Lingzhi or Reishi Medicinal Mushroom Ganoderma lucidum (Agaricomycetes) Nanogel in a Complete Freund's Adjuvant-Induced Rheumatoid Arthritis Rat Model: Anti-Arthritic, Anti-Inflammatory, and Antioxidative Activity.

Lingzhi or reishi mushroom, Ganoderma lucidum, is a medicinal mushroom quite widely developed as herbal medicine because it has acted as an anticancer, antitumor, antioxidant, and anti-inflammatory. The active mycochemical compounds of G. lucidum mushrooms, such as flavonoids and polysaccharides, can suppress the release of pro-inflammatory cytokines and prevent lipid peroxidation due to oxidative stress. Rheumatoid arthritis (RA) is an autoimmune disease where the exact cause is unknown, and RA prevalence continues to increase yearly. In patients with RA, joint damage and inflammation occur. This study aims to evaluate the effectiveness of G. lucidum nanogels as anti-arthritis, anti-inflammatory, and antioxidative. The research method was a true experiment using a control group and treatment group that randomly assigned, using 24 male Wistar rats (Rattus norvegicus) induced with complete Freund's adjuvant (CFA) 0.1 mL. The rats were divided into six groups; healthy control/HCt (did not receive the treatment), negative control/NCt (induced by CFA), and positive control/PCt (given 0.012 diclofenac sodium). TG1 (given 250 mg G. lucidum nanogels), TG2 (given 500 mg G. lucidum nanogels), TG3 (given 750 mg G. lucidum nanogels). IgG, eNOS, IL-1ß, COX-2, NOS, TNF-α, and IL-6 parameters were measured using ELISA, and the data obtained were analyzed by one-way ANOVA using SPSS (P < 0.05). The results showed that administering G. lucidum nanogels significantly reduced IgG, NOS, TNF-α, COX-2, IL-1ß, and IL-6 and increased eNOS levels. The anti-inflammatory and antioxidative activities in suppressing pro-inflammatory cytokines and increasing eNOS levels prove that the nanogel extract G. lucidum have the potential to be developed as anti-arthritis natural therapeutic.

Karanjin-loaded soya lecithin-based ethosomal nanogel for the therapeutic intervention of psoriasis: formulation development, factorial design based-optimization,in vitroandin vivoassessment.

This study aimed to develop and optimize karanjin-loaded ethosomal nanogel formulation and evaluate its efficacy in alleviating symptoms of psoriasis in an animal model induced by imiquimod. These karanjin-loaded ethosomal nanogel, were formulated to enhance drug penetration into the skin and its epidermal retention. Karanjin was taken to formulate ethosomes due to its potential ani-psoriatic activity. Ethosomes were formulated using the cold method using 32full factorial designs to optimize the formulation components. 9 batches were prepared using two independent variablesX1: concentration of ethanol andX2: concentration of phospholipid whereas vesicle size (Y1) and percentage entrapment efficiency (Y2) were selected as dependent variables. All the dependent variables were found to be statistically significant. The optimized ethosomal suspension (B3) exhibited a vesicle size of 334 ± 2.89 nm with an entrapment efficiency of 94.88 ± 1.24% and showed good stability. The morphology of vesicles appeared spherical with smooth surfaces through transmission electron microscopy analysis. X-ray diffraction analysis confirmed that the drug existed in an amorphous state within the ethosomal formulation. The optimized ethosome was incorporated into carbopol 934 to develop nanogel for easy application on the skin. The nanogel underwent characterization for various parameters including spreadability, viscosity, pH, extrudability, and percentage drug content. The ethosomal formulation remarkably enhanced the skin permeation of karanjin and increased epidermal retention of the drug in psoriatic skin compared to marketed preparation and pure drug. A skin retention study showed that ethosomal nanogel formulation has 48.33% epidermal retention in 6 h.In vivo,the anti-psoriatic activity of karanjin ethosomal nanogel demonstrated significant improvement in psoriasis, indicated by a gradual decrease in skin thickness and scaling as reflected in the Psoriasis Severity Index grading. Therefore, the prepared ethosomal nanogel is a potential vehicle for improved topical delivery of karanjin for better treatment of psoriasis.

