Combining antimiR-25 and cGAMP Nanocomplexes Enhances Immune Responses via M2 Macrophage Reprogramming.

Glioblastoma (GBM) is an aggressive brain cancer with a highly immunosuppressive tumor microenvironment (TME), invariably infiltrated by tumor-associated macrophages (TAMs). These TAMs resemble M2 macrophages, which promote tumor growth and suppress immune responses. GBM cells secrete extracellular vesicles (EVs) containing microRNA-25, which inhibits the cGAS-STING pathway and prevents TAMs from adopting a pro-inflammatory M1 phenotype.

Cartilage-targeted drug nanocarriers for osteoarthritis therapy.

Osteoarthritis (OA) is a joint disease common worldwide. Currently, no disease-modifying osteoarthritis drugs (DMOADs) have successfully passed clinical trials, often due to a lack of cartilage penetration. Thus, targeting the extracellular matrix (ECM) is a major priority.

Hyaluronan-based hydrogel delivering glucose to mesenchymal stem cells intended to treat osteoarthritis.

Mesenchymal stem cell (MSC) therapy shows promise in regenerative medicine. For osteoarthritis (OA), MSCs delivered to the joint have a temporal window in which they can secrete growth factors and extracellular matrix molecules, contributing to cartilage regeneration and cell proliferation. However, upon injection in the non-vascularized joint, MSCs lacking energy supply, starve and die too quickly to efficiently deliver enough of these factors.

Unveiling the challenges of engineered protein corona from the proteins' perspective.

It is well known that protein corona affects the "biological identity" of nanoparticles (NPs), which has been seen as both a challenge and an opportunity. Approaches have moved from avoiding protein adsorption to trying to direct it, taking advantage of the formation of a protein corona to favorably modify the pharmacokinetic parameters of NPs. Although promising, the results obtained with engineered NPs still need to be completely understood.

Nanocrystals and nanosuspensions: an exploration from classic formulations to advanced drug delivery systems.

Nanocrystals and nanosuspensions have become realistic approaches to overcome the formulation challenges of poorly water-soluble drugs. They also represent a less-known but versatile platform for multiple therapeutic applications. They can be integrated into a broad spectrum of drug delivery systems including tablets, hydrogels, microneedles, microparticles, or even functionalized liposomes.

Highly Potent Cationic Chitosan Derivatives Coupled to Antimicrobial Peptide Dendrimers to Combat Pseudomonas aeruginosa.

The burden of bacterial wound infections has considerably increased due to antibiotic resistance to most of the currently available antimicrobial drugs. Herein, for the first time, a chemical coupling of two cationic N-aryl (pyridyl and aminocinnamyl) chitosan derivatives to antimicrobial peptide dendrimers (AMPDs) of different generations (first, second, and third) via thioether-haloacetyl reaction is reported. The new chitosan-AMPD conjugates show high selectivity by killing Pseudomonas aeruginosa and very low toxicity toward mammalian cells, as well as extremely low hemolysis to red blood cells.

Clinical Perspectives on the Injectability of Cross-Linked Hyaluronic Acid Dermal Fillers: A Standardized Methodology for Commercial Product Benchmarking with Inter-Injector Assessments.

The injectability of cross-linked hyaluronic acid (HA) dermal fillers is influenced by polymer concentration, polymer cross-linking type and degree, the presence of lidocaine or other functional excipients, types of syringes, and injection techniques. Finished product injectability constitutes a critical quality attribute for clinical injectors, as it strongly influences product applicability and ease of use in aesthetic medicine. While injectable product extrusion force specifications are provided by the respective device manufacturers, the qualitative informative value of such datasets is low for injectors wishing to compare product brands and technologies from an injectability standpoint.

Hypoxic glioblastoma-cell-derived extracellular vesicles impair cGAS-STING activity in macrophages.

Background: Solid tumors such as glioblastoma (GBM) exhibit hypoxic zones that are associated with poor prognosis and immunosuppression through multiple cell intrinsic mechanisms. However, release of extracellular vesicles (EVs) has the potential to transmit molecular cargos between cells. If hypoxic cancer cells use EVs to suppress functions of macrophages under adequate oxygenation, this could be an important underlying mechanism contributing to the immunosuppressive and immunologically cold tumor microenvironment of tumors such as GBM.

Nanocrystal-chitosan particles for intra-articular delivery of disease-modifying osteoarthritis drugs.

Osteoarthritis is the most common chronic joint disease and a major health care concern due to the lack of efficient treatments. This is mainly related to the local and degenerative nature of this disease. Kartogenin was recently reported as a disease-modifying osteoarthritis drug that promotes cartilage repair, but its therapeutic effect is impeded by its very low solubility.

