate in the regulation of growth and development and promote the development of diseases through short-distance signal transduction between cells. To study the mechanism of Eph/ephrin and oral-related diseases, we provided a new theoretical basis and a strategy for the treatment of oral diseases. The Eph/ephrin pathway has been used to regulate oral diseases, especially in periodontal disease prevention, orthodontic bone reconstruction, and biological treatment of oral tumors. This paper reviews the research progress of Eph/ephrin pathway in oral-related diseases.

Nanofiber-based materials have recently gained increasing attention in food packaging, drug delivery, and biomedical applications. In this study, a multi-nanofibers composite film was developed based on bacterial cellulose nanofiber (BCNF)/chitin nanofiber (CNF) hybridization. The nanofibers were responsible for the formation of well-dispersed curcumin (Cur) micro/nanoparticles in the nanocomposite films. The release of Cur from the films were affected by CNF and the sizes of Cur particles formed in situ. The Cur particles reduced tensile strength and increased water vapor permeability of BCNF film. However, CNF improved the mechanical strength and barrier property of the Cur/BCNF/CNF composite film. Moreover, the multi-nanofibers composite film showed excellent dynamic antioxidant capacity and antibacterial activity, as well as was capable to monitor pH change and trace amount of boric acid. Results of this study suggested that the Cur/BCNF/CNF composite film can be used as a smart and active food packaging material., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Fibrinolytic treatments for venous or arterial thrombotic syndromes using systemic administration of thrombolytics, such as streptokinase, can induce life-threatening bleeding complications. In this study, we offer the first proof of concept for a targeted photothermal fibrin clot prevention and reduction technology using macrophages loaded with polypyrrole-polyethylenimine nanocomplexes (Ppy-PEI NCs) and subjected to near-infrared radiation (NIR). We first show that the developed Ppy-PEI NCs could be taken up by defensive macrophages in vitro through endocytosis. The Ppy-PEI NCs generated local hyperthermia upon NIR treatment, which appeared to produce reactive oxygen species in Ppy-PEI NC-loaded macrophages. Preliminary evidence of efficacy as an antithrombotic tool is provided, in vitro, using fibrinogen-converted fibrin clots, and in vivo, in a rat femoral vascular thrombosis model generated by exposure to ferric chloride substance. The in vivo biocompatibility, photothermal behavior, biodistribution, and histological observation of cellular interactions with the Ppy-PEI NCs in the rat model provide rationale in support of further preclinical studies. This Ppy-PEI NC/NIR-based method, which uses a unique macrophage-guided targeting approach to prevent and lyse fibrin clots, may potentially overcome some of the disadvantages of current thrombolytic treatments. STATEMENT OF SIGNIFICANCE: Fibrinolytic treatments for venous or arterial thrombotic syndromes using systemic administration of thrombolytics, such as streptokinase, can induce life-threatening bleeding complications. In this study, we offer the first proof of concept for a targeted photothermal fibrin clot reduction technology using macrophages loaded with polypyrrole-polyethylenimine nanocomplexes (Ppy-PEI NCs) and subjected to near-infrared radiation (NIR). We first show that the developed Ppy-PEI NCs can be taken up by defensive macrophages in vitro through endocytosis. The Ppy-PEI NCs generated local hyperthermia upon NIR treatment, which appeared to produce reactive oxygen species in Ppy-PEI NC-loaded macrophages. Preliminary evidence of efficacy as an antithrombotic tool is provided, in vitro, using fibrinogen-converted fibrin clots, and in vivo, in a rat femoral vascular thrombosis model generated by exposure to ferric chloride substance. The in vivo biocompatibility, photothermal behavior, biodistribution, and histological observation of cellular interactions with the Ppy-PEI NCs in the rat model provide rationale in support of further preclinical studies. This Ppy-PEI NC/NIR-based method, which uses a unique macrophage-guided targeting approach to disintegrate fibrin clots, may potentially overcome some of the disadvantages of current thrombolytic treatments., (Copyright © 2019. Published by Elsevier Ltd.)

