Glucocorticoids are potent anti-inflammatory drugs, although their use is associated with severe side effects. Loading glucocorticoids into suitable nanocarriers can significantly reduce these undesirable effects. Macrophages play a crucial role in inflammation, making them strategic targets for glucocorticoid-loaded nanocarriers. The main objective of this study is to develop a glucocorticoid-loaded PLGA nanocarrier specifically targeting liver macrophages, thereby enabling the localized release of glucocorticoids at the site of inflammation. Dexamethasone acetate (DA)-loaded PLGA nanospheres designed for passive macrophage targeting are synthesized using the nanoprecipitation method. Two types of PLGA NSs in the size range of 100-300 nm are prepared, achieving a DA-loading efficiency of 19 %. Sustained DA release from nanospheres over 3 days is demonstrated. Flow cytometry analysis using murine bone marrow-derived macrophages demonstrates the efficient internalization of fluorescent dye-labeled PLGA nanospheres, particularly into pro-inflammatory macrophages. Significant down-regulation in pro-inflammatory cytokine genes mRNA is observed without apparent cytotoxicity after treatment with DA-loaded PLGA nanospheres. Subsequent experiments in mice confirm liver macrophage-specific nanospheres accumulation following intravenous administration using in vivo imaging, flow cytometry, and fluorescence microscopy. Taken together, the data show that the DA-loaded PLGA nanospheres are a promising drug-delivery system for the treatment of inflammatory liver diseases.
- MeSH
- Anti-Inflammatory Agents pharmacology chemistry MeSH
- Dexamethasone * pharmacology chemistry analogs & derivatives MeSH
- Liver * drug effects metabolism MeSH
- Polylactic Acid-Polyglycolic Acid Copolymer * chemistry MeSH
- Macrophages * drug effects metabolism MeSH
- Mice MeSH
- Nanospheres * chemistry MeSH
- Drug Carriers chemistry pharmacology MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
INTRODUCTION: The immunosuppressive roles of galectin-3 (Gal-3) in carcinogenesis make this lectin an attractive target for pharmacological inhibition in immunotherapy. Although current clinical immunotherapies appear promising in the treatment of solid tumors, their efficacy is significantly weakened by the hostile immunosuppressive tumor microenvironment (TME). Gal-3, a prominent TME modulator, efficiently subverts the elimination of cancer, either directly by inducing apoptosis of immune cells or indirectly by binding essential effector molecules, such as interferon-gamma (IFNγ). METHODS: N-(2-Hydroxypropyl)methacrylamide (HPMA)-based glycopolymers bearing poly-N-acetyllactosamine-derived tetrasaccharide ligands of Gal-3 were designed, synthesized, and characterized using high-performance liquid chromatography, dynamic light scattering, UV-Vis spectrophotometry, gel permeation chromatography, nuclear magnetic resonance, high-resolution mass spectrometry and CCK-8 assay for evaluation of glycopolymer non-toxicity. Pro-immunogenic effects of purified glycopolymers were tested by apoptotic assay using flow cytometry, competitive ELISA, and in vitro cell-free INFγ-based assay. RESULTS: All tested glycopolymers completely inhibited Gal-3-induced apoptosis of monocytes/macrophages, of which the M1 subtype is responsible for eliminating cancer cells during immunotherapy. Moreover, the glycopolymers suppressed Gal-3-induced capture of glycosylated IFNγ by competitive inhibition to Gal-3 carbohydrate recognition domain (CRD), which enables further inherent biological activities of this effector, such as differentiation of monocytes into M1 macrophages and repolarization of M2-macrophages to the M1 state. CONCLUSION: The prepared glycopolymers are promising inhibitors of Gal-3 and may serve as important supportive anti-cancer nanosystems enabling the infiltration of proinflammatory macrophages and the reprogramming of unwanted M2 macrophages into the M1 subtype.