Dexamethasone-loaded ROS stimuli-responsive nanogels for topical ocular therapy of corneal neovascularization.

Dexamethasone (DEX) has been demonstrated to inhibit the inflammatory corneal neovascularization (CNV). However, the therapeutic efficacy of DEX is limited by the poor bioavailability of conventional eye drops and the increased risk of hormonal glaucoma and cataract associated with prolonged and frequent usage. To address these limitations, we have developed a novel DEX-loaded, reactive oxygen species (ROS)-responsive, controlled-release nanogel, termed DEX@INHANGs. This advanced nanogel system is constructed by the formation of supramolecular host-guest complexes by cyclodextrin (CD) and adamantane (ADA) as a cross-linking force. The introduction of the ROS-responsive material, thioketal (TK), ensures the controlled release of DEX in response to oxidative stress, a characteristic of CNV. Furthermore, the nanogel's prolonged retention on the corneal surface for over 8 h is achieved through covalent binding of the integrin ß1 fusion protein, which enhances its bioavailability. Cytotoxicity assays demonstrated that DEX@INHANGs was not notably toxic to human corneal epithelial cells (HCECs). Furthermore, DEX@INHANGs has been demonstrated to effectively inhibit angiogenesis in vitro. In a rabbit model with chemically burned eyes, the once-daily topical application of DEX@INHANGs was observed to effectively suppress CNV. These results collectively indicate that the nanomedicine formulation of DEX@INHANGs may offer a promising treatment option for CNV, offering significant advantages such as reduced dosing frequency and enhanced patient compliance.

Pongamia pinnata seed extract-mediated green synthesis of silver nanoparticle loaded nanogel for estimation of their antipsoriatic properties.

This research describes the eco-friendly green synthesis of silver nanoparticles employing Pongamia pinnata seed extracts loaded with nanogel formulations (AgNPs CUD NG) to improve the retention, accumulation, and the penetration of AgNPs into the epidermal layer of psoriasis. AgNPs were synthesized using the Box-Behnken design. Optimized AgNPs and AgNPs CUD NG were physico-chemically evaluated using UV-vis spectroscopy, SEM, FT-IR, PXRD, viscosity, spreadability, and retention studies. It was also functionally assessed using an imiquimod-induced rat model. The entrapment efficiency of AgNPs revealed ~ 79.35%. Physico-chemical parameters announced the formation of AgNPs via surface plasmon resonance and interaction between O-H, C = O, and amide I carbonyl group of protein extract and AgNO3. Optimized AgNPs showed spherical NPs ~ 116 nm with better physical stability and suitability for transdermal applications. AgNPs CUD NG revealed non-Newtonian, higher spreadability, and better extrudability, indicating its suitability for a transdermal route. AgNPs CUD NG enhanced the retention of AgNPs on the psoriatic skin compared to normal skin. Optimized formulations exhibit no irritation by the end of 72 h, indicating formulation safety. AgNPs CUD NG at a dose of 1 FTU showed significant recovery from psoriasis with a PASI score of ~ 0.8 compared to NG base and marketed formulations. Results indicated that seed extract-assisted AgNPs in association with CUD-based NG formulations could be a promising nanocarrier for psoriasis and other skin disorders.

Facile synthesis of elastin nanogels encapsulated decursin for castrated resistance prostate cancer therapy.

Nanogels offer hope for precise drug delivery, while addressing drug delivery hurdles is vital for effective prostate cancer (PCa) management. We developed an injectable elastin nanogels (ENG) for efficient drug delivery system to overcome castration-resistant prostate cancer (CRPC) by delivering Decursin, a small molecule inhibitor that blocks Wnt/ßcatenin pathways for PCa. The ENG exhibited favourable characteristics such as biocompatibility, flexibility, and low toxicity. In this study, size, shape, surface charge, chemical composition, thermal stability, and other properties of ENG were used to confirm the successful synthesis and incorporation of Decursin (DEC) into elastin nanogels (ENG) for prostate cancer therapy. In vitro studies demonstrated sustained release of DEC from the ENG over 120 h, with a pH-dependent release pattern. DU145 cell line induces moderate cytotoxicity of DEC-ENG indicates that nanomedicine has an impact on cell viability and helps strike a balance between therapeutics efficacy and safety while the EPR effect enables targeted drug delivery to prostate tumor sites compared to free DEC. Morphological analysis further supported the effectiveness of DEC-ENG in inducing cell death. Overall, these findings highlight the promising role of ENG-encapsulated decursin as a targeted drug delivery system for CRPC.

