Hyaluronic Acid Nanoparticles Research Articles

Bile Acid-Targeted Hyaluronic Acid Nanoparticles for Enhanced Oral Absorption of Deferoxamine.

Patients with β-thalassemia and sickle cell disease often rely on blood transfusions which can lead to hemochromatosis and chronic oxidative stress in cells and tissues. Deferoxamine (DFO) is clinically approved to treat hemochromatosis but is suboptimal to patients due to its poor pharmacokinetics which requires long-term infusion regimens. Although the oral route is preferable, DFO has limited oral bioavailability. Studies have shown that hyaluronic acid (HA) and bile acid (BA) can enhance the oral absorption of poorly absorbed drugs. To improve upon the oral delivery of DFO, we report on the synthesis and characterization of HA (MW 15 kD) conjugated to two types of BA, deoxycholic acid (DOCA) and taurocholic acid (TCA), and DFO. The resulting seven polymeric conjugates all formed self-assembled nanoparticles. The degree of BA and DFO conjugation to the HA polymer was confirmed at each step through nuclear magnetic resonance, Fourier transform infrared spectroscopy, and UV-Vis spectroscopy. The best formulations for further in vitro testing were determined based on physicochemical characterizations and included HA-DFO, TCA9-HA-DFO, and DOCA9-HA-DFO. Results from in vitro assays revealed that TCA9-HA-DFO enhanced the permeation of DFO the most and was also less cytotoxic to cells compared to the free drug DFO. In addition, ferritin reduction studies indicated that the conjugation of DFO to TCA9-HA did not compromise its chelation efficiency at equivalent free DFO concentrations. This research provides supportive data for the idea that TCA conjugated to HA may enhance the oral absorption of DFO, improve its cytocompatibility, and maintain its iron chelation efficiency.

Ozone-delivering nanocomposite hydrogel for acute Staphylococcus aureus osteomyelitis treatment via neutrophil regulation

Treatment of acute osteomyelitis (OM) poses a significant challenge because of the difficulty in removing bacteria and the aberrant innate immune responses at the infection site. Topical ozone therapy has demonstrated favorable outcomes in treating OM, but its high reactivity and short half-life severely limit its clinical application. To address this issue, a suitable ozone delivery system that can promote the therapeutic effects of topical ozone therapy in OM is needed. In this study, we developed ozone-loaded fluorinated hyaluronic acid nanoparticles embedded in a thermoresponsive hydroxypropyl chitin (HPCH) hydrogel (Ozone@Gel) for treating acute OM. The ozone-delivering nanocomposite hydrogel could release ozone continuously and stably at the injection site for over 15 days. The ozone loaded in this ozone-delivering nanocomposite hydrogel was about 100 mg/L. In vitro antibacterial experiments demonstrated that the Ozone@Gel effectively attenuated Staphylococcus aureus proliferation and reduced biofilm formation by inhibiting the expression of bacterial polysaccharide-related genes (agr, atlE, aap, icaA, and icaBC). Further, animal experiments showed that Ozone@Gel effectively reduced bacterial load at the site of infection by enhancing neutrophil antimicrobial activity, thereby alleviating the progression of acute OM. Thus, this novel therapeutic strategy based on topical ozone therapy is a promising and feasible intervention for treating acute S. aureus OM.

Combination of Molecule-Targeted Therapy and Photodynamic Therapy Using Nanoformulated Verteporfin for Effective Uveal Melanoma Treatment.

Uveal melanoma (UM) is the most common primary ocular malignancy in adults and has high mortality. Recurrence, metastasis, and therapeutic resistance are frequently observed in UM, but no beneficial systemic therapy is available, presenting an urgent need for developing effective therapeutic drugs. Verteporfin (VP) is a photosensitizer and a Yes-Associated Protein (YAP) inhibitor that has been used in clinical practice. However, VP's lack of tumor targetability, poor biocompatibility, and relatively low treatment efficacy hamper its application in UM management. Herein, we developed a biocompatible CD44-targeting hyaluronic acid nanoparticle (HANP) carrying VP (HANP/VP) to improve UM treatment efficacy. We found that HANP/VP showed a stronger inhibitory effect on cell proliferation than that of free VP in UM cells. Systemic delivery of HANP/VP led to targeted accumulation in the UM-tumor-bearing mouse model. Notably, HANP/VP mediated photodynamic therapy (PDT) significantly inhibited UM tumor growth after laser irradiation compared with no treatment or free VP treatment. Consistently, in HANP/VP treated tumors after laser irradiation, the tumor proliferation and YAP expression level were decreased, while the apoptotic tumor cell and CD8+ immune cell levels were elevated, contributing to effective tumor growth inhibition. Overall, the results of this preclinical study showed that HANP/VP is an effective nanomedicine for tumor treatment through PDT and inhibition of YAP in the UM tumor mouse model. Combining phototherapy and molecular-targeted therapy offers a promising approach for aggressive UM management.