Understanding protein-nanoparticle interactions leading to protein corona formation: In vitro - in vivo correlation study.

Nanoparticles (NPs) in contact with biological fluids form a biomolecular corona through interactions with proteins, lipids, and sugars, acquiring new physicochemical properties. This work explores the interaction between selected proteins (hemoglobin and fetuin-A) that may alter NP circulation time and NPs of different surface charges (neutral, positive, and negative). The interaction with key proteins albumin and transferrin, the two of the most abundant proteins in plasma was also studied.

Spray-dried nanocrystal-loaded polymer microparticles for long-term release local therapies: an opportunity for poorly soluble drugs.

Nano- and micro-technologies can salvage drugs with very low solubility that were doomed to pre-clinical and clinical failure. A unique design approach to develop drug nanocrystals (NCs) loaded in extended release polymeric microparticles (MPs) for local treatments is presented here through the case of a potential osteoarthritis (OA) drug candidate for intra-articular (IA) administration. Optimizing a low-shear wet milling process allowed the production of NCs that can be subsequently freeze-dried (FD) and redispersed in a hydrophobic polymer-organic solvent solution to form spray-dried MPs.

Ex Vivo Functional Benchmarking of Hyaluronan-Based Osteoarthritis Viscosupplement Products: Comprehensive Assessment of Rheological, Lubricative, Adhesive, and Stability Attributes.

While many injectable viscosupplementation products are available for osteoarthritis (OA) management, multiple hydrogel functional attributes may be further optimized for efficacy enhancement. The objective of this study was to functionally benchmark four commercially available hyaluronan-based viscosupplements (Ostenil, Ostenil Plus, Synvisc, and Innoryos), focusing on critical (rheological, lubricative, adhesive, and stability) attributes. Therefore, in vitro and ex vivo quantitative characterization panels (oscillatory rheology, rotational tribology, and texture analysis with bovine cartilage) were used for hydrogel product functional benchmarking, using equine synovial fluid as a biological control.

Explosomes: A new modality for DEB-TACE local delivery of sorafenib: In vivo proof of sustained release.

The current medical practice in treating Hepatocellular carcinoma (HCC) using Drug Eluting Transarterial chemoembolization (DEB-TACE) technique is limited only to hydrophilic ionizable drugs, that can be attached ionically to the oppositely charged beads. This limitation has forced physicians to subscribe the more hydrophobic, first treatment option drugs, like sorafenib systemically via the oral route, thus flooding the patient system with a very powerful, non-specific, multiple-receptor tyrosine kinase inhibitor that is associated with notorious side effects. In this paper, a new modality is introduced, where highly charged, drug loaded liposomes are added to oppositely charged DEBs in a manner causing them to "explode" and the drug is eventually attached to the beads in the lipid patches covering their surfaces; therefore we call them "Explosomes".

Identification of the Proteins Determining the Blood Circulation Time of Nanoparticles.

The therapeutic efficacy and adverse impacts of nanoparticles (NPs) are strongly dependent on their systemic circulation time. The corona proteins adsorbed on the NPs determine their plasma half-lives, and hence, it is crucial to identify the proteins shortening or extending their circulation time. In this work, the circulation time and corona composition of superparamagnetic iron oxide nanoparticles (SPIONs) with different surface charges/chemistries were analyzed over time.

Injectable Hyaluronan-Based Thermoresponsive Hydrogels for Dermatological Applications.

Most marketed HA-based dermal fillers use chemical cross-linking to improve mechanical properties and extend their lifetime in vivo; however, stiffer products with higher elasticity require an increased extrusion force for injection in clinical practice. To balance longevity and injectability, we propose a thermosensitive dermal filler, injectable as a low viscosity fluid that undergoes gelation in situ upon injection. To this end, HA was conjugated via a linker to poly(N-isopropylacrylamide) (pNIPAM), a thermosensitive polymer using "green chemistry", with water as the solvent.

Thermo-Responsive Hyaluronan-Based Hydrogels Combined with Allogeneic Cytotherapeutics for the Treatment of Osteoarthritis.

Thermo-responsive hyaluronan-based hydrogels and FE002 human primary chondroprogenitor cell sources have both been previously proposed as modern therapeutic options for the management of osteoarthritis (OA). For the translational development of a potential orthopedic combination product based on both technologies, respective technical aspects required further optimization phases (e.g.

