Pirfenidone-Loaded Polymeric Micelles as an Effective Mechanotherapeutic to Potentiate Immunotherapy in Mouse Tumor Models.

Ongoing research is actively exploring the use of immune checkpoint inhibitors to treat solid tumors by inhibiting the PD-1/PD-L1 axis and reactivating the function of cytotoxic T effector cells. Many types of solid tumors, however, are characterized by a dense and stiff stroma and are difficult to treat. Mechanotherapeutics have formed a recent class of drugs that aim to restore biomechanical abnormalities of the tumor microenvironment, related to increased stiffness and hypo-perfusion. Here, we have developed a polymeric formulation containing pirfenidone, which has been successful in restoring the tumor microenvironment in breast tumors and sarcomas. We found that the micellar formulation can induce similar mechanotherapeutic effects to mouse models of 4T1 and E0771 triple negative breast tumors and MCA205 fibrosarcoma tumors but with a dose 100-fold lower than that of the free pirfenidone. Importantly, a combination of pirfenidone-loaded micelles with immune checkpoint inhibition significantly delayed primary tumor growth, leading to a significant improvement in overall survival and in a complete cure for the E0771 tumor model. Furthermore, the combination treatment increased CD4+ and CD8+ T cell infiltration and suppressed myeloid-derived suppressor cells, creating favorable immunostimulatory conditions, which led to immunological memory. Ultrasound shear wave elastography (SWE) was able to monitor changes in tumor stiffness during treatment, suggesting optimal treatment conditions. Micellar encapsulation is a promising strategy for mechanotherapeutics, and imaging methods, such as SWE, can assist their clinical translation.

Polymeric micelles effectively reprogram the tumor microenvironment to potentiate nano-immunotherapy in mouse breast cancer models.

Nano-immunotherapy improves breast cancer outcomes but not all patients respond and none are cured. To improve efficacy, research focuses on drugs that reprogram cancer-associated fibroblasts (CAFs) to improve therapeutic delivery and immunostimulation. These drugs, however, have a narrow therapeutic window and cause adverse effects. Developing strategies that increase CAF-reprogramming while limiting adverse effects is urgent. Here, taking advantage of the CAF-reprogramming capabilities of tranilast, we developed tranilast-loaded micelles. Strikingly, a 100-fold reduced dose of tranilast-micelles induces superior reprogramming compared to free drug owing to enhanced intratumoral accumulation and cancer-associated fibroblast uptake. Combination of tranilast-micelles and epirubicin-micelles or Doxil with immunotherapy increases T-cell infiltration, resulting in cures and immunological memory in mice bearing immunotherapy-resistant breast cancer. Furthermore, shear wave elastography (SWE) is able to monitor reduced tumor stiffness caused by tranilast-micelles and predict response to nano-immunotherapy. Micellar encapsulation is a promising strategy for TME-reprogramming and SWE is a potential biomarker of response.

Ofloxacin Removal from Aqueous Media by Means of Magnetoactive Electrospun Fibrous Adsorbents.

Functionalized electrospun polymer microfibrous membranes were fabricated by electrospinning and further surface-functionalized with magnetic iron oxide (FexOy) nanoparticles to yield magnetoactive nanocomposite fibrous adsorbents. The latter were characterized in respect to their morphology, mechanical properties and magnetic properties while they were further evaluated as substrates for removing Ofloxacin (OFL) from synthetic aqueous media and secondary urban wastewater (UWW) under varying physicochemical parameters, including the concentration of the pharmaceutical pollutant, the solution pH and the membranes' magnetic content. The magnetic-functionalized fibrous adsorbents demonstrated significantly enhanced adsorption efficacy in comparison to their non-functionalized fibrous analogues while their magnetic properties enabled their magnetic recovery and regeneration.

Binuclear VIV/V, MoVI and ZnII - hydroquinonate complexes: Synthesis, stability, oxidative activity and anticancer properties.

Since the discovery of the anticancer properties of cis-platin the road for the development of less toxic and more specific metal ion based anticancer drugs has opened. Based on the low toxicity of VIV/V, MoVI and ZnII metal ions, their binuclear hydroquinonate complexes have been synthesized and their biological activity towards their anticancer properties on various cancerous and non-cancerous cell lines has been evaluated. The new complexes of ZnII with the ligands 2,5-bis((bis(pyridin-2-ylmethyl)amino)methyl)benzene-1,4-diol (H2bpymah) and 2,2'-(((2,5-dihydroxy-1,4-phenylene)bis(methylene))bis((carboxymethyl)ammoniumdiyl))diacetate (H6bicah) have been synthesized and characterized by X-ray crystallography in solid state and 1H NMR in aqueous solution. The binuclear nature of the complexes increases their hydrolytic stability in aqueous solutions at pD 7.0, depending on the metal ion. The most hydrolytic stable VV and ZnII hydroquinonate complexes show to activate O2 towards oxidation of mercaptoethanol in aqueous solutions at physiological pHs. Only the strongest oxidant, the VV complex with bicah6-, significantly activates the intracellular radical oxygen species (ROS) generation. Apparently, the mercaptoethanol oxidation experiment vs time can be used as a preliminary experiment for the prediction of the in vitro ROS generation activity of the complexes in aqueous solutions.

Multiresponsive polymer conetworks capable of responding to changes in pH, temperature, and magnetic field: synthesis, characterization, and evaluation of their ability for controlled uptake and release of solutes.

This study deals with the preparation of novel multiresponsive (magnetoresponsive, thermoresponsive and pH-responsive) nanocomposite conetworks consisting of oleic acid-coated magnetite nanoparticles (OA·Fe(3)O(4)), hydrophilic/thermoresponsive hexa(ethylene glycol) methyl ether methacrylate (HEGMA), hydrophobic/metal binding 2-(acetoacetoxy)ethyl methacrylate (AEMA), and pH-responsive/thermoresponsive N-diethylaminoethyl methacrylate (DEAEMA) and 2-(dimethylamino)ethyl methacrylate (DMAEMA) moieties. Conventional free radical copolymerization was employed for the synthesis of random conetworks in the absence and presence of preformed OA·Fe(3)O(4). Further, in characterization of these materials in regards to their swelling behavior in organic and aqueous solvents, thermal/thermoresponsive properties, and composition, assessment of their magnetic characteristics disclosed tunable superparamagnetic behavior. These systems were also evaluated toward their ability to adsorb and release a solute (benzoic acid) in a controlled manner upon varying the pH.

Superparamagnetic hybrid micelles, based on iron oxide nanoparticles and well-defined diblock copolymers possessing beta-ketoester functionalities.

The quality of surface coating of magnetic nanoparticles destined as nanoprobes in clinical applications is of utmost significance for their colloidal stability and biocompatibility. A novel approach for the fabrication of such a coating involves the synthesis of well-defined diblock copolymers based on 2-(acetoacetoxy)ethyl methacrylate (chelating) and poly(ethylene glycol)methyl ether methacrylate (water-soluble, thermoresponsive), prepared by reversible addition-fragmentation chain transfer polymerization. Fabrication of magneto-responsive micelles was accomplished via chemical coprecipitation of Fe(III)/Fe(II) in the presence of diblock copolymers. Further to the characterization of micellar morphologies, optical and thermal properties, assessment of magnetic characteristics disclosed superparamagnetic behavior. The hybrid micelles did not compromise cell viability in cultures, while in vitro uptake by macrophage cells was significantly lower in comparison to that of the clinically applicable contrast agent Resovist, suggesting that these systems can evade rapid uptake by the reticuloendothelial system and be useful agents for in vivo applications.