Abstract 2858: Phenotypic screens identify genetic regulators of nanoparticle delivery to pediatric brain tumors

Abstract Pediatric central nervous system tumors are the leading cause of cancer death in children. Diffuse midline glioma (DMG) is a universally fatal pediatric brain tumor and despite many clinical trials over the past decades, less than 10% of patients are long-term survivors. The clinical standard of care is radiotherapy, however it only provides limited symptom relief. There is a clear need to develop creative treatment strategies for patients with DMG. Nanomedicine has the potential to address this challenge, allowing the encapsulation of difficult to deliver therapeutic cargoes, and selectively targeting them to tumors while crossing innate biological barriers. However, a deep understanding of disease-specific nano-bio interactions is crucial to leverage the full potential of these therapies. To functionally validate the role of candidate biomarkers in nanoparticle delivery to DMGs, we performed pooled genetic perturbation screens using a flow based phenotypic output. We developed a lentiviral all-in-one CRISPR/Cas9 knock-out library paired with fluorescence-activated cell sorting to probe the functional impact of 700 genes on the delivery of nanoparticles to DMG. Layer-by-layer electrostatic assembly was used to generate liposomal nanoparticles with a polymer surface coating of hyaluronic acid. Two patient-derived neurosphere models of DMG were transduced with the pooled all-in-one CRISPR/Cas9 library. Following antibiotic selection, cells were incubated with hyaluronic acid or polymeric nanoparticles for 4 or 24 hours and sorted into populations based on nanoparticle affinity. A dynamic cell-sorting strategy was optimized to separate cells infected with inert DNA barcodes based on their degree of nanoparticle-association. DNA was isolated from sorted cells and subjected to next generation sequencing. The enrichment of each single guide was determined relative to matched controls. We found strong agreement between biologic replicates, and determined which genes, when knocked down, shifted nanoparticle uptake into DMG cells. Our pooled phenotypic screen revealed strong biologic regulators of nanoparticle uptake. These can be categorized as formulation dependent and independent, as well as time-dependent. We identified several negative regulators of nanoparticle uptake including members of the mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) pathways. The top target genes are currently being validated in DMG and human neural stem cell models. In ongoing work, we are leveraging genetic and chemical inhibition to sensitize DMG cells to nanoparticle therapeutics. We plan to leverage our screening technique to develop novel combination therapy approaches that could be implemented across multiple administration routes (intravenous, intraventricular, or intratumoral) to enhance the use of nanomedicine for DMG and other pediatric brain tumors. Citation Format: Marissa Coppola, Julianna Kenny-Serrano, John G. Doench, Paula Hammond, Pratiti Bandopadhayay, Jessica W. Tsai, Joelle Straehla. Phenotypic screens identify genetic regulators of nanoparticle delivery to pediatric brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2858.

Fabrication of hyaluronic acid‐based nanoparticles and studies on their radical scavenging activity

AbstractThe purpose of this paper is to study the stability, radical scavenging activities, and bio‐safety of cysteine‐conjugated hyaluronic acid nanoparticles (Cys‐conj‐HA NPs). Additionally, the feasibility of utilizing these NPs as drug delivery systems is discussed. The structures of synthesized Cys‐conj‐HA polymers were analyzed using 1H nuclear magnetic spectrum (1H NMR) and Fourier transform infrared spectroscopy (FTIR) spectra. The stability, radical scavenging activity, and bio‐safety of fabricated Cys‐conj‐HA NPs were investigated. Transmission electron microscopy (TEM) photograph illustrated that Cys‐conj‐HA NPs possessed spherical shapes with an average diameter of approximately 230 nm. Furthermore, these NPs exhibited high stability at temperatures of 4, 25, and 37°C. Notably, Cys‐conj‐HA NPs demonstrated significant free radical scavenging capabilities. The high cell viability observed indicated the absence of cytotoxicity from Cys‐conj‐HA NPs. Additionally, bio‐safety studies revealed that these NPs did not induce acute toxicity in the blood and viscera of cargo‐free NPs treated mice. Elisa assays indicated that there was no significant difference in the concentrations of interferon‐γ (INF‐γ) and tumor necrosis factor‐α (TNF‐α) between Cys‐conj‐HA NPs and normal saline (NS) treated mice (ns, p > 0.05), suggesting the absence of an inflammatory reaction caused by these NPs. Consequently, it can be concluded that Cys‐conj‐HA NPs are sufficiently safe to be employed as a vehicle for delivering oxidizing drugs.