A dual-prodrug nanogel combining Vorinostat and Pyropheophorbide a for a high efficient photochemotherapy.

The challenges posed by intractable relapse and metastasis in cancer treatment have led to the development of various forms of photodynamic therapy (PDT). However, traditional drug delivery systems, such as virus vectors, liposomes, and polymers, often suffer from issues like desynchronized drug release, carrier instability, and drug leakage during circulation. To address these problems, we have developed a dual-prodrug nanogel (PVBN) consisting of Pyro (Pyropheophorbide a) and SAHA (Vorinostat) bound to BSA (Bovine Serum Albumin), which facilitates synchronous and spontaneous drug release in situ within the lysosome. Detailed results indicate that PVBN-treated tumor cells exhibit elevated levels of ROS and Acetyl-H3, leading to necrosis, apoptosis, and cell cycle arrest, with PDT playing a dominant role in the synergistic therapeutic effect. Furthermore, the anti-tumor efficacy of PVBN was validated in melanoma-bearing mice, where it significantly inhibited tumor growth and pulmonary metastasis. Overall, our dual-prodrug nanogel, formed by the binding of SAHA and Pyro to BSA and releasing drugs within the lysosome, represents a novel and promising strategy for enhancing the clinical efficacy of photochemotherapy.

Supramolecularly-Cross-Linked Nanogel Assemblies for On-Demand, Ultrasound-Triggered Chemotherapy.

Stimulating the release of small nanoparticles (NPs) from a larger NP via the application of an exogenous stimulus offers the potential to address the different size requirements for circulation versus penetration that hinder chemotherapeutic drug delivery. Herein, we report a size-switching nanoassembly-based drug delivery system comprised of ultrasmall starch nanoparticles (SNPs, ∼20-50 nm major size fraction) encapsulated in a poly(oligo(ethylene glycol) methyl ether methacrylate) nanogel (POEGMA, ∼150 nm major size fraction) cross-linked via supramolecular PEG/α-cyclodextrin (α-CD) interactions. Upon heating the nanogel using a non-invasive, high-intensity focused ultrasound (HIFU) trigger, the thermoresponsive POEGMA-CD nanoassemblies are locally de-cross-linked, inducing in situ release of the highly penetrative drug-loaded SNPs. HIFU triggering increased the release of nanoassembly-loaded DOX from 17 to 37% after 3 h, a result correlated with significantly more effective tumor killing relative to nanoassemblies in the absence of HIFU or drug alone. Furthermore, 1.5× more total fluorescence was observed inside a tumor spheroid when nanoassemblies prepared with fluorophore-labeled SNPs were triggered with HIFU relative to the absence of HIFU. We anticipate this strategy holds promise for delivering tunable doses of chemotherapeutic drugs both at and within a tumor site using a non-invasive triggering approach.

Theranostic nanogels: multifunctional agents for simultaneous therapeutic delivery and diagnostic imaging.

In recent years, there has been a growing interest in multifunctional theranostic agents capable of delivering therapeutic payloads while facilitating simultaneous diagnostic imaging of diseased sites. This approach offers a comprehensive strategy particularly valuable in dynamically evolving diseases like cancer, where combining therapy and diagnostics provides crucial insights for treatment planning. Nanoscale platforms, specifically nanogels, have emerged as promising candidates due to their stability, tunability, and multifunctionality as carriers. As a well-studied subgroup of soft polymeric nanoparticles, nanogels exhibit inherent advantages due to their size and chemical compositions, allowing for passive and active targeting of diseased tissues. Moreover, nanogels loaded with therapeutic and diagnostic agents can be designed to respond to specific stimuli at the disease site, enhancing their efficacy and specificity. This capability enables fine-tuning of theranostic platforms, garnering significant clinical interest as they can be tailored for personalized treatments. The ability to monitor tumor progression in response to treatment facilitates the adaptation of therapies according to individual patient responses, highlighting the importance of designing theranostic platforms to guide clinicians in making informed treatment decisions. Consequently, the integration of therapy and diagnostics using theranostic platforms continues to advance, offering intelligent solutions to address the challenges of complex diseases such as cancer. In this context, nanogels capable of delivering therapeutic payloads and simultaneously armed with diagnostic modalities have emerged as an attractive theranostic platform. This review focuses on advances made toward the fabrication and utilization of theranostic nanogels by highlighting examples from recent literature where their performances through a combination of therapeutic agents and imaging methods have been evaluated.

