Polymer Microparticles Prolong Delivery of the 15-PGDH Inhibitor SW033291

As the prevalence of age-related fibrotic diseases continues to increase, novel antifibrotic therapies are emerging to address clinical needs. However, many novel therapeutics for managing chronic fibrosis are small-molecule drugs that require frequent dosing to attain effective concentrations. Although bolus parenteral administrations have become standard clinical practice, an extended delivery platform would achieve steady-state concentrations over a longer time period with fewer administrations. This study lays the foundation for the development of a sustained release platform for the delivery of (+)SW033291, a potent, small-molecule inhibitor of the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) enzyme, which has previously demonstrated efficacy in a murine model of pulmonary fibrosis. Herein, we leverage fine-tuned cyclodextrin microparticles—specifically, β-CD microparticles (β-CD MPs)—to extend the delivery of the 15-PGDH inhibitor, (+)SW033291, to over one week.

DEVELOPMENT OF POLYMERIC MICROPARTICLES WITH RADACHLORINE AND ESTIMATION OF THE PROSPECTS OF THEIR USE IN PHOTODYNAMIC THERAPY

Introduction. Nowadays, the development of delivery systems based on micro- and nanoparticles is being actively pursued to increase the selectivity and efficiency of photosensitizers in photodynamic therapy. Such microparticles could increase the effectiveness of the already used chemotherapeutic drugs due to their accumulation in the tumor and help to overcome the drug resistance of tumor cells.The aim of this research was to obtain microparticles based on a biocompatible block copolymer of lactic and glycolic acids with the inclusion of the photosensitizer radachlorin, magnetic nanoparticles, and perfluorodecalin and their subsequent evaluation as therapeutic agents for photodynamic therapy.Materials and methods. Microparticles were obtained using the double emulsion method, described using of electron microscopy. Evaluation of their photodynamic properties was carried out using spectrophotometry and MTTtest on cell culture.Results. Spherical microparticles with a size of less than 1 μm were obtained. The release of the active substance from microparticles occurred gradually over two weeks, and in the case of the presence of magnetic nanoparticles, the concentration of radachlorin remained practically unchanged for a month. Exposure of microparticles to the light of LED is accompanied by the formation ofsinglet oxygen. Electron microscopy indicated intracellular position of microparticlesin tumor cells. The MTT test revealed a significant inhibition of cell viability in the presence of microparticles.Conclusion. The research results allow us to consider the obtained biocompatible polymer microparticles with the inclusion of radachlorin as a depot of radachlorin for local use in photodynamic therapy of tumors.

Polymer microparticles prolong delivery of the 15-PGDH inhibitor SW033291

As the prevalence of age-related fibrotic diseases continues to increase, novel antifibrotic therapies are emerging to address clinical needs. However, many novel therapeutics for managing chronic fibrosis are small-molecule drugs that require frequent dosing to attain effective concentrations. While bolus parenteral administrations have become standard clinical practice, an extended delivery platform would achieve steady state concentrations over a longer time period with fewer administrations. This study lays the foundation for the development of a sustained release platform for the delivery of (+)SW033291, a potent, small-molecule inhibitor of the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) enzyme, which has previously demonstrated efficacy in a murine model of pulmonary fibrosis. Herein, we leverage fine-tuned cyclodextrin microparticles - specifically β-CD microparticles (β-CD MPs) - to extend the delivery of 15-PGDH inhibitor, (+)SW033291, to over one week.

Formation of Myoglobin Corona at Polymer Microparticles

Adsorption of myoglobin molecules at negatively charged polystyrene microparticles was studied using the dynamic light scattering (DLS), electrophoresis (LDV) and the solution depletion method involving atomic force microscopy (AFM). The measurements were carried out at pH 3.5 and NaCl concentration of 10−2 and 0.15 M. Initially, the stability of myoglobin solutions and the particle suspensions as a function of pH were determined. Afterward, the formation of myoglobin molecule corona was investigated via the direct electrophoretic mobility measurements, which were converted to the zeta potential. The experimental results were quantitatively interpreted in terms of the general electrokinetic model. This approach yielded the myoglobin corona coverage under in situ conditions. The maximum hard corona coverage was determined using the AFM concentration depletion method. It was equal to 0.9 mg m−2 for the NaCl concentration in the range 0.01 to 0.15 M and pH 3.5. The electrokinetic properties of the corona were investigated using the electrophoretic mobility measurements for a broad pH range. The obtained results confirmed that thorough physicochemical characteristics of myoglobin molecules can be acquired using nM amounts of the protein. It was also argued that this method can be used for performing electrokinetic characteristics of other proteins such as the SARS-Cov-2 spike protein exhibiting, analogously to myoglobin, a positive charge at acidic pHs.

Impact of Excipients on Stability of Polymer Microparticles for Autoimmune Therapy

Therapies for autoimmune diseases such as multiple sclerosis and diabetes are not curative and cause significant challenges for patients. These include frequent, continued treatments required throughout the lifetime of the patient, as well as increased vulnerability to infection due to the non-specific action of therapies. Biomaterials have enabled progress in antigen-specific immunotherapies as carriers and delivery vehicles for immunomodulatory cargo. However, most of this work is in the preclinical stage, where small dosing requirements allow for on-demand preparation of immunotherapies. For clinical translation of these potential immunotherapies, manufacturing, preservation, storage, and stability are critical parameters that require greater attention. Here, we tested the stabilizing effects of excipients on the lyophilization of polymeric microparticles (MPs) designed for autoimmune therapy; these MPs are loaded with peptide self-antigen and a small molecule immunomodulator. We synthesized and lyophilized particles with three clinically relevant excipients: mannitol, trehalose, and sucrose. The biophysical properties of the formulations were assessed as a function of excipient formulation and stage of addition, then formulations were evaluated in primary immune cell culture. From a manufacturing perspective, excipients improved caking of lyophilized product, enabled more complete resuspension, increased product recovery, and led to smaller changes in MP size and size distribution over time. Cocultures of antigen-presenting cells and self-reactive T cells revealed that MPs lyophilized with excipients maintained tolerance-inducing function, even after significant storage times without refrigeration. These data demonstrate that excipients can be selected to drive favorable manufacturing properties without impacting the immunologic properties of the tolerogenic MPs.