Antiangiogenic therapy is widely administered in many cancers, and the antiangiogenic drug sorafenib offers moderate benefits in advanced hepatocellular carcinoma (HCC). However, antiangiogenic therapy can also lead to hypoxia-driven angiogenesis and immunosuppression in the tumor microenvironment (TME) and metastasis. Here, we report the synthesis and evaluation of NanoMnSor, a tumor-targeted, nanoparticle drug carrier that efficiently codelivers oxygen-generating MnO 2 and sorafenib into HCC. We found that MnO 2 not only alleviates hypoxia by catalyzing the decomposition of H 2 O 2 to oxygen but also enhances pH/redox-responsive T1-weighted magnetic resonance imaging and drug-release properties upon decomposition into Mn 2+ ions in the TME. Moreover, macrophages exposed to MnO 2 displayed increased mRNA associated with the immunostimulatory M1 phenotype. We further show that NanoMnSor treatment leads to sorafenib-induced decrease in tumor vascularization and significantly suppresses primary tumor growth and distal metastasis, resulting in improved overall survival in a mouse orthotopic HCC model. Furthermore, NanoMnSor reprograms the immunosuppressive TME by reducing the hypoxia-induced tumor infiltration of tumor-associated macrophages, promoting macrophage polarization toward the immunostimulatory M1 phenotype, and increasing the number of CD8 + cytotoxic T cells in tumors, thereby augmenting the efficacy of anti-PD-1 antibody and whole-cell cancer vaccine immunotherapies. Our study demonstrates the potential of oxygen-generating nanoparticles to deliver antiangiogenic agents, efficiently modulate the hypoxic TME, and overcome hypoxia-driven drug resistance, thereby providing therapeutic benefit in cancer.

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Traumatic brain injury (TBI) could result in edema and cause an increase in intracranial pressure of the brain resulting in mortality and morbidity. Although there is hyperosmolarity therapy available for this pathophysiological event, it remains controversial. Recently, several groups have shown docosahexaenoic acid (DHA) to improve functional and histological outcomes following brain injury based on reduction of neuroinflammation and apoptosis. However, the effect of DHA on blood–brain barrier (BBB) dysfunction after brain injury has not been fully studied. Here, a controlled cortical impact rat model was used to test the effect of a single dose of DHA administered 30 min post injury. Modified neurological severity score (mNSS) and forelimb asymmetry were used to determine the functional outcomes. Neuroimaging and histology were used to characterize the edema and BBB dysfunction. The study showed that DHA-treated TBI rats had better mNSS and forelimb asymmetry score than vehicle-treated TBI rats. Temporal analysis of edema using MRI revealed a significant reduction in edema level with DHA treatment compared to vehicle in TBI rats. Histological analysis using immunoglobulin G (IgG) extravasation showed that there was less extravasation, which corresponded with a reduction in aquaporin 4 and astrocytic metalloprotease 9 expression, and greater endothelial occludin expression in the peri-contusional site of the TBI rat brain treated with DHA in comparison to vehicle treatment. In conclusion, the study shows that DHA can exert its functional improvement by prevention of the edema formation via prevention of BBB dysfunction after TBI.

The selection of the appropriate hemodynamic response function (HRF) for signal modeling in functional magnetic resonance imaging (fMRI) is important. Although the use of the boxcar-shaped hemodynamic response function (BHRF) and canonical hemodynamic response (CHRF) has gained increasing popularity in rodent fMRI studies, whether the selected HRF affects the results of rodent fMRI has not been fully elucidated. Here we investigated the signal change and t -statistic sensitivities of BHRF, CHRF, and impulse response function (IRF). The effect of HRF selection on different tasks was analyzed by using data collected from two groups of rats receiving either 3 mA whisker pad or 3 mA forepaw electrical stimulations ( n = 10 for each group). Under whisker pad stimulation with large blood-oxygen-level dependent (BOLD) signal change (4.31 ± 0.42%), BHRF significantly underestimated signal changes ( P < 0.001) and t -statistics ( P < 0.001) compared with CHRF or IRF. CHRF and IRF did not provide significantly different t -statistics ( P > 0.05). Under forepaw stimulation with small BOLD signal change (1.71 ± 0.34%), different HRFs provided insignificantly different t -statistics ( P > 0.05). Therefore, the selected HRF can influence data analysis in rodent fMRI experiments with large BOLD responses but not in those with small BOLD responses.

The present study systemically investigated the influence of gated/non-gated sequences, velocity encoding (VENC), and spatial resolution on blood flow, wall shear stress (WSS), and artery area evaluations when scanning the common carotid artery (CCA) in rats using phase-contrast magnetic resonance imaging (PC-MRI). We first tested whether or not non-gated PC-MRI was appropriate for evaluating blood flow and WSS in rats. For both gated and non-gated techniques, VENC values in the range of 60-120 cm/s with an interval of 10 cm/s were also tested. Second, we optimized the inplane resolution of PC-MRI for blood flow and WSS measurements. Results showed the usage of a gated instrument can provide more reproducible assessments, whereas VENC had an insignificant influence on all hemodynamic measurements (all P > 0.05). Lower resolutions, such as 0.63 mm, led to significant overestimations in blood flow and artery area quantifications and to an underestimation in WSS measurements (all P < 0.05). However, a higher resolution of 0.16 mm slightly increased measurement variation. As a tradeoff between accuracy and scan time, we propose a gated PC-MRI sequence with a VENC of 120 cm/s and a resolution of 0.21 mm to be used to extract hemodynamic information about rat CCA.Evaluating local flow profiles in vessels is a useful means to assess cardiovascular function and physiopathological conditions 1, 2 . It is expected to gain increased popularity in both clinical routine and pre-clinical studies. Doppler ultrasound (US) and phase-contrast (PC) MRI are the methods of choice for measuring flow-related parameters. Doppler US has the advantage of better temporal resolution to capture the peak systolic blood flow velocity. However, US measurement requires considerable technical ability, and it is therefore susceptible to the operator dependency 3 . By using phase shifts in moving spins to quantify the velocity information in flowing vessels, PC-MRI enables the noninvasive assessment of blood rheology 4, 5 . Because it is user-independent and allows straightforward flow quantification, PC-MRI has had an immediate impact on various fields.The major use of PC-MRI is to provide insight into the hemodynamic characteristics of blood flow in large vessels, such as cerebral vessels and carotid arteries. By measuring and integrating flow volume from the main feeding arteries of the brain, e.g., the left/right internal carotid arteries (ICA) and the vertebral artery (VA), one can quantify whole brain cerebral blood flow (CBF) 6, 7 . Wall shear stress (WSS) is the frictional force exerted on the endothelium of vessel walls by the circulation. Prior studies have shown that common carotid arteries (CCA) with a relatively low WSS are prone to developing atherosclerosis 8 and are associated with other cerebrovascular diseases 9 . PC-MRI covers a wide range of significant applications and the derived parameters allow comparisons between normal and pathological blood flow. Optimizing the scanning parameters for PC-MRI is therefore nontrivial, and ...