The selective disruption of tumor-associated vasculature represents an attractive therapeutic approach. We have undertaken the first in vivo evaluation of KGP265, a water-soluble prodrug of a benzosuberene-based tubulin-binding agent, and found promising vascular-disrupting activity in three distinct tumor types. Dose escalation in orthotopic MDA-MB-231-luc breast tumor xenografts in mice indicated that higher doses produced more effective vascular shutdown, as revealed by dynamic bioluminescence imaging (BLI). In syngeneic orthotopic 4T1-luc breast and RENCA-luc kidney tumors, dynamic BLI and oxygen enhanced multispectral optoacoustic tomography (OE-MSOT) were used to compare vascular shutdown following the administration of KGP265 (7.5 mg/kg). The BLI signal and vascular oxygenation response (ΔsO₂) to a gas breathing challenge were both significantly reduced within 2 h, indicating vascular disruption, which continued over 24 h. A correlative histology confirmed increased necrosis and hemorrhage. Twice-weekly doses of KGP265 caused significant growth delay in both MDA-MB-231 and 4T1 breast tumors, with no obvious systemic toxicity. A combination with carboplatin produced significantly greater tumor growth delay than carboplatin alone, though significant carboplatin-associated toxicity was observed (whole-body weight loss). KGP265 was found to be effective at low concentrations, generating long-term vascular shutdown and tumor growth delay, thus providing strong rationale for further development, particularly in combination therapies.

A nanomaterial life-cycle risk assessment (Nano LCRA) was conducted for second-generation functionalized cellulose nanomaterials (CNs) in five case studies, including applications in water filtration, food contact packaging (including as an additive and coating), and food additives, to identify and prioritize potential occupational, health, consumer, and environmental risks. Exposure scenarios were developed and ranked for each product life-cycle stage. A Safer-by-Design Toolbox (SbD Toolbox) representing a compendium of high-throughput physical, chemical, and toxicological new approach methodologies (NAMs) was used for a screening-level hazard assessment. Overall, risks identified for the CN-enabled products were low. Of the exposure scenarios, occupational inhalation exposures during product manufacturing and application ranked the highest. Despite differences in chemistry and morphology, the materials behaved similarly in oral, dermal, and inhalation models, supporting their grouping and read-across. The screening-level hazard assessment identified potential lung inflammation associated with CN exposure, and a review of the literature supported this funding, suggesting CNs behave as poorly soluble, low-toxicity dusts with the potential to irritate the lung. Key research gaps to reduce uncertainty include evaluating long-term, low-dose exposures typical of the workplace, as well as the potential release and toxicity of CN-containing composite particles.

The vascular disrupting activity of a promising tubulin-binding agent (OXi6196) was demonstrated in mice in MDA-MB-231 human breast tumor xenografts growing orthotopically in mammary fat pad and syngeneic RENCA kidney tumors growing orthotopically in the kidney. To enhance water solubility, OXi6196, was derivatized as its corresponding phosphate prodrug salt OXi6197, facilitating effective delivery. OXi6197 is stable in water, but rapidly releases OXi6196 in the presence of alkaline phosphatase. At low nanomolar concentrations OXi6196 caused G2/M cell cycle arrest and apoptosis in MDA-MB-231 breast cancer cells and monolayers of rapidly growing HUVECs underwent concentration-dependent changes in their morphology. Loss of the microtubule structure and increased bundling of filamentous actin into stress fibers followed by cell collapse, rounding and blebbing was observed. OXi6196 (100 nM) disrupted capillary-like endothelial networks pre-established with HUVECs on Matrigel^®. When prodrug OXi6197 was administered to mice bearing orthotopic MDA-MB-231-luc tumors, dynamic bioluminescence imaging (BLI) revealed dose-dependent vascular shutdown with >80% signal loss within 2 h at doses ≥30 mg/kg and >90% shutdown after 6 h for doses ≥35 mg/kg, which remained depressed by at least 70% after 24 h. Twice weekly treatment with prodrug OXi6197 (20 mg/kg) caused a significant tumor growth delay, but no overall survival benefit. Similar efficacy was observed for the first time in orthotopic RENCA-luc tumors, which showed massive hemorrhage and necrosis after 24 h. Twice weekly dosing with prodrug OXi6197 (35 mg/kg) caused tumor growth delay in most orthotopic RENCA tumors. Immunohistochemistry revealed extensive necrosis, though with surviving peripheral tissues. These results demonstrate effective vascular disruption at doses comparable to the most effective vascular-disrupting agents (VDAs) suggesting opportunities for further development.

Microplastics (MPs) in wastewater treatment plants are exposed to oxidative conditions during disinfection and advanced oxidation processes (AOPs), which can alter morphology and surface chemistry and influence interactions with coexisting contaminants. Here, accelerated chemical oxidation was simulated using heat-activated potassium persulfate (K₂S₂O₈) and sodium hypochlorite (NaOCl) to examine the oxidative aging of MPs made from polyethylene (PE), polyethylene terephthalate (PET), and polypropylene (PP). Changes in particle morphology and surface chemistry before and after oxidant treatment were characterized using scanning electron microscopy (SEM) for morphological analysis and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy for chemical characterization. Carbonyl formation, an indicator of polymer oxidation, was evaluated using the carbonyl index (CI). Both oxidants induced surface morphological defects and carbonyl functional groups in the MPs, with CI increasing with degradation time. The CI trends suggest that MP oxidation varies with polymer type and oxidant. The effect of oxidative aging on MP sorption capacity was also investigated using copper ions as a model inorganic constituent. Although oxidative aging introduced oxygen-containing functional groups, no statistically significant differences in copper sorption were observed between pristine and oxidized MPs, indicating that MPs can act as vectors for copper regardless of their degree of surface oxidation.