Electrostimulable polymeric films with hyaluronic acid and lipid nanoparticles for simultaneous topical delivery of macromolecules and lipophilic drugs.

This study focused on developing electrically stimulable hyaluronic acid (HA) films incorporating lipid nanoparticles (NPs) designed for the topical administration of lipophilic drugs and macromolecules. Based on beeswax and medium-chain triglycerides, NPs were successfully integrated into silk fibroin/chitosan films containing HA (NP-HA films) at a density of approximately 1011 NP/cm2, ensuring a uniform distribution. This integration resulted in a 40% increase in film roughness, a twofold decrease in Young's modulus, and enhanced film flexibility and bioadhesion work. The NP-HA films, featuring Ag/AgCl electrodes, demonstrated the capability to conduct a constant electrical current of 0.2mA/cm2 without inducing toxicity in keratinocytes and fibroblasts during a 15-min application. Moreover, the NPs facilitated the homogeneous distribution of lipophilic drugs within the film, effectively transporting them to the skin and uniformly distributing them in the stratum corneum upon film administration. The sustained release of HA from the films, following Higuchi kinetics, did not alter the macroscopic characteristics of the film. Although anodic iontophoresis did not noticeably affect the release of HA, it did enhance its penetration into the skin. This enhancement facilitated the permeation of HA with a molecular weight (MW) of up to 2 × 105 through intercellular and transcellular routes. Confocal Raman spectroscopy provided evidence of an approximate 100% increase in the presence of HA with a MW in the range of 1.5-1.8 × 106 in the viable epidermis of human skin after only 15min of iontophoresis applied to the films. Combining iontophoresis with NP-HA films exhibits substantial potential for noninvasive treatments focused on skin rejuvenation and wound healing.

PH-sensitive docetaxel-loaded chitosan/thiolated hyaluronic acid polymeric nanoparticles for colorectal cancer.

Aim: This study aimed to develop and evaluate pH-sensitive docetaxel-loaded thiolated hyaluronic acid (HA-SH) nanoparticles (NPs) for targeted treatment of colon cancer. Materials & methods: HA-SH, synthesized via oxidation and subsequent covalent linkage to cysteamine, served as the precursor for developing HA-SH NPs through polyelectrolyte complexation involving chitosan and thiol-bearing HA. Results & conclusion: HA-SH NPs displayed favorable characteristics, with small particle sizes (184-270nm), positive zeta potential (15.4-18.6mV) and high entrapment efficiency (91.66-95.02%). In vitro, NPs demonstrated potent mucoadhesion and enhanced cytotoxicity compared with free docetaxel. In vivo assessments confirmed safety and biocompatibility, suggesting HA-SH NPs as promising pH-sensitive drug carriers with enhanced antitumor activity for colorectal cancer treatments.

Ultrasound-powered hydrogen peroxide-responsive Janus micromotors for targeted thrombolysis and recurrence inhibition