- MeSH
- Acrylamides chemistry pharmacology MeSH
- Apoptosis drug effects MeSH
- Galectin 3 * antagonists & inhibitors MeSH
- Galectins MeSH
- Interferon-gamma * metabolism MeSH
- Blood Proteins MeSH
- Humans MeSH
- Macrophages drug effects MeSH
- Monocytes * drug effects MeSH
- Tumor Microenvironment drug effects MeSH
- Polymers * chemistry pharmacology MeSH
- Antineoplastic Agents * pharmacology chemistry MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Well-defined gold nanoparticles (AuNPs) are accessible via simple synthetic methods, and their surface chemistry stands as a key factor in determining applications in the biomedical field. While macromolecules featuring amino groups are already known to successfully mediate the formation of stable gold colloids in one-pot, two-reactant, no workup reactions in aqueous media, we herein report the discovery that, under mild reaction temperatures, polymers of outstanding biomedical interest not only can play the simultaneous role of reducing and capping agent but also lead to particulate systems with unique features. From a library of samples that included branched polyethylenimine (BPEI), poly-(l-lysine) (PLL), bovine serum albumin (BSA), poly-(2-methyl-2-oxazoline) (PMeOx), poly-(N-(2-hydroxypropyl) methacrylamide) (PHPMA), and amine-functionalized poly-(N-(2-hydroxypropyl)-methacrylamide-co-N-(3-aminopropyl)-methacrylamide) P-(HPMA-co-APMA), we found that PHPMA end-functionalized with nitrile motifs generate spherical and stable AuNPs@PHPMA of very small size (diameter of ∼2.4 nm), as underlined by imaging experiments. Cell viability experiments indicated exceptionally good biocompatibility up to very high numerical particle concentrations as compared to the other systems. The reduced size imparted to the AuNPs@PHPMA outstanding catalytic properties (no induction time and high reaction rate constant for the hydrogenation of p-nitrophenol) and antimicrobial activity (total antibacterial activity against Escherichia coli and dose-dependent antibacterial activity against Staphylococcus aureus). The introduction of primary amine groups (13.4 mol %) of higher nucleophilicity known to work better for AuNP synthesis makes these unique features disappear, as evidenced for P-(HPMA-co-APMA). The other systems yielded 6-28 nm particles whose properties reflected both the size of the metallic core and chemical nature and conformation of the capping agent. These findings point to novel applications of PHPMA polymers worthy of further development, especially in light of their excellent water solubility and biocompatibility.
- Publication type
- Journal Article MeSH
Periodontitis is a globally prevalent chronic inflammatory disease that leads to periodontal pocket formation and eventually destroys tooth-supporting structures. Hence, the drastic increase in dental implants for periodontitis has become a severe clinical issue. Injectable hydrogel based on extracellular matrix (ECM) is highly biocompatible and tissue-regenerative with tailor-made mechanical properties and high payload capacity for in situ delivery of bioactive molecules to treat periodontitis. This therapeutic tool not only enhances the drug release efficiency and treatment efficacy but also reduces operation time. Nevertheless, it remains challenging to optimize the mechanical properties and intelligent control drug release rate of injectable hydrogels to achieve the highest therapeutic outcome. Literature precedent has shown the modulation of polymer backbones (synthetic polymers, natural polysaccharides, and proteins), crosslinking strategies, other bioactive constituents, and potentially the incorporation of nanomaterials that overall improve the desirable physiochemical and biological performances as well as biodegradability. In this review, we summarize the recent advances in the development, design, and material characterizations of common injectable hydrogels. Furthermore, we highlight cutting-edge representative examples of polysaccharide-, protein- and nanocomposite-based hydrogels that mediate regenerative factors and anti-inflammatory drugs for periodontal regeneration. Finally, we express our perspectives on potential challenges and future development of multifunctional injectable hydrogels for periodontitis.
- Publication type
- Journal Article MeSH
- Review MeSH
Graphene-based materials (GBMs) have shown significant promise in cancer therapy due to their unique physicochemical properties, biocompatibility, and ease of functionalization. Their ability to target solid tumors, penetrate the tumor microenvironment (TME), and act as efficient drug delivery platforms highlights their potential in nanomedicine. However, the complex and dynamic nature of the TME, characterized by metabolic heterogeneity, immune suppression, and drug resistance, poses significant challenges to effective cancer treatment. GBMs offer innovative solutions by enhancing tumor targeting, facilitating deep tissue penetration, and modulating metabolic pathways that contribute to tumor progression and immune evasion. Their functionalization with targeting ligands and biocompatible polymers improves their biosafety and specificity, while their ability to modulate immune cell interactions within the TME presents new opportunities for immunotherapy. Given the role of metabolic reprogramming in tumor survival and resistance, GBMs could be further exploited in metabolism-targeted therapies by disrupting glycolysis, mitochondrial respiration, and lipid metabolism to counteract the immunosuppressive effects of the TME. This review focuses on discussing research studies that design GBM nanocomposites with enhanced biodegradability, minimized toxicity, and improved efficacy in delivering therapeutic agents with the intention to reprogram the TME for effective anticancer therapy. Additionally, exploring the potential of GBM nanocomposites in combination with immunotherapies and metabolism-targeted treatments could lead to more effective and personalized cancer therapies. By addressing these challenges, GBMs could play a pivotal role in overcoming current limitations in cancer treatment and advancing precision oncology.