Vaccination is an effective medical intervention for preventing disease. However, without an adjuvant, most subunit vaccines are poorly immunogenic. This work develops a bioinspired nanocomposite hyaluronic acid hydrogel system that incorporates N-trimethyl chitosan nanoparticles (TMC/NPs) that carry a model subunit vaccine ovalbumin (OVA) that can elicit a potent and prolonged antigen-specific humoral response. Experimental results indicate that the nanocomposite hydrogel system (NPs-Gel) can retain a large proportion of its TMC/NPs that are bonded by covalent/electrostatic interactions and extend the release of the encapsulated OVA, enabling their localization at the site of hydrogel injection. The positively charged TMC/NPs can be effectively internalized by dendritic cells, significantly augmenting their maturation, suggesting that TMC can function as an adjuvant-based OVA delivery system. Upon subcutaneous implantation in mice, the NPs-Gel acts as an in situ depot that recruits and concentrates immune cells. The TMC/NPs that do not have any specific interactions with the hydrogel network are released rapidly and internalized by the neighboring immune cells, providing a priming dose, while those retained inside the NPs-Gel are ingested by the recruited and concentrated immune cells over time, acting as a booster dose, eliciting high titers of OVA-specific antibody responses. These experimental results suggest particulate vaccines that are integrated in such a bioinspired hydrogel system may be used as single-injection prime-boost vaccines, enabling effective and persistent humoral immune responses., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Hydroxypropyl chitosan (HPCS) has recently attracted increasing attention in biomedical applications because it has enhanced water solubility, excellent biocompatibility, and better antioxidant and antibacterial activities compared with chitosan. However, HPCS doesn't meet the mechanical strength requirement in bone tissue engineering and is not suitable for cell adhesion and growth because of its hydrophilic nature and low crystallinity. In this study, nano-scaled hydroxyapatite (n-HA) and HPCS were synthesized, respectively, and then n-HA/HPCS nanocomposite scaffolds were developed by incorporating n-HA into HPCS matrix accompanied with crosslinking of HPCS by a naturally occurring compound, genipin (GP), which in turn greatly altered the hydrophilicity and mechanical properties. The nanocomposite scaffolds showed an open structure with interconnected pores and a rough morphology with n-HA inserted in the GP-crosslinked HPCS matrix. The porosity, swelling capacity, compressive strength, fluorescence emission and degradation rate can be regulated by varying GP concentrations and n-HA contents. An osteoconductive and osteogenic marine algae polysaccharide, fucoidan, was further adsorbed to the composite scaffolds via electrostatic interactions. Incorporation of n-HA and adsorption of FD into the composite scaffolds increased ALP activity in 7F2 osteoblast cells and promoted their mineralization. The FD-adsorbed n-HA/HPCS composite scaffolds can be a potential biomaterial for BTE applications., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Platelet-rich plasma (PRP) is rich in growth factors and has commonly been utilized in&nbsp;the repair and regeneration of damaged articular cartilage. However, the major drawbacks of direct PRP injection are unstable biological fixation and fast or burst release of growth factors. Fucoidan is a heparinoid compound that can bind growth factors to control their release rate. Furthermore, fucoidan can reduce arthritis through suppressing inflammatory responses and thus it has been reported to prevent the progression of osteoarthritis, promote bone regeneration and accelerate healing of cartilage injury. Injectable hydrogels can be used to deliver cells and growth factors for an alternative, less invasive treatment of cartilage defects. In this study, hyaluronic acid (HA) and fucoidan (FD) was blended with gelatin (GLT) and the GLT/HA/FD hybrid was further cross-linked with genipin (GP) to prepare injectable GP-GLT/HA/FD hydrogels. The gelation rate was affected by the GP, GLT, HA and FD concentrations, as well as the pH values. The addition of HA and FD to GLT networks improved the mechanical strength of the hydrogels and facilitated the sustained release of PRP growth factors. The GP-GLT/HA/FD hydrogel showed adequate injectability, shape-persistent property and strong adhesive ability, and was more resistant to enzymatic degradation. The PRP-loaded GP-GLT/HA/FD hydrogel promoted cartilage regeneration in rabbits, which may lead to an advanced PRP therapy for enhancing cartilage repair., Competing Interests: The authors declare no conflict of interest.