Thrombosis seriously endangers human health with high incidence and mortality worldwide, and the clinical treatment is challenged by low bioavailability of thrombolytic agents, high bleeding risk and thrombosis relapse. Herein, ultrasound-powered Janus micromotors with stimuli-responsive multiple release capabilities are developed for efficient thrombolysis and inhibition of thrombosis recurrence. Resveratrol-loaded hyaluronic acid (HARes) nanoparticles (NPs) and urokinase plasminogen activator (uPA) were entrapped into H2O2-sensitive poly(1,4-cyclohexanedimethanol-co-oxalate) (POX) microparticles (MPs), followed by polydopamine capping and RGD grafting to obtain Janus rJPox@u-HARes MPs. After RGD-mediated delivery to the thrombus site, the peroxalate ester bonds of POX are oxidized by the elevated H2O2 to produce CO2, and the MP collapse accelerates the local release of uPA and HARes NPs. The resulting CO2 bubbles amplify the cavitation effect of ultrasound to promote thrombus penetration and site-specific uPA thrombolysis. The endothelial cell targeting and sustained resveratrol release from HARes NPs dramatically improve endothelial cell viability, nitric oxide production and migration. Compared with free drug administration, the uPA loading into MPs significantly extends the half-life (15 folds) and bioavailability (7 folds), while the resveratrol inoculation into NPs increases the bioavailability 29 times. On an acute lower limb thrombosis model, the thrombus accumulation of MPs is promoted by RGD-mediated interactions with the activated platelets and ultrasound-driven penetration into thrombi, leading to almost full removal of blood clots. The H2O2-scavenging capability of POX, sustained resveratrol release and efficient thrombolysis alleviate oxidative stresses, eliminate coagulation biomarkers and repair the damaged endothelial layer to effectively inhibit thrombosis relapse. It is demonstrated that rJPox@u-HARes/US treatment could not only achieve safe and site-specific thrombolytic therapy at the early stage but also restore vascular homeostasis to effectively prevent thrombosis recurrence.

Effective Strategies in Designing Chitosan-hyaluronic Acid Nanocarriers: From Synthesis to Drug Delivery Towards Chemotherapy.

The biomedical field faces an ongoing challenge in developing more effective anti-cancer medication due to the significant burden that cancer poses on human health. Extensive research has been conducted on the utilization of natural polysaccharides in nanomedicine owing to their properties of biocompatibility, biodegradability, non-immunogenicity, and non-toxicity. These characteristics make them a potent drug delivery system for cancer therapy. The chitosan hyaluronic acid nanoparticle (CSHANp) system, consisting of chitosan and hyaluronic acid nanoparticles, has exhibited considerable potential as a nanocarrier for various cancer drugs, rendering it one of the most auspicious systems presently accessible. The CSHANps demonstrate remarkable drug loading capacity, precise control over drug release, and exceptional selectivity towards cancer cells. These properties enhance the therapeutic effectiveness against cancerous cells. This article aims to provide a comprehensive analysis of CSHANp, focusing on its characteristics, production techniques, applications, and future prospects.

A copper-platinum nanoplatform for synergistic photothermal and chemodynamic tumor therapy via ROS outburst and GSH exhaustion.

A multifunctional nanoplatform is obtained by modifying copper hexacyanoferrate (Cu-HCF) nanozyme with hyaluronic acid (HA) and further loading platinum (Pt) nanoparticles. This Cu-HCF-HA@Pt platform shows peroxidase-like and glutathione oxidase-like dual-enzyme catalytic activities and photothermal properties, enabling synergistic chemodynamic and photothermal tumor therapy. HA binds to the CD44 receptor, which is highly expressed on the exterior surface of tumor cells, endowing the nanoplatform with tumor specificity. Cu-HCF-HA@Pt catalyzes the decomposition of H2O2 to produce abundant hydroxyl radicals within tumor cells, increasing intracellular oxidative stress levels and inducing tumor cell apoptosis. Meanwhile, Cu-HCF-HA@Pt catalyzes the conversion of intracellular reduced glutathione (GSH) to oxidized glutathione, resulting in GSH exhaustion. The conversion of CuII to CuI in Cu-HCF via a Fenton-like reaction can improve the peroxidase-like property of Cu-HCF-HA@Pt. After the probe is targeted to the tumor site, irradiation by an 808 nm near-infrared laser causes local heating and brings about photothermal tumor apoptosis when reaching 45 °C. The prepared Cu-HCF-HA@Pt combines nanozyme-catalyzed therapy with photothermal therapy to induce apoptosis in tumor cells.

An injectable gel based on photo-cross-linkable hyaluronic acid and mesoporous bioactive glass nanoparticles for periodontitis treatment