- MeSH
- Graphite * chemistry therapeutic use MeSH
- Immunotherapy methods MeSH
- Drug Delivery Systems methods MeSH
- Humans MeSH
- Tumor Microenvironment * drug effects MeSH
- Neoplasms * drug therapy metabolism MeSH
- Nanocomposites * chemistry therapeutic use MeSH
- Antineoplastic Agents pharmacology therapeutic use MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
PURPOSE: Surgical mesh, often made from polypropylene, is commonly recommended to enhance hernia repair outcomes in adults. Concerns about polypropylene, as a cause of allergy and/or autoimmune disease prompted this study to evaluate immunological parameters in patients with mesh and healthy controls. METHODOLOGY: A case-control cohort study was conducted at a university hospital. Electronic patient records of hernia repairs using polypropylene mesh (January 2018-April 2022) were analysed. Blood samples from patients and healthy controls were assessed using various methods, including enzyme-linked immunosorbent assay (ELISA), immunofluorescence, immunoblotting, and flow cytometry. RESULTS: The database search identified 1544 participants. After applying the exclusion criteria 33 patients remained in the polypropylene mesh group. Patients with mesh had lower median IgG3 levels (p = 0.02) and Rheumatoid factor (RF) IgM (p = 0.018) compared to the control group. Although both IgG3 and RF IgM levels were in the normal reference range. In addition, 5 patients in the mesh group tested positive for serum ANCA levels compared to none in the control group (p = 0.053). No other differences in immunoglobulins, autoantibodies, complement, or immune cell subtypes were observed. CONCLUSION: Patients with polypropylene mesh exhibited median IgG3 and RF IgM serum levels that were within the normal reference range but slightly lower compared to the control group. Among patients with polypropylene mesh, five displayed positive serum ANCA levels without autoimmune-related symptoms. Overall, no definitive signs of autoimmunity caused by polypropylene mesh. A larger, prospective study is warranted to further explore potential immune responses to polypropylene mesh.
- MeSH
- Surgical Mesh * adverse effects MeSH
- Adult MeSH
- Immunoglobulin G blood MeSH
- Immunoglobulin M blood MeSH
- Cohort Studies MeSH
- Middle Aged MeSH
- Humans MeSH
- Herniorrhaphy * instrumentation MeSH
- Polypropylenes * adverse effects MeSH
- Rheumatoid Factor blood MeSH
- Aged MeSH
- Case-Control Studies MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Recent advances in optical sensing technologies underpin the development of high-performance, surface-sensitive analytical tools capable of reliable and precise detection of molecular targets in complex biological media in non-laboratory settings. Optical fibre sensors guide light to and from a region of interest, enabling sensitive measurements of localized environments. This positions optical fibre sensors as a highly promising technology for a wide range of biochemical and healthcare applications. However, their performance in real-world biological media is often limited by the absence of robust post-modification strategies that provide both high biorecognition and antifouling capabilities. In this study, we present the proof-of-concept antifouling and biorecognition performance of a polymer brush nano-coating synthesized at the sensing region of optical fibre long-period grating (LPG) sensors. Using a newly developed antifouling terpolymer brush (ATB) composed of carboxybetaine methacrylamide, sulfobetaine methacrylamide, and N-(2-hydroxypropyl)methacrylamide, we achieve state-of-the-art antifouling properties. The successful on-fibre ATB synthesis is confirmed through scanning electron microscopy (SEM), fluorescence microscopy, and label-free bio-detection experiments based on antibody-functionalized ATB-coated LPG optical fibres. Despite the challenges in handling optical fibres during polymerization, the resulting nano-coating retains its remarkable antifouling properties upon exposure to blood plasma and enables biorecognition element functionalization. These capabilities are demonstrated through the detection of IgG in buffer and diluted blood plasma using anti-IgG-functionalized ATB-coated sensing regions of LPG fibres in both label-based (fluorescence) and label-free real-time detection experiments. The results show the potential of ATB-coated LPG fibres for use in analytical biosensing applications.