Lyophilized Progenitor Tenocyte Extracts: Sterilizable Cytotherapeutic Derivatives with Antioxidant Properties and Hyaluronan Hydrogel Functionalization Effects.

Cultured primary progenitor tenocytes in lyophilized form were previously shown to possess intrinsic antioxidant properties and hyaluronan-based hydrogel viscosity-modulating effects in vitro. The aim of this study was to prepare and functionally characterize several stabilized (lyophilized) cell-free progenitor tenocyte extracts for inclusion in cytotherapy-inspired complex injectable preparations. Fractionation and sterilization methods were included in specific biotechnological manufacturing workflows of such extracts.

Characterization Challenges of Self-Assembled Polymer-SPIONs Nanoparticles: Benefits of Orthogonal Methods.

Size and zeta potential are critical physicochemical properties of nanoparticles (NPs), influencing their biological activity and safety profile. These are essential for further industrial upscale and clinical success. However, the characterization of polydisperse, non-spherical NPs is a challenge for traditional characterization techniques (ex.

Bioadhesive Perivascular Microparticle-Gel Drug Delivery System for Intimal Hyperplasia Prevention: In Vitro Evaluation and Preliminary Biocompatibility Assessment.

Intimal hyperplasia (IH) is an undesirable pathology occurring after peripheral or coronary bypass surgery. It involves the proliferation and migration of vascular smooth muscle cells, leading to a reduction in the diameter of the vascular lumen, which can lead to stenosis and graft failure. Topically applied atorvastatin (ATV) has been shown to slow down this process.

Synthesis, Formulation and Characterization of Immunotherapeutic Glycosylated Dendrimer/cGAMP Complexes for CD206 Targeted Delivery to M2 Macrophages in Cold Tumors.

Anti-tumor responses can be achieved via the stimulation of the immune system, a therapeutic approach called cancer immunotherapy. Many solid tumor types are characterized by the presence of immune-suppressive tumor-associated macrophage (TAMs) cells within the tumor microenvironment (TME). Moreover, TAM infiltration is strongly associated with poor survival in solid cancer patients and hence a low responsiveness to cancer immunotherapy.

Bioadhesive Hyaluronic Acid/Dopamine Hydrogels for Vascular Applications Prepared by Initiator-Free Crosslinking.

Intimal hyperplasia, a vascular pathology characterized by vessel wall thickening, is implicated in vein graft failures. For efficient prevention, a biodegradable drug delivery system should be applied externally to the graft for an extended time. Finding a gel suitable for such a system is challenging.

Nanoforming Hyaluronan-Based Thermoresponsive Hydrogels: Optimized and Tunable Functionality in Osteoarthritis Management.

Hyaluronic acid (HA) constitutes a versatile chemical framework for the development of osteoarthritis pain treatment by means of injection in the joints, so-called viscosupplementation. Without appropriate physico-chemical tuning, such preparations are inherently hindered by prompt in vivo degradation, mediated by hyaluronidases and oxidative stress. To prolong hydrogel residence time and confer optimized product functionality, novel thermoresponsive nanoforming HA derivatives were proposed and characterized.

Pharmacological prevention of intimal hyperplasia: A state-of-the-art review.

Intimal hyperplasia (IH) occurs in a considerable number of cases of blood vessel reconstruction by stenting or balloon angioplasty, venous bypass grafting, and arteriovenous dialysis accesses. It is triggered by endothelial injury during the vascular intervention and leads to vessel restenosis with life-threatening consequences for patients. To date, the drugs used for IH prevention in clinics-paclitaxel and rapalog drugs-have been focusing primarily on the vascular smooth muscle cell (VSMC) proliferation pathway of IH development.

Combination of mesenchymal stem cells and bioactive molecules in hydrogels for osteoarthritis treatment.

Osteoarthritis (OA) is a chronic and inflammatory disease with no effective regenerative treatments to date. The therapeutic potential of mesenchymal stem cells (MSCs) remains to be fully explored. Intra-articular injection of these cells promotes cartilage protection and regeneration by paracrine signaling and differentiation into chondrocytes.

Synergistic effects of antimicrobial peptide dendrimer-chitosan polymer conjugates against Pseudomonas aeruginosa.

We report herein a new chemical platform for coupling chitosan derivatives to antimicrobial peptide dendrimers (AMPDs) with different degrees of ramification and molecular weights via thiol-maleimide reactions. Previous studies showed that simple incorporation of AMPDs to polymeric hydrogels resulted in a loss of antibacterial activity and augmented cytotoxicity to mammalian cells. We have shown that coupling AMPDs to chitosan derivatives enabled the two compounds to act synergistically.