Oral administration is a highly attractive approach for the delivery of protein drugs. However, oral protein therapeutics typically exhibit extremely poor bioavailability due to the harsh gastrointestinal (GI) environments and low permeability of protein across the intestinal barrier. Trimethyl chitosan (TMC) shows excellent mucoadhesive and absorption-enhancing properties while fucoidan (FD) has hypoglycemic effects and can prevent diabetes-related complications. Here we report, for the first time, that TMC combined with FD can be developed to a mutlifunctional nanoplatform for enhancing the transepithelial permeation of insulin through the intestinal epithelial cell barrier and inhibiting the α-glucosidase activity. TMC and FD self-assembled into spherical nanoparticles (NPs) for insulin encapsulation. TMC/FD NPs protected insulin against degradation by releasing insulin in a pH-dependent manner in the gastrointestinal tract fluids. The NPs were able to modulate the barrier function of the Caco-2 intestinal epithelial cell monolayer, and enhance paracellular transport of insulin across the intestinal barrier. TMC/FD NPs also showed α-glucosidase inhibitory activity, with an inhibition ratio of 33.2% at 2 mg/mL. The superior transepithelial absorption enhancing property of the TMC/FD NPs is expected to combine in the future with the functions of fucoidan against diabetes-related complications for development of advanced mutlifunctional therapeutic platforms for diabetes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The major obstacle in current cancer therapy is the existence of cancer stem cells (CSCs), which are responsible for therapeutic resistance and contribute to metastasis and recurrence. Identification of reliable biomarkers for diagnostic and therapeutic targets is necessary for drug development and cancer treatment. In this study, we identified that the antipsychotic chlorpromazine (CPZ) exhibited potent anti-breast cancer and anti-CSC capabilities. Treatment with CPZ suppressed stemness properties including mammosphere formation, aldehyde dehydrogenase (ALDH) activity, and stemness-related gene expressions in breast cancer cells and CSCs. Moreover, CPZ increased the susceptibility of breast cancer MCF7 cells and drug-resistant MCF7/ADR cells when combined with chemotherapies. Mechanistically, we identified that CPZ suppressed yes-associated protein (YAP) through modulating Hippo signaling and promoting proteasomal degradation of YAP. Elevated expression of YAP was confirmed to be crucial for stemness-related gene expressions, and was associated with invasiveness and stem-like signatures in breast cancer patients. Moreover, overexpression of YAP conferred poor outcomes particularly of basal-like breast cancer patients. Our data showed that YAP is a promising therapeutic target for breast CSCs, and CPZ has the potential to be a repurposed drug for breast cancer treatment., (Copyright © 2019 Elsevier B.V. All rights reserved.)

An in situ forming gel based on simply blending carboxymethyl hexanoyl chitosan (CHC) with low molecular weight hyaluronic acid (LMW HA) was developed, without needing cross-linking, photopolymerization or thermal treatments. The CHC/LMW HA blends formed nanoparticles and then rapidly transformed into supermolecular hydrogels under stirring. The gel formation mechanism was examined by Förster resonance energy transfer (FRET). The gels were injectable, cytocompatible and biodegradable, and showed shape-persistent behavior and adhesive property. Berberine, an anti-apoptotic and anti-arthritis naturally occurring compound, was encapsulated within the CHC/LMW HA gels. The gels demonstrated a pH-responsive characteristic which were able to release berberine in a sustained manner at pH 6.0 (simulating inflamed arthritic articular cartilage) and the degradation rates were accelerated at pH 7.4 (simulating healed normal tissue). The berberine-loaded gels effectively protected chondrocytes against sodium nitroprusside-induced apoptosis. The gels may be potentially useful as an injectable system for intra-articular drug delivery and cartilage tissue engineering., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The encapsulation of insulin in micro- or nanodelivery systems may eliminate the need for frequent subcutaneous injections, improving the quality of life of diabetic patients. Formulations for oral, intranasal, pulmonary, subcutaneous, and transdermal administration have been developed. The use of stimuli-responsive polymeric carriers that can release the encapsulated drug in response to changes of the environmental stimuli or external activation enables the design of less invasive or non-invasive systems for smart insulin delivery from depots in the body. This article will look at strategies for the development of responsive delivery systems and the future meeting