Spray drying and hot-melt extrusion are among the most prevalent preparation techniques used in the pharmaceutical industry to produce amorphous solid dispersions (ASDs). This study advances previous research by integrating sample production, comprehensive analytical characterization, intrinsic dissolution rate measurements, and assessments of the behavior of ASDs under elevated temperature and humidity conditions. The study focuses on indomethacin, a widely used model for poorly soluble drugs, processed with PVP K30 or HPMC E5, both commonly used polymers. The findings demonstrate that hot-melt extruded samples exhibit superior stability against recrystallization, whereas spray dried samples achieve higher intrinsic dissolution rates. Furthermore, PVP K30 significantly outperforms HPMC E5 in the co-processing of indomethacin, enhancing both the intrinsic dissolution rate and the stability.
- MeSH
- Hypromellose Derivatives chemistry MeSH
- Chemistry, Pharmaceutical methods MeSH
- Indomethacin * chemistry MeSH
- Crystallization * MeSH
- Povidone chemistry MeSH
- Drug Compounding methods MeSH
- Solubility * MeSH
- Spray Drying * MeSH
- Drug Stability * MeSH
- Hot Melt Extrusion Technology * methods MeSH
- Drug Liberation MeSH
- Humidity MeSH
- Hot Temperature MeSH
- Desiccation methods MeSH
- Publication type
- Journal Article MeSH
The integration of 3D printing into the pharmaceutical sciences opens new possibilities for personalized medicine. Poly(lactide) (PLA), a biodegradable and biocompatible polymer, is highly suitable for biomedical applications, particularly in the context of 3D printing. However, its processability often requires the addition of plasticizers. This study investigates the use of phase diagram modeling as a tool to guide the rational selection of plasticizers and to assess their impact on the thermodynamic and kinetic stability of PLA-based amorphous solid dispersions (ASDs) containing active pharmaceutical ingredients (APIs). Thermodynamic stability against API recrystallization was predicted based on the API solubility in PLA and Plasticizer-PLA carriers using the Conductor-like Screening Model for Real Solvents (COSMO-RS), while the kinetic stability of the ASDs was evaluated by modeling the glass transition temperatures of the mixtures. Two APIs, indomethacin (IND) and naproxen (NAP), with differing glass-forming abilities (i.e., recrystallization tendencies), and three plasticizers, triacetin (TA), triethyl citrate (TEC), and poly(L-lactide-co-caprolactone) (PLCL), were selected for investigation. The physical stability of ASD formulations containing 9 wt% API and plasticizer to PLA in two ratios, 10:81 and 20:71 w/w %, was monitored over time using differential scanning calorimetry and X-ray powder diffraction and compared with phase diagram predictions. All formulations were predicted to be thermodynamically unstable; however, those containing no plasticizer or with TEC and TA at 10 wt% were predicted to exhibit some degree of kinetic stability. Long-term physical studies corroborated these predictions. The correlation between the predicted phase behavior and long-term physical stability highlights the potential of phase diagram modeling as a tool for the rational design of ASDs in pharmaceutical 3D printing.
- MeSH
- Printing, Three-Dimensional * MeSH
- Citrates chemistry MeSH
- Calorimetry, Differential Scanning methods MeSH
- Chemistry, Pharmaceutical methods MeSH
- Technology, Pharmaceutical methods MeSH
- Indomethacin * chemistry MeSH
- Crystallization MeSH
- Naproxen chemistry MeSH
- Polyesters * chemistry MeSH
- Solvents chemistry MeSH
- Solubility * MeSH
- Drug Stability MeSH
- Thermodynamics MeSH
- Transition Temperature MeSH
- Triacetin chemistry MeSH
- Plasticizers * chemistry MeSH
- Publication type
- Journal Article MeSH