Nanoscopic gel particle for intra-articular injection formulation.

Hyaluronic acid (HA) based nanogels showed effective intracellular delivery efficacy for anti-cancer and anti-inflammatory drugs, characterized by their ability targeting relevant cell receptors. In the present study, we demonstrate the ability of hyaluronic acid-polyethyleneimine (HA-PEI) nanogels as a promising dual-functional interfacial active for intra-articular injection to intervene arthritis. Nanomechanical measurements on both model substrates and human cartilage samples confirm that the HA-PEI nanogels can significantly improve interfacial lubrication, in comparison to HA molecules, or silica-based nanoparticles. We show that the Coefficient of Friction significantly decreases with a decreasing nanogel size. The exceptional lubricating performance, coupled with the proven drug delivery capability, evidences the great potential of nanoscopic hydrogels for early-stage arthritis treatment. The flexibility in choosing the chemical nature, molecular architecture, and structural characteristics of nanogels makes it possible to modulate both drug delivery kinetics and interfacial lubrication, thus representing an innovative approach to treat degenerative joint diseases.

Tumor-specific enhanced NIR-II photoacoustic imaging via photothermal and low-pH coactivated AuNR@PNIPAM-VAA nanogel.

BACKGROUND: Properly designed second near-infrared (NIR-II) nanoplatform that is responsive tumor microenvironment can intelligently distinguish between normal and cancerous tissues to achieve better targeting efficiency. Conventional photoacoustic nanoprobes are always "on", and tumor microenvironment-responsive nanoprobe can minimize the influence of endogenous chromophore background signals. Therefore, the development of nanoprobe that can respond to internal tumor microenvironment and external stimulus shows great application potential for the photoacoustic diagnosis of tumor. RESULTS: In this work, a low-pH-triggered thermal-responsive volume phase transition nanogel gold nanorod@poly(n-isopropylacrylamide)-vinyl acetic acid (AuNR@PNIPAM-VAA) was constructed for photoacoustic detection of tumor. Via an external near-infrared photothermal switch, the absorption of AuNR@PNIPAM-VAA nanogel in the tumor microenvironment can be dynamically regulated, so that AuNR@PNIPAM-VAA nanogel produces switchable photoacoustic signals in the NIR-II window for tumor-specific enhanced photoacoustic imaging. In vitro results show that at pH 5.8, the absorption and photoacoustic signal amplitude of AuNR@PNIPAM-VAA nanogel in NIR-II increases up obviously after photothermal modulating, while they remain slightly change at pH 7.4. Quantitative calculation presents that photoacoustic signal amplitude of AuNR@PNIPAM-VAA nanogel at 1064 nm has ~ 1.6 folds enhancement as temperature increases from 37.5 °C to 45 °C in simulative tumor microenvironment. In vivo results show that the prepared AuNR@PNIPAM-VAA nanogel can achieve enhanced NIR-II photoacoustic imaging for selective tumor detection through dynamically responding to thermal field, which can be precisely controlled by external light. CONCLUSIONS: This work will offer a viable strategy for the tumor-specific photoacoustic imaging using NIR light to regulate the thermal field and target the low pH tumor microenvironment, which is expected to realize accurate and dynamic monitoring of tumor diagnosis and treatment.

Nanogel-based nitric oxide-driven nanomotor for deep tissue penetration and enhanced tumor therapy.

