Insights into Factors Affecting Ethylene-Vinyl Acetate Copolymer Crystallinity in Islatravir Implant.

Islatravir, a highly potent nucleoside reverse transcriptase translocation inhibitor (NRTTI) for the treatment of HIV, has great potential to be formulated as ethylene-vinyl acetate (EVA) copolymer-based implants via hot melt extrusion. The crystallinity of EVA determines its physical and rheological properties and may impact the drug-eluting implant performance. Herein, we describe the systematic analysis of factors affecting the EVA crystallinity in islatravir implants. Differential scanning calorimetry (DSC) on EVA and solid-state NMR revealed drug loading promoted EVA crystallization, whereas BaSO4 loading had negligible impact on EVA crystallinity. The sterilization through γ-irradiation appeared to significantly impact the EVA crystallinity and surface characteristics of the implants. Furthermore, DSC analysis of thin implant slices prepared with an ultramicrotome indicated that the surface layer of the implant was more crystalline than the core. These findings provide critical insights into factors affecting the crystallinity, mechanical properties, and physicochemical properties of the EVA polymer matrix of extruded islatravir implants.

Degradation Profiles of Poly(ethylene glycol) diacrylate (PEGDA)-based hydrogel nanoparticles.

Hydrogel nanoparticles (also known as nanogels) have been utilized for a wide range of applications including analytics, sensors, drug delivery, immune engineering, and biotechnology. While these types of nanoparticles can be characterized using standard colloidal characterization techniques, degradation profiles typically must be inferred from those of bulk gels with the same formulation, typically by applying swelling ratios and rheological measurements that tend to severely underestimate nanoparticle degradation rates. Herein, we present an analysis of the degradation via ester hydrolysis of poly(ethylene glycol) diacrylate (PEGDA)-based hydrogel nanoparticles in water, varied pH conditions, and redox environments. We perform this characterization using thermogravimetric analysis and mass spectrometry to analyze rates of degradation and products released, respectively, and compare results to those for equivalent bulk gel formulations. Our findings show that PEGDA-based nanoparticles display significant mass loss over time accompanied by negligible changes in hydrodynamic diameter, indicating a bulk mode of degradation. Nanoparticle mass loss occurs at a much higher rate than for bulk gels under comparable incubation conditions, confirming that bulk gel degradation serves as a poor surrogate for nanoparticle degradation. We further demonstrate that the incorporation of other diacrylate-based co-monomers drastically accelerates nanoparticle degradation rates. Through formulation considerations of co-monomer content and weight percent of PEGDA, we demonstrate the ability to tune the degradation rates of PEGDA-based nanoparticles on a range of hours to weeks. These findings highlight critical design considerations for enhancing the tunability and utility of PEGDA hydrogel nanoparticles and introduce a rigorous framework for the characterization of nanogel degradation.

Catalytic activity and thermal stability of horseradish peroxidase encapsulated in self-assembled organic nanotubes.

Horseradish peroxidase (HRP) was encapsulated in self-assembled lithocholic acid (LCA) based organic nanotubes and its catalytic activity before and after thermal treatment was measured for comparison with free HRP. The apparent kcat (kcat/Km) for nanotube encapsulated HRP remained almost the same before and after thermal treatment, reporting an average value of 3.7 ± 0.4 µM(-1) s(-1). The apparent kcat value for free HRP decreased from 14.8 ± 1.3 µM(-1) s(-1) for samples stored at 4 °C to 2.4 ± 0.1 µM(-1) s(-1) after thermal treatment for 8 h at 55 °C. The Michaelis-Menten constants, Km, determined for encapsulated HRP and free HRP were relatively unperturbed by storage conditions at 4 °C or thermally treated at 55 °C for varying time periods from 2-8 h, with encapsulated HRP having a slightly higher Km than free HRP (13.4 ± 0.9 µM versus 11.7 ± 0.4 µM). The amount of HRP encapsulated in LCA nanotubes increased dramatically when the mixture of HRP and LCA nanotubes was brought to an elevated temperature. Within 4 h of thermal treatment at 55 °C, the amount of HRP encapsulated by the LCA nanotubes was more than 4 times the amount of HRP encapsulated when equilibrated at 4 °C for 7 days. Molecular dynamics (MD) simulations show that the higher degree of exposure of hydrophobic residues in HRP at elevated temperatures enhances the hydrophobic interaction between HRP and the nanotube wall, resulting in the increased amount of HRP surface adsorption and, hence, the overall amount of encapsulation inside the nanotubes.