Guided bone regeneration (GBR) is an effective strategy to promote periodontal tissue repair. The current study aimed to develop an injectable gel for GBR, composed of photo-cross-linkable hyaluronic acid and mesoporous bioactive glass nanoparticles (MBGNs) loaded with antibacterial minocycline hydrochloride (MNCl). Hyaluronic acid modified with methacrylic anhydride (MHA) that could be cross-linked under UV irradiation was first synthesized. Dynamic rheological evaluation of MHA under UV was carried out to determine its in-situ gelling feasibility and stability. Morphological and mechanical characterization was performed to determine the optimal concentration of MHA gels. Sol-gel derived MBGNs loaded with MNCl were further incorporated into MHA gels to obtain the injectable drug-loaded MBGN-MNCl/MHA gels. In vitro antibacterial, anti-inflammatory and osteogenic effects of this gel were evaluated. It was shown that the MHA gel obtained from 3 % MHA under UV treatment of 30s exhibited a suitable porous structure with a compressive strength of 100 kPa. MBGNs with particle size of ∼120 nm and mesopores were confirmed by TEM and SEM. MBGNs had a loading capacity of ∼120 mg/g for MNCl, exhibiting a sustained release behavior. The MBGN-MNCl/MHA gel was shown to effectively inhibit the proliferation of Streptococcus mutans and the expression of pro-inflammatory factors IL-6 and TNF-α by macrophages. It could on the other hand significantly promote the expression of osteogenic-related genes ALP, Runx2, OPN, and osterix of MC3T3-E1 cells. In conclusion, the current design using photo-crosslinkable MHA gel embedded with MNCl loaded MBGNs can serve as a promising injectable formulation for GBR treatment of irregular periodontal defects.

Mesoporous silicon based nano-particles for photothermal and H2O2-elevation dually-augmented chemodynamic therapy

Chemodynamic therapy (CDT) has gained significant attention due to its high tumor selectivity and minimal damage to normal tissues. However, to achieve optimal therapeutic outcomes, it is crucial to enhance the generation rate and amount of hydroxyl radicals (·OH) as they have a short lifespan. In this study, we developed hyaluronic acid-coated supramolecular nanoparticles (NPs) using β-cyclodextrin-modified hyaluronic acid (HA-CD) and ferrocene-modified mesoporous silica nanoparticles (FMSN). L-ascorbyl palmitate (PA), a prooxidant, and photosensitizers IR825 were loaded into the NPs to create NPs@PA&IR825. Through active targeted cellular internalization, PA reacts with specific proteins, thereby increasing the production of hydrogen peroxide (H2O2). The elevated H2O2 levels facilitate the generation of more ·OH through the Fenton reaction, promoting apoptosis in cancer cells. Additionally, near-infrared (NIR) activation induces hyperthermia, further enhancing the levels of ·OH. Therefore, the combination of up-regulated H2O2 and hyperthermia properties in NPs@PA&IR825 is expected to enhance the effectiveness of CDT. The excellent therapeutic performance of NPs@PA&IR825 has been demonstrated both in vitro and in vivo. This innovative approach holds promise for improving CDT efficacy by synergistically enhancing H2O2 levels and leveraging hyperthermia-induced ·OH generation.

Virulence factors analysis and determination of the suitable chemical agent to inhibit Streptococcus mutans growth and biofilm formation

Streptococcus mutans is one of the most important causes of tooth decay and oral diseases, and it has received wide attention from researchers worldwide. The present work aimed to investigate, evaluation and comparisons effect of the antimicrobial and anti-biofilm property of some commercial compounds (chlorhexidine, hyaluronic acid, sodium fluoride and silver nanoparticles) against oral bacteria pathogens of S. mutans. In this work, S. mutans ATCC 25175 was used and its virulence factors were analyzed using Seed Viewer and The Comprehensive Antibiotic Resistance Database (CARD). The antibacterial susceptibility testing (AST) confirms effects of chlorhexidine mouthwash on S. mutans ATCC 25175 beggar than all components. The minimum inhibitory concentration (MIC) minimum bactericidal concentration (MBC) and Minimum biofilm inhibition concentration (MBIC) of the commercial compounds were determined. The statistical analysis was performed using One-Way ANOVA (Tukey test). The VITEK2system was used to confirm the biochemical features of S. mutans ATCC 25175 and susceptibility testing was done to compare the results with Seed Viewer and CARD analysis. The findings showed that The MICs, MBCs, and MBIC means of chlorhexidine against S. mutans ATCC 25175 was 0.0079, 0.0038, and 0.0039 μg/mL respectively, where its biological activity was significantly (P < 0.05) higher compared to other commercial compounds included in this study. The S. mutans strain used in this study showed sensitivity to all tested antibiotics and the Seed Viewer and CARD reported that it has several virulence factors such as adhesion genes (hsp33, Cpa, PrtF, PrtF2, MsmRL, Nra, SOF, LepAL, Spy0135, and RofA) and antibiotic-resistant genes (vanY, vanT, and mdeA). This study concluded that chlorhexidine was the best in inhibiting S. mutans growth as well as preventing biofilm formation, and the study recommends further investigation about antibiotic resistance genes and susceptibility profile.

