Optimizing Oxygen-Production Kinetics of Manganese Dioxide Nanoparticles Improves Hypoxia Reversal and Survival in Mice with Bone Metastases.

Persistent hypoxia in bone metastases induces an immunosuppressive environment, limiting the effectiveness of immunotherapies. To address chronic hypoxia, we have developed manganese dioxide (MnO2) nanoparticles with tunable oxygen production kinetics for sustained oxygenation in bone metastases lesions. Using polyethylene glycol (PEG)-stabilized MnO2 or poly(lactic[50]-co-glycolic[50] acid) (50:50 PLGA), poly(lactic[75]-co-glycolic[25] acid) (75:25 PLGA), and polylactic acid (PLA)-encapsulated MnO2 NPs, we demonstrate that polymer hydrophobicity attenuates burst oxygen production and enables tunable oxygen production kinetics. The PEG-MnO2 NPs resulted in rapid hypoxia reduction in spheroids, which was rapidly attenuated, while the PLA-MnO2 NPs exhibited delayed hypoxia control in cancer spheroids. The 50:50 PLGA-MnO2 NPs exhibited the best short- and long-term control of hypoxia in cancer spheroids, resulting in sustained regulation of the expression of HIF-1α and immunosuppressive genes. The sustained control of hypoxia by the 50:50 PLGA-MnO2 NPs enhanced the cytotoxicity of natural killer cells against cancer spheroids. In vivo, 50:50 PLGA-MnO2 showed greater accumulation in the long bones and pelvis, common sites for bone metastases. The NPs decreased hypoxia in bone metastases and decreased regulatory T cell levels, resulting in enhanced survival of mice with established bone metastases.

Branched and Fenestrated Aortic Endovascular Grafts.

Endovascular repair of abdominal and descending thoracic aortic aneurysms has become the standard of care due to improvements in morbidity and mortality compared to open surgical repair. Late durability, however, remains an issue because persistent endoleaks can lead to continued aneurysm expansion and eventual rupture, sometimes years following the original repair. Branched, fenestrated, and physician-modified endografts in the thoracic arch and thoracoabdominal aorta have extended the seal zone in order to mitigate the risks of proximal and distal endoleaks. This review summarizes the current state of branched, fenestrated, and physician-modified endografts used in complex aortic pathologies.

Endovascular Management of the Ascending Aorta: State of the Art.

Endovascular stent graft repair (EVAR) has revolutionized the management of aneurysms and dissections of the thoracic and abdominal aorta and is considered the first-line treatment in such pathologies. Initially designed for patients unfit for open repair, EVAR and thoracic endovascular aortic stent graft repair are associated with improved morbidity and mortality and a faster recovery process. The endovascular revolution of the aorta continues moving proximally, with fenestrated and branch stent grafts currently in clinical trials for the management of thoracoabdominal aortic aneurysms, and several branched thoracic devices are either approved or in trial for management of aortic arch pathologies. The final frontier in the endovascular management of the aorta is the aortic root and ascending aorta. The first early feasibility trial for management of type A aortic dissection has recently concluded with a multicenter phase 2 study slated for the spring of 2023. The following article updates the reader on the unique challenges of endovascular management of the ascending aorta and a look at the future technologies that will define this space.