Antitumor agents often lack effective penetration and accumulation to achieve high therapeutic efficacy in treating solid tumors. Nanomotor-based nanomaterials offer a potential solution to address this obstacle. Among them, nitric oxide (NO) based nanomotors have garnered attention for their potential applications in nanomedicine. However, there widespread clinical adoption has been hindered by their complex preparation processes. To address this limitation, we have developed a NO-driven nanomotor utilizing a convenient and scalable nanogel preparation procedure. These nanomotors, loaded with the fluorescent probe / sonosensitizer chlorin e6 (Ce6), were specifically engineered for sonodynamic therapy. Through comprehensive in vitro investigations using both 2D and 3D cell models, as well as in vivo analysis of Ce6 fluorescent signal distribution in solid tumor models, we observed that the self-propulsion of these nanomotors significantly enhances cellular uptake and tumor penetration, particularly in solid tumors. This phenomenon enables efficient access to challenging tumor regions and, in some cases, results in complete tumor coverage. Notably, our nanomotors have demonstrated long-term in vivo biosafety. This study presents an effective approach to enhancing drug penetration and improving therapeutic efficacy in tumor treatment, with potential clinical relevance for future applications.

An antibacterial, multifunctional nanogel for efficient treatment of neutrophilic asthma.

Asthma is a chronic and heterogeneous disease affecting the lungs and respiratory tract. In particular, the neutrophil subtype of asthma was described as persistent, more severe, and corticosteroid-resistant. Growing evidence suggested that nontypeable Haemophilus influenzae (NTHi) infection contributes to the development of neutrophilic asthma, exacerbating clinical symptoms and increasing the associated medical burden. In this work, arginine-grafted chitosan (CS-Arg) was ionically cross-linked with tris(2-carboxyethyl) phosphine (TCEP), and a highly-efficient antimicrobial agent, poly-ε-L-Lysine (ε-PLL), was incorporated to prepare ε-PLL/CS-Arg/TCEP (ECAT) composite nanogels. The results showed that ECAT nanogels exhibited highly effective inhibition against the proliferation of NTHi, Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). In addition, ECAT nanogels could effectively inhibit the formation of mucins aggregates in vitro, suggesting that the nanogel might have the potential to destroy mucin in respiratory disease. Furthermore, in the ovalbumin (OVA)/NTHi-induced Balb/c mice model of neutrophilic asthma, the number of neutrophils in the alveolar lavage fluid and the percentage of inflammatory cells in the blood were effectively reduced by exposure to tower nebulized administration of ECAT nanogels, and reversing airway hyperresponsiveness (AHR) and reducing inflammation in neutrophilic asthma mice. In conclusion, the construction of ECAT nanogels was a feasible anti-infective and anti-inflammatory therapeutic strategy, which demonstrated strong potential in the clinical treatment of neutrophilic asthma.

The preparation and dual-mode detection of ascorbic acid based on poly(N-isopropylacrylamide) nanogel with oxidase-like activity.

Nanozymes have recently become a research hotspot because of the advantages of good stability, excellent catalytic performance and easy storage in comparison to natural enzymes. Nanozymes with oxidase-like activity get special attention because they needn't the participation of hydrogen peroxide. In this paper, poly(N-isopropylacrylamide) nanogel with oxidase-like activity was synthesized for the first time. The catalytic mechanism was explored by EPR and UV spectroscopy after adding specific trapping agents of ROS, and the results showed that PNIPAM NG can catalyze O2 to 1O2. In the presence of PNIPAM NG, o-phenylenediamine (OPD) and ascorbic acid (AA) can be oxidized to 2,3-diaminophenazine (oxOPD) and dehydroascorbic acid (DHA), and DHA can further react with OPD to produce a fluorescence substance. The colorimetric and fluorescence detection platforms for AA were constructed based on the above principles. Both platforms have satisfactory results in real samples. The fluorescence platform has better sensitivity and selectivity than the colorimetric platform.

Design and applications of polymer-like peptides in biomedical nanogels.

INTRODUCTION: Polymer nanogels are among the most promising nanoplatforms for use in biomedical applications. The substantial interest for these drug carriers is to enhance the transportation of bioactive substances, reduce the side effects, and achieve optimal action on the curative sites by targeting delivery and triggering the release of the drugs in a controlled and continuous mode. AREA COVERED: The review discusses the opportunities, applications, and challenges of synthetic polypeptide nanogels in biomedicine, with an emphasis on the recent progress in cancer therapy. It is evidenced by the development of polypeptide nanogels for better controlled drug delivery and release, in complex in vivo microenvironments in biomedical applications. EXPERT OPINION: Polypeptide nanogels can be developed by choosing the amino acids from the peptide structure that are suitable for the type of application. Using a stimulus - sensitive peptide nanogel, it is possible to obtain the appropriate transport and release of the drug, as well as to achieve desirable therapeutic effects, including safety, specificity, and efficiency. The final system represents an innovative way for local and sustained drug delivery at a specific site of the body.