Dual Targeted Nanoparticles for the Codelivery of Doxorubicin and siRNA Cocktails to Overcome Ovarian Cancer Stem Cells.

Most anticancer treatments only induce the death of ordinary cancer cells, while cancer stem cells (CSCs) in the quiescent phase of cell division are difficult to kill, which eventually leads to cancer drug resistance, metastasis, and relapse. Therefore, CSCs are also important in targeted cancer therapy. Herein, we developed dual-targeted and glutathione (GSH)-responsive novel nanoparticles (SSBPEI-DOX@siRNAs/iRGD-PEG-HA) to efficiently and specifically deliver both doxorubicin and small interfering RNA cocktails (siRNAs) (survivin siRNA, Bcl-2 siRNA and ABCG2 siRNA) to ovarian CSCs. They are fabricated via electrostatic assembly of anionic siRNAs and cationic disulfide bond crosslinking-branched polyethyleneimine-doxorubicin (SSBPEI-DOX) as a core. Interestingly, the SSBPEI-DOX could be degraded into low-cytotoxic polyethyleneimine (PEI). Because of the enrichment of glutathione reductase in the tumor microenvironment, the disulfide bond (-SS-) in SSBPEI-DOX can be specifically reduced to promote the controlled release of siRNA and doxorubicin (DOX) in the CSCs. siRNA cocktails could specifically silence three key genes in CSCs, which, in combination with the traditional chemotherapy drug DOX, induces apoptosis or necrosis of CSCs. iRGD peptides and "sheddable" hyaluronic acid (HA) wrapped around the core could mediate CSC targeting by binding with neuropilin-1 (NRP1) and CD44 to enhance delivery. In summary, the multifunctional delivery system SSBPEI-DOX@siRNAs/iRGD-PEG-HA nanoparticles displays excellent biocompatibility, accurate CSC-targeting ability, and powerful anti-CSC ability, which demonstrates its potential value in future treatments to overcome ovarian cancer metastasis and relapse. To support this work, as exhaustive search was conducted for the literature on nanoparticle drug delivery research conducted in the last 17 years (2007-2023) using PubMed, Web of Science, and Google Scholar.

A Microfluidic Approach for Synthesis of Silver Nanoparticles as a Potential Antimicrobial Agent in Alginate-Hyaluronic Acid-Based Wound Dressings.

The recognized antimicrobial activity of silver nanoparticles is a well-studied property, especially when designing and developing biomaterials with medical applications. As biological activity is closely related to the physicochemical characteristics of a material, aspects such as particle morphology and dimension should be considered. Microfluidic systems in continuous flow represent a promising method to control the size, shape, and size distribution of synthesized nanoparticles. Moreover, using microfluidics widens the synthesis options by creating and controlling parameters that are otherwise difficult to maintain in conventional batch procedures. This study used a microfluidic platform with a cross-shape design as an innovative method for synthesizing silver nanoparticles and varied the precursor concentration and the purging speed as experimental parameters. The compositional and microstructural characterization of the obtained samples was carried out by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and dynamic light scattering (DLS). Four formulations of alginate-based hydrogels with the addition of hyaluronic acid and silver nanoparticles were obtained to highlight the antimicrobial activity of silver nanoparticles and the efficiency of such a composite in wound treatment. The porous structure, swelling capacity, and biological properties were evaluated through physicochemical analysis (FT-IR and SEM) and through contact with prokaryotic and eukaryotic cells. The results of the physicochemical and biological investigations revealed desirable characteristics for performant wound dressings (i.e., biocompatibility, appropriate porous structure, swelling rate, and degradation rate, ability to inhibit biofilm formation, and cell growth stimulation capacity), and the obtained materials are thus recommended for treating chronic and infected wounds.

Sorafenib-Based Drug Delivery Systems: Applications and Perspectives.