of the demands of new modes of insulin delivery., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Bone tissue engineering holds great promise and clinical efficacy for the regeneration of bone defects. In this study, an amphoteric N,O-carboxymethyl chitosan (NOCC) and fucoidan (FD) were covalently cross-linked via an amidation reaction to synthesize NOCC/FD composite hydrogels. The hydrogels were lyophilized and then three-dimensional scaffolds with interconnected macropores were obtained. To enhance the mechanical properties and osteogenic activity, the NOCC/FD scaffolds were biomineralized for the growth of hydroxyapatite crystals. A comparative assessment of the structures, morphologies, and physical properties of the original and mineralized scaffolds were performed by SEM, EDS, X-ray diffraction and FT-IR analysis. FD regulated the growth of hydroxyapatite nanocrystallites (n-HAp) and thus the NOCC/FD scaffolds showed better mineralization efficiency than NOCC scaffolds. The compressive strength of the scaffolds was greatly enhanced after mineralization with n-HAp. The n-HAp/NOCC/FD scaffolds enhanced the proliferation, ALP activity, and mineralization of osteoblast cells more strongly than the original and mineralized NOCC scaffolds. Hence, the n-HAp-mineralized NOCC/FD scaffolds may prove to be an excellent and versatile scaffold for bone tissue engineering., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The clinical treatment of gastric cancer is hampered by the development of anticancer drug resistance as well as the unfavorable pharmacokinetics, nontarget toxicity, and inadequate intratumoral accumulation of current chemotherapies. The polyphenol epigallocatechin gallate in combination with doxorubicin exhibits synergistic inhibition P-glycoprotein efflux pump activity and cancer cell growth. This study evaluated a potential activated nanoparticle delivery system comprising a hyaluronic acid complex with polyethylene glycol-conjugated gelatin containing encapsulated epigallocatechin gallate and low-dose doxorubicin, which may facilitate targeted drug administration to gastric cancer cells. We confirmed successful delivery of bioactive combination drugs and internalization into gastric cancer cells through CD44 ligand recognition and ensuing inhibition of cell proliferation via caspase-induced apoptosis and G2/M phase cell cycle arrest. Furthermore, the targeted nanoparticles significantly suppressed gastric tumor activity and reduced both tumor and heart tissue inflammatory reaction in vivo compared to systemic combination treatment.

Self-assembled nanoparticles (NPs) from arginine-modified chitosan (CS-N-Arg) and thiolated fucoidan (THL-fucoidan) were synthesized to enhance the transport of dextran and curcumin across intestinal epithelial cell layer. CS-N-Arg/THL-fucoidan NPs exhibited a pH-sensitive assembly-disassembly and drug release property. Evaluations of the NPs in enhancing the transport of a hydrophilic macromolecule (FITC-dextran) and a hydrophobic drug (curcumin) were investigated in Caco-2 cell monolayers. The cationic CS-N-Arg in the NPs induced disruption of intestinal epithelial tight junctions as indicated by the decrease of transepithelial electrical resistance (TEER). Permeation studies revealed that the NPs enhanced the paracellular permeation of macromolecular dextran through the monolayer barrier. In addition, the multifunctional NPs increased the permeability of rhodamine 123 because the thiomer THL-fucoidan in the NPs inhibited P-glycoprotein. Cellular uptake and permeability of curcumin encapsulated in the NPs were improved due to increasing their water solubility and stability., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Efficient nonviral oral gene delivery offers an attractive modality for chronic protein replacement therapy. Herein, the oral delivery of insulin gene is reported by a nonviral vector comprising a copolymer with a high degree of substitution of branched polyethylenimine on chitosan (CS-g-bPEI). Protecting the plasmid from gastric acidic degradation and facilitating transport across the gut epithelium, the CS-g-bPEI/insulin plasmid DNA nanoparticles (NPs) can achieve systemic transgene expression for days. A single dose of orally administered NPs (600 µg plasmid insulin (pINS)) to diabetic mice can protect the animals from hyperglycemia for more than 10 d. Three repeated administrations spaced over a 10 d interval produce similar glucose-lowering results with no hepatotoxicity detected. Positron-emission-tomography and computed-tomography images also confirm the glucose utilization by muscle cells. While this work suggests the feasibility of basal therapy for diabetes mellitus, its significance lies in the demonstration of a nonviral oral gene delivery system that can impact chronic protein replacement therapy and DNA vaccination.