Intestinal Targeted Nanogel with Broad-Spectrum Autonomous ROS Scavenging Performance for Enhancing the Bioactivity of trans-Resveratrol.

Introduction: To improve the bioavailability of trans-resveratrol (trans-Res), it is commonly co-delivered with antioxidant bioactives using a complex synthetic intestinal targeted carrier, however, which makes practical application challenging. Methods: A nanogel (Ngel), as broad-spectrum autonomous ROS scavenger, was prepared using selenized thiolated sodium alginate (TSA-Se) and crosslinked with calcium lactate (CL) for loading trans-Res to obtain Ngel@Res, which maintained spherical morphology in the upper digestive tract but broke down in the lower digestive tract, resulting in trans-Res release. Results: Under protection of Ngel, trans-Res showed enhanced stability and broad-spectrum ROS scavenging activity. The synergistic mucoadhesion of Ngel prolonged the retention time of trans-Res in the intestine. Ngel and Ngel@Res increased the lifespan of Caenorhabditis elegans to 26.00 ± 2.17 and 26.00 ± 4.27 days by enhancing the activity of antioxidases, upregulating the expression of daf-16, sod-5 and skn-1, while downregulating the expression of daf-2 and age-1. Conclusion: This readily available, intestinal targeted selenized alginate-based nanogel effectively improves the bioactivity of trans-Res.

Hybrid Nanogel Drug Delivery Systems: Transforming the Tumor Microenvironment through Tumor Tissue Editing.

The future of drug delivery offers immense potential for the creation of nanoplatforms based on nanogels. Nanogels present a significant possibility for pharmaceutical advancements because of their excellent stability and effective drug-loading capability for both hydrophobic and hydrophilic agents. As multifunctional systems, composite nanogels demonstrate the capacity to carry genes, drugs, and diagnostic agents while offering a perfect platform for theranostic multimodal applications. Nanogels can achieve diverse responsiveness and enable the stimuli-responsive release of chemo-/immunotherapy drugs and thus reprogramming cells within the TME in order to inhibit tumor proliferation, progression, and metastasis. In order to achieve active targeting and boost drug accumulation at target sites, particular ligands can be added to nanogels to improve the therapeutic outcomes and enhance the precision of cancer therapy. Modern "immune-specific" nanogels also have extra sophisticated tumor tissue-editing properties. Consequently, the introduction of a multifunctional nanogel-based drug delivery system improves the targeted distribution of immunotherapy drugs and combinational therapeutic treatments, thereby increasing the effectiveness of tumor therapy.

Lipid-based microemulsion gel for the topical delivery of methotrexate: an optimized, rheologically acceptable formulation with conducive dermatokinetics.

In the present study, we have formulated a methotrexate (MTX)-loaded microemulsion topical gel employing quality-by-design optimization. The optimized lipid-based microemulsion was incorporated into a 2% carbopol gel. The prepared formulation was characterized for micromeritics, surface charge, surface morphology, conductivity studies, rheology studies, texture analysis/spreadability, drug entrapment, and drug loading studies. The formulation was further evaluated for drug release and release kinetics, cytotoxicity assays, drug permeation and drug retention studies, and dermatokinetics. The developed nanosystem was not only rheologically acceptable but also offered substantial drug entrapment and loading. From drug release studies, it was observed that the nanogel showed higher drug release at pH 5.0 compared to plain MTX, plain gel, and plain microemulsion. The developed system with improved dermatokinetics, nanometric size, higher drug loading, and enhanced efficacy towards A314 squamous epithelial cells offers a huge promise in the topical delivery of methotrexate.

Clot-Targeted Nanogels for Dual-Delivery of AntithrombinIII and Tissue Plasminogen Activator to Mitigate Disseminated Intravascular Coagulation Complications.