As a Food and Drug Administration (FDA)-approved molecular-targeted chemotherapeutic drug, sorafenib (SF) can inhibit angiogenesis and tumor cell proliferation, leading to improved patient overall survival of hepatocellular carcinoma (HCC). In addition, SF is an oral multikinase inhibitor as a single-agent therapy in renal cell carcinoma. However, the poor aqueous solubility, low bioavailability, unfavorable pharmacokinetic properties and undesirable side effects (anorexia, gastrointestinal bleeding, and severe skin toxicity, etc.) seriously limit its clinical application. To overcome these drawbacks, the entrapment of SF into nanocarriers by nanoformulations is an effective strategy, which delivers SF in a target tumor with decreased adverse effects and improved treatment efficacy. In this review, significant advances and design strategies of SF nanodelivery systems from 2012 to 2023 are summarized. The review is organized by type of carriers including natural biomacromolecule (lipid, chitosan, cyclodextrin, etc.); synthetic polymer (poly(lactic-co-glycolic acid), polyethyleneimine, brush copolymer, etc.); mesoporous silica; gold nanoparticles; and others. Co-delivery of SF and other active agents (glypican-3, hyaluronic acid, apolipoprotein peptide, folate, and superparamagnetic iron oxide nanoparticles) for targeted SF nanosystems and synergistic drug combinations are also highlighted. All these studies showed promising results for targeted treatment of HCC and other cancers by SF-based nanomedicines. The outlook, challenges and future opportunities for the development of SF-based drug delivery are presented.

Manufacture of Bilayered Composite Hydrogels with Strong, Elastic, and Tough Properties for Osteochondral Repair Applications.

Layered composite hydrogels have been considered attractive materials for use in osteochondral repair and regeneration. These hydrogel materials should be mechanically strong, elastic, and tough besides fulfilling some basic requirements such as biocompatibility and biodegradability. A novel type of bilayered composite hydrogel with multi-network structures and well-defined injectability was thus developed for osteochondral tissue engineering using chitosan (CH), hyaluronic acid (HA), silk fibroin (SF), CH nanoparticles (NPs), and amino-functionalized mesoporous bioglass (ABG) NPs. CH was combined with HA and CH NPs to build the chondral phase of the bilayered hydrogel, and CH, SF, and ABG NPs were used together to construct the subchondral phase of the bilayer hydrogel. Rheological measurements showed that the optimally achieved gels assigned to the chondral and subchondral layers had their elastic moduli of around 6.5 and 9.9 kPa, respectively, with elastic modulus/viscous modulus ratios higher than 36, indicating that they behaved like strong gels. Compressive measurements further demonstrated that the bilayered hydrogel with an optimally formulated composition had strong, elastic, and tough characteristics. Cell culture revealed that the bilayered hydrogel had the capacity to support the in-growth of chondrocytes in the chondral phase and osteoblasts in the subchondral phase. Results suggest that the bilayered composite hydrogel can act as an injective biomaterial for osteochondral repair applications.

Therapeutic potential and protection enhancement of mesenchymal stem cell against cisplatin-induced nephrotoxicity using hyaluronic acid-chitosan nanoparticles as an adjuvant

A newly synthesized nanoplatform of hyaluronic acid and chitosan nanoparticles (HA/CNPs) was applied to improve the therapeutic efficacy and protection of bone marrow mesenchymal stem cells (BM-MSCs) against cisplatin (CDDP)-induced nephrotoxicity in rats. CDDP administration causes significant increases in levels of serum creatinine (SCr), urea, and KIM-1 coupled with significant albumin level falls, as indicative of acute renal dysfunction. Moreover, the level of the antioxidant enzyme (GSH) was significantly decreased, while the levels of lipid peroxidation (MDA) and inflammatory (IL-6) and apoptotic (caspase-3) markers were significantly increased, indicating a decline in the kidney's antioxidant defense and increased inflammation. In contrast, when rats were pre-treated with either MSCs or MSCs-HA/CNPs before receiving CDDP, the levels of SCr, urea, KIM-1, MDA, IL-6, and caspase-3 were significantly decreased with simultaneous significant rises in GSH and albumin, impelling a great improvement in the antioxidant and anti-inflammatory defenses of the kidney as well as its functions. Intriguingly, MSCs-HA/CNPs were more effective against caspase-3 than MSCs alone, revealing the high anti-apoptotic capability of HA/CNPs. This finding suggests that HA/CNPs could effectively protect MSCs from oxidative stress and apoptosis and thus increase their stability and longevity.

PH-responsive Sulfated Hyaluronic Acid Nanoparticles Targeting Tumor Cells and CAFs for the Treatment of Breast Cancer.