This study attempted to develop chitosan-based nanoparticles with increased stability and antibacterial activity. The chitosan/protamine hybrid nanoparticles were formed based on an ionic gelation method by mixing chitosan with protamine and subsequently cross-linking the mixtures with sodium tripolyphosphate (TPP). The effects of protamine on the chemical structures, physical properties, and antibacterial activities of the hybrid nanoparticles were investigated. The antibacterial experiments demonstrated that the addition of protamine (125 µg/mL) in the hybrid nanoparticles (500 µg/mL chitosan and 166.67 µg/mL TPP) improved the antimicrobial specificity with the minimum inhibitory concentration (MIC) value of 31.25 µg/mL towards Escherichia coli ( E. coli ), while the MIC value was higher than 250 µg/mL towards Bacillus cereus . The chitosan/protamine hybrid nanoparticles induced the formation of biofilm-like structure in B. cereus and non-motile-like structure in E. coli . The detection of bacterial cell ruptures showed that the inclusion of protamine in the hybrid nanoparticles caused different membrane permeability compared to chitosan nanoparticles and chitosan alone. The chitosan/protamine nanoparticles also exhibited lower binding affinity towards B. cereus than E. coli . The results suggested that the hybridization of chitosan with protamine improved the antibacterial activity of chitosan nanoparticles towards pathogenic E. coli , but the inhibitory effect against probiotic B. cereus was significantly reduced., Competing Interests: The authors declare no conflict of interest.

Bacterial cellulose (BC) is a biopolymer composed of nanofibers which has excellent film-forming ability. However, BC do not have antibacterial or antioxidant activity, thus limiting the applicability of BC for food and biomedical applications. In this study, flavonoid silymarin (SMN) and zein were assembled into spherical SMN-Zein nanoparticles that could be effectively adsorbed onto BC nanofibers. SMN-Zein nanoparticles greatly changed the wettability and swelling property of BC films due to the formation of nanoparticles/nanofibers nanocomposites. SMN-Zein nanoparticles enhanced the release of sparingly soluble silymarin from the nanocomposite films. The active films showed more effective antioxidant and antibacterial activities as compared with pure BC films and thus were able to protect salmon muscle from deterioration and lipid oxidation. These findings suggest that the nanoparticle/nanofiber composites may offer a suitable platform for modification of BC films with improved drug release properties and biological activities., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The tumor microenvironments are often acidic and overexpress specific enzymes. In this work, we synthesized a poly(AA-b-NIPAAm) copolymer (PAA-b-PNIPAAm) using a reversible addition-fragmentation chain transfer (RAFT) polymerization method. PAA-b-PNIPAAm and a cationic protein (protamine) were self-assembled into nanogels, which effectively reduced the cytotoxicity of protamine. The protamine/PAA-b-PNIPAAm nanogels were responsive to the stimuli including temperature, pH, and enzyme due to disaggregation of PAA-b-PNIPAAm, change in random coil/α-helix conformation of protamine, and enzymatic hydrolysis of the protein. Changing the pH from 7.4 to a lowered pHe (6.5-5.0) resulted in an increase in mean particle size and smartly converted surface charge from negative to positive. The cationic nanogels easily passed through the cell membrane and enhanced intracellular localization and accumulation of doxorubicin-loaded nanogels in multidrug resistant MCF-7/ADR breast cancer cells. Cold shock treatment triggered rapid intracellular release of doxorubicin against P-glycoprotein (Pgp)-mediated drug efflux, showing significantly improved anticancer efficacy as compared with free DOX. Furthermore, the nanogels were able to carry a rose bengal photosensitizer and caused significant damage to the multidrug resistant cancer cells under irradiation. The cationic nanogels with stimuli-responsive properties show promise as drug carrier for chemotherapy and photodynamic therapy against cancers.