Disseminated intravascular coagulation (DIC) is a pathologic state that follows systemic injury and other diseases. Often a complication of sepsis or trauma, DIC causes coagulopathy associated with paradoxical thrombosis and hemorrhage. DIC upregulates the thrombotic pathways while simultaneously downregulating the fibrinolytic pathways that cause excessive fibrin deposition, microcirculatory thrombosis, multiorgan dysfunction, and consumptive coagulopathy with excessive bleeding. Given these opposing disease phenotypes, DIC management is challenging and includes treating the underlying disease and managing the coagulopathy. Currently, no therapies are approved for DIC. We have developed clot-targeted therapeutics that inhibit clot polymerization and activate clot fibrinolysis to manage DIC. We hypothesize that delivering both an anticoagulant and a fibrinolytic agent directly to clots will inhibit active clot polymerization while also breaking up pre-existing clots; therefore, reversing consumptive coagulopathy and restoring hemostatic balance. To test this hypothesis, we single- and dual-loaded fibrin-specific nanogels (FSNs) with antithrombinIII (ATIII) and/or tissue plasminogen activator (tPA) and evaluated their clot preventing and clot lysing abilities in vitro and in a rodent model of DIC. In vivo, single-loaded ATIII-FSNs decreased fibrin deposits in DIC organs and reduced blood loss when DIC rodents were injured. We also observed that the addition of tPA in dual-loaded ATIII-tPA-FSNs intensified the antithrombotic and fibrinolytic mechanisms, which proved advantageous for clot lysis and restoring platelet counts. However, the addition of tPA may have hindered wound healing capabilities when an injury was introduced. Our data supports the benefits of delivering both anticoagulants and fibrinolytic agents directly to clots to reduce the fibrin load and restore hemostatic balance in DIC.

Supramolecular DNA nanogels through host-guest interaction for targeted drug delivery.

DNA hydrogels have been demonstrated with the advantages of good stability, easy modification, and extraordinary biocompatibility, which enables their great application prospects in biosensing, tissue engineering, and biomedicine. Based on the host-guest recognition properties of cucurbit[8]uril (CB[8]), we proposed a general method for constructing functional supramolecular DNA nanogels. Guest molecules have been conjugated into the DNA building units, which could be further crosslinked with CB[8] to construct supramolecular DNA nanogels. At the same time, the aptamer has also been modified into the hydrogel network to achieve cell targeting. These supramolecular DNA nanogels have been demonstrated with a controllable size and multiple stimuli responses, in addition to the excellent biocompatibility, stability and good targeting drug transport ability. Such a host-guest based strategy will provide a molecular library as a "toolbox" for the functionalization of DNA nanogels.

Polyelectrolyte complexes of chitosan and hyaluronic acid or carboxymethylpullulan and their aminoguaiacol derivatives with biological activities as potential drug delivery systems.

Polyelectrolyte complexes (PECs) were elaborated from chitosan as cationic polymer and carboxy-methylpullulan (CMP), hyaluronic acid (HA) and their derivatives grafted with aminoguaiacol (G) with different degrees of substitution (DSGA) with the aim of obtaining nanogels for drug delivery. For each couple of polysaccharides, the charge ratios giving the smaller size with the lower PDI were selected to produce PECs. CMP_CHIT and CMP-G_CHIT PECs had smaller sizes (220-280 nm) than HA_CHIT and HA-G_CHIT PECs (280-390 nm). PECs were stable at 4 °C during 28 days at pH 5. In phosphate buffer saline (PBS) at pH 7.4, at 4 °C, a better stability of PECs based on CMP-G derivatives was observed. The hydrophobic associations between aminoguaiacol groups (highlighted by measurements of pyrene fluorescence) led to a better PECs' stabilization in PBS. The PECs' antioxidant and antibacterial activities were demonstrated and related to the DSGA. Diclofenac and curcumin were used as drug models: their loading reached 260 and 53 µg/mg PEC, respectively. The release of diclofenac in PBS at 37 °C followed a quasi-Fickian diffusion mechanism with release constant between 0.88 and 1.04 h-1. The curcumin release followed a slow linear increase in PBS/EtOH (60/40 V/V) with an effect of DSGA.