Tumor metastasis is a main cause of death in patients with breast cancer. The cross-talk between cancer-associated fibroblasts (CAFs) and tumor cells plays an important role in promoting tumor invasion and metastasis. It is important to develop a novel delivery system to inhibit tumor development by simultaneously targeting both CAFs and tumor cells. The main objective of this research was to prepare nanoparticles to inhibit tumor proliferation and migration by blocking the cross-talk of tumor-CAFs. Additionally, a novel "MCF- 7+NIH/3T3" mixed cell model was established to mimic the tumor microenvironment (TME). In this study, the pH-responsive nanoparticles (MIF/DOX-sul-HA NPs) based on sulfated hyaluronic acid (sul-HA) polymers were prepared for co-delivery of doxorubicin (DOX) and mifepristone (MIF). The effects of anti-proliferation and anti-metastasis of MIF/DOX-sul-HA NPs were investigated both in vitro and in vivo. The results showed that MIF/DOX-sul-HA NPs were nearly spherical in shape with narrow particle size distribution and pH-responsive drug release, and could be taken up by both MCF-7 and NIH/3T3 cells. Compared with MCF-7 cells alone, the anti-tumor effect of single DOX was weak in the "MCF-7+NIH/3T3" mixed cell model. MIF/DOX-sul-HA NPs exhibited strong effects of anti-proliferation and anti-metastasis than the free single drug. The sul-HA nanoparticles for co-delivery of DOX and MIF could be a promising combined therapy strategy for the treatment of breast cancer.

Abstract 811: Development of a NOX-ROS nanoinhibitor for enhancing response to radiotherapy in lung cancer cells while mitigation radiation-induced inflammation and injury in the normal lung tissue

Abstract Objective: One of the unmet clinical challenges is that many tumors remain insensitive to radiotherapy owing to intrinsic resistance or acquired resistance that leads to tumor progression or recurrence. Moreover, radiation-induced acute injury and chronic inflammation in normal tissues limit the radiation dose that can be applied to the tumor, and tolerable doses are often linked to suboptimal tumor control—even accepting side effects that lead to decreased quality of life. Our goal of the study is to develop a nanoformulated radiosensitizer that inhibits NOX-ROS signal pathway to enhance therapeutic response in tumor cells while reducing radiotoxicity in normal tissues. Methods: We developed a biomaterial-based nanoparticle radiosensitizer that acts upon abnormal redox status and altered metabolism in tumor cells to trigger a cascade of changes in signal pathways to enhance response to radiotherapy. This CD44-targeted radiosensitizer consists of a biodegradable and bioactive hyaluronic acid nanoparticle (HANP) encapsulated with a dual NOX1/4 inhibitor, GKT831 (HANP/GKT831). Orthotopic and subcutaneous NSCLC tumor mouse models using a WRJ388 cell line that was isolated from a metastatic lung adenocarcinoma in a lymph node of a KrasG12D/Lkb1null GEMM mouse were established for evaluation of the effect on the inhibition of tumor growth and protection of normal tissue after the treatment with intravenous administrations of HANP/GKT831 at 5 mg/kg (twice per week for five times) combined with radiation (2 Gy/each dose, twice per week for five times). The anti-tumor effect, immune response, and inflammation in the normal lung tissues were investigated using histological and immunofluorescence analyses. Results: Our results showed that HANP/GKT831 had stronger inhibitory effects on ROS generation and cell proliferation than that of GKT831 in mouse NSCLC tumor cells in vitro. Systemic injection of HANP/GKT831 combined with radiation had the strongest inhibition on tumor growth (~79%) compared with the combination of non-nanoformulated GKT831 with radiation treated mouse group (&amp;lt;50%). HANP/GKT831 combined with radiation led to an increased tumor specific CD8+ T cells in tumors and markedly reduced the level of myeloid derived suppressive cells (CD11b+/GR1+) in tumors. Furthermore, the combination of radiation and HANP/GKT831 reduced inflammatory cytokines, such as IFN-γ and TNF-α, and cells (CD11b+ cells) in the irradiated normal lung tissues. Conclusion: HANP/GKT831 is a biomaterial-based nanoparticle radiosensitizer that acts upon abnormal redox status and altered metabolism in tumor cells to trigger a cascade of changes in signal pathways to enhance the response of tumor cells to radiotherapy. It also has the potential to reduce the radiation-induced inflammatory response in normal lung tissues. Citation Format: Lei Zhu, Lumeng Zhang, Tongrui Liu, Wei Ping Qian, Wei Zhou, Lily Yang. Development of a NOX-ROS nanoinhibitor for enhancing response to radiotherapy in lung cancer cells while mitigation radiation-induced inflammation and injury in the normal lung tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 811.