Sodium dodecyl sulfate (SDS) is generally regarded as a potent permeability enhancer in oral formulations; however, one concern related to the use of any permeation enhancer is its possible absorption of unwanted toxins during the period of epithelial permeability enhancement. In this work, the safety and efficacy of an SDS-containing bubble carrier system that is developed from an orally administered enteric-coated capsule are evaluated. The bubble carriers comprise diethylene triamine pentaacetic acid (DTPA) dianhydride, sodium bicarbonate (SBC), SDS, and insulin. Upon exposure to the intestinal fluid, DTPA dianhydride hydrolyzes to yield acids, and SBC rapidly reacts with these acids to generate CO 2 , producing bubble carriers, each containing a self-assembling water film. The hydrophilic insulin is entrapped in the self-assembled water film, which is stabilized by SDS. The SDS in the bubble carrier system can act as a dissolution enhancer in the dispersion of insulin molecules, as a surfactant that stabilizes the bubble carriers, as a protease inhibitor that protects the protein drug, and as a permeation enhancer that augments its oral bioavailability. Hence, a significant increase in the plasma insulin level and an excellent blood glucose-lowering response in diabetic rats are effectively achieved. Moreover, the enhancement of epithelial permeation by this SDS-containing formulation does not promote the absorption of intestinal endotoxins. The above facts indicate that the bubble carrier system that is stabilized by SDS can be used as a safe and potent carrier in the oral delivery of therapeutic proteins., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Cancer cells exhibit specific physiological differences compared to normal cells. Most surface membranes of cancer cells are characterized by high expression of given protein receptors, such as albumin, transferrin, and growth factors that are also present in the plasma of patients themselves, but are lacking on the surface of normal cells. These distinct features between cancer and normal cells can serve as a niche for developing specific treatment strategies. Near-infrared (NIR)-light-triggered therapy platforms are an interesting novel avenue for use in clinical nanomedicine. As a photothermal agent, conducting polymer nanoparticles, such as polypyrrole (PPy), of great NIR light photothermal effects and good biocompatibility, show promising applications in cancer treatments through the hyperthermia mechanism. Autologous plasma proteins coated PPy nanoparticles for hyperthermia therapy as a novel core technology platform to treat cancers through secreted protein acid and rich in cysteine targeting are developed here. This approach can provide unique features of specific targeting toward cancer cell surface markers and immune transparency to avoid recognition and attack by defense cells and achieve prolonged circulation half-life. This technology platform unveils new clinical options for treatment of cancer patients, supporting the emergence of innovative clinical products., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Fucoidan, a sulfated marine polysaccharide, has many potential biological functions, including anticancer activity. Recently, fucoidan has been reported to target P-selectin expressed on metastatic cancer cells. Increasing research attention has been devoted to the developments of fucoidan-based nanomedicine. However, the application of traditional chitosan/fucoidan nanoparticles in anticancer drug delivery may be limited due to the deprotonation of chitosan at a pH greater than 6.5. In this study, a mutli-stimuli-responsive nanoparticle self-assembled by fucoidan and a cationic polypeptide (protamine) was developed, and their pH-/enzyme-responsive properties were characterized by circular dichroism (CD) spectroscopy, dynamic light scattering (DLS), and zeta potential analysis. Enzymatic digestion and acidic intracellular microenvironment (pH 4.5-5.5) in cancer cells triggered the release of an anticancer drug (doxorubicin) from the nanoparticles. The protamine/fucoidan complex nanoparticles with P-selectin mediated endocytosis, charge conversion and stimuli-tunable release properties showed an improved inhibitory effect against a metastatic breast cancer cell line (MDA-MB-231)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)