Balbino Yagüe

Bladder cancer treatment via intravesical drug administration achieves reasonable survival rates but suffers from low therapeutic efficacy. To address the latter, self-propelled nanoparticles or nanobots have been proposed, taking advantage of their enhanced diffusion and mixing capabilities in urine when compared with conventional drugs or passive nanoparticles. However, the translational capabilities of nanobots in treating bladder cancer are underexplored. Here, we tested radiolabelled mesoporous silica-based urease-powered nanobots in an orthotopic mouse model of bladder cancer. In vivo and ex vivo results demonstrated enhanced nanobot accumulation at the tumour site, with an eightfold increase revealed by positron emission tomography in vivo. Label-free optical contrast based on polarization-dependent scattered light-sheet microscopy of cleared bladders confirmed tumour penetration by nanobots ex vivo. Treating tumour-bearing mice with intravesically administered radio-iodinated nanobots for radionuclide therapy resulted in a tumour size reduction of about 90%, positioning nanobots as efficient delivery nanosystems for bladder cancer therapy.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) requires innovative therapeutic strategies to counteract its progression and metastatic potential. Since the majority of patients are diagnosed with advanced metastatic disease, treatment strategies targeting not only the primary tumor but also metastatic lesions are needed. Tumor-Associated Macrophages (TAMs) have emerged as central players, significantly influencing PDAC progression and metastasis. Our objective was to validate an innovative therapeutic strategy involving the reprogramming of TAMs using lipid nanosystems to prevent the formation of a pro-metastatic microenvironment in the liver. RESULTS: In vitro results demonstrate that M2-polarized macrophages lose their M2-phenotype following treatment with lipid nanoemulsions composed of vitamin E and sphingomyelin (VitE:SM), transitioning to an M0/M1 state. Specifically, VitE:SM nanoemulsion treatment decreased the expression of macrophage M2 markers such as Arg1 and Egr2, while M1 markers such as Cd86, Il-1b and Il-12b increased. Additionally, the TGF-βR1 inhibitor Galunisertib (LY2157299) was loaded into VitE:SM nanoemulsions and delivered to C57BL/6 mice orthotopically injected with KPC PDAC tumor cells. Treated mice showed diminished primary tumor growth and reduced TAM infiltration in the liver. Moreover, we observed a decrease in liver metastasis with the nanoemulsion treatment in an intrasplenic model of PDAC liver metastasis. Finally, we validated the translatability of our VitE:SM nanosystem therapy in a human cell-based 3D co-culture model in vivo, underscoring the pivotal role of macrophages in the nanosystem's therapeutic effect in the context of human PDAC metastasis. CONCLUSIONS: The demonstrated effectiveness and safety of our nanosystem therapy highlights a promising therapeutic approach for PDAC, showcasing its potential in reprogramming TAMs and mitigating the occurrence of liver metastasis.

seven and fourteen days after CCH, the function of the BBB was evaluated through permeability assays by systemic administration of a cocktail containing Evans blue and Na-fluorescein tracers.In addition, the expression of zonula occludens-1 (ZO-1) and occludin was evaluated by western blot in the prefrontal cortex, ventral-and dorsal-hippocampus.CCH induced BBB dysfunction, as shown by increased BBB permeability to Evans blue and Na-fluorescein in both brain regions.CCH also decreased tight junction protein expression in the frontal cortex and hippocampus.Treatment with P4 improved the BBB function by reducing the tracers brain entry and by restoring the expression of the tight junction proteins in both brain regions.These results suggest that, in old male rats with disrupted blow-flow, P4 plays an important role in restoring BBB function, which may contribute to the neuroprotective effects that have been previously reported.