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IntroductionIschemic stroke is a devastating neurovascular condition that occurs when cerebral tissue fails to receive an adequate supply of oxygen. Despite being a leading cause of death and disability worldwide, therapeutic interventions are currently limited. Polyamidoamine (PAMAM) dendrimers are nanomolecules commonly used in biomedical applications due to their ability to encapsulate small-molecules and improve their pharmacokinetic properties. Curcumin is known to have anti-inflammatory and antioxidant effects yet suffers from poor solubility and bioavailability. The purpose of this study is to investigate the efficacy of curcumin encapsulated in PAMAM dendrimers as a potential therapeutic treatment for ischemic stroke by studying post-stroke lesion size, astrocyte reactivity, and functional recovery in a rat model of cerebral ischemia.MethodsForty-eight male and female Sprague-Dawley rats (280–380 g) underwent either a 90-min middle cerebral artery occlusion (MCAo) or sham surgery before receiving one of four treatments: (1) Hanks’ balanced salt solution (HBSS) control, (2) empty dendrimer control, (3) curcumin control, or (4) curcumin encapsulated in PAMAM dendrimer. Neurobehavioral outcomes were evaluated at 1-, 3-, 5-, and 7-day post-surgery, after which animals were euthanized on day 8 to assess infarct volume and GFAP immunoreactivity.ResultsAnimals that received formulations containing dendrimers (curcumin encapsulated in dendrimers or empty dendrimers) demonstrated significantly lower levels of GFAP immunoreactivity and improved functional recovery, including weight and neurobehavioral scores, compared to the formulations that did not contain dendrimers (curcumin and HBSS control). Additionally, the dendrimer-curcumin treatment group exhibited a significantly improved paw laterality index over the course of the study compared with the other three treatment groups.ConclusionAlthough the post-stroke administration of curcumin encapsulated in PAMAM dendrimers modulates the astrocytic response and promotes functional recovery following ischemic stroke in rats, its therapeutic benefits may be driven by PAMAM dendrimers as the empty dendrimer treatment group also showed significant improvements post-stroke. Further investigation regarding PAMAM dendrimers in treating neuroinflammatory conditions remains warranted.

It is crucial to inhibit the neuroinflammation response as it is a prominent factor contributing to the pathogenesis of neurodegenerative disorders. However, the limited development of neuroinflammation models dramatically hinders the efficiency of nanomedicine discovery. In recent years, the optically transparent zebrafish model provided unique advantages for in vivo imaging of the whole body, allowing the progression of the disease to be visualized. In this study, a lipopolysaccharide (LPS)-mediated zebrafish neuroinflammation model was established to visualize the brain distribution and quickly evaluate the anti-inflammation effect of human ferritin-loaded curcumin (Cur@HFn) nanoparticles. The Cur@HFn drug delivery system was successfully prepared and characterized. The HFn nanocage demonstrated significant brain accumulation and prolonged circulation in a zebrafish larval model. In the LPS-induced zebrafish model, Cur@HFn significantly reduced neutrophil recruitment within the brain region of the LPS-treated zebrafish. Additionally, Cur@HFn mitigated nitric oxide (NO) release and downregulated the mRNA expression levels of proinflammatory cytokines, including TNF-α and IL-1β. Lastly, Cur@HFn significantly reduced the damage of raphe nucleus neurons and alleviated the locomotion deficiency caused by LPS. Overall, our findings highlight that Cur@HFn is a promising drug delivery system for the targeted treatment of brain disorders. This zebrafish neuroinflammation model could be used for high-throughput in vivo drug screening and discovery.

Purpose: In brain tumors, disruption of the blood-brain barrier (BBB) indicates malignancy. Clinical assessment is qualitative; quantitative evaluation is feasible using the K 2 leakage parameter from dynamic susceptibility contrast MRI. However, contrast agent-based techniques are limited in patients with renal dysfunction and insensitive to subtle impairments. Assessing water transport times across the BBB (T ex ) by multi-echo arterial spin labeling promises to detect BBB impairments noninvasively and potentially more sensitively. We hypothesized that reduced T ex indicates impaired BBB. Furthermore, we assumed higher sensitivity for T ex than dynamic susceptibility contrast-based K 2 , because arterial spin labeling uses water as a freely diffusible tracer., Methods: We acquired 3T MRI data from 28 patients with intraparenchymal brain tumors (World Health Organization Grade 3 & 4 gliomas [n = 17] or metastases [n = 11]) and 17 age-matched healthy controls. The protocol included multi-echo and single-echo Hadamard-encoded arterial spin labeling, dynamic susceptibility contrast, and conventional clinical imaging. T ex was calculated using a T 2 -dependent multi-compartment model. Areas of contrast-enhancing tissue, edema, and normal-appearing tissue were automatically segmented, and parameter values were compared across volumes of interest and between patients and healthy controls., Results: T ex was significantly reduced (-20.3%) in contrast-enhancing tissue compared with normal-appearing gray matter and correlated well with |K 2 | (r = -0.347). Compared with healthy controls, T ex was significantly lower in tumor patients' normal-appearing gray matter (T ex,tumor  = 0.141 ± 0.032 s vs. T ex,HC  = 0.172 ± 0.036 s) and normal-appearing white matter (T ex,tumor  = 0.116 ± 0.015 vs. T ex,HC  = 0.127 ± 0.017 s), whereas |K 2 | did not differ significantly. Receiver operating characteristic analysis showed a larger area under the curve for T ex (0.784) than K 2 (0.604)., Conclusion: T ex is sensitive to pathophysiologically impaired BBB. It agrees with contrast agent-based K 2 in contrast-enhancing tissue and indicates sensitivity to subtle leakage., (© 2025 The Author(s). Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

The blood-brain barrier (BBB) remains a major obstacle for effective delivery of therapeutics to treat central nervous system (CNS) disorders. Although transferrin receptor (TfR)-mediated transcytosis is widely employed for brain drug delivery, the inefficient release of therapeutic payload hinders their efficacy from crossing the BBB. Here, we developed a pH-responsive anti-polyethylene glycol (PEG) × anti-TfR bispecific antibody (pH-PEG engager TfR ) that can complex with PEGylated nanomedicine at physiological pH to trigger TfR-mediated transcytosis in the brain microvascular endothelial cells, while rapidly dissociating from PEGylated nanomedicine at acidic endosomes for efficient release of PEGylated nanomedicine to cross the BBB. The pH-PEG engager TfR significantly increased the accumulation of PEGylated nanomedicine in the mouse brain compared to wild-type PEG engager TfR (WT-PEG engager TfR ). pH-PEG engager TfR -decorated PEGylated liposomal doxorubicin exhibited an enhanced antitumor effect and extended survival in a human glioblastoma (GBM) orthotopic xenograft mice model. Conditional release of PEGylated nanomedicine during BBB-related receptor-mediated transcytosis by pH-PEG engager TfR is promising for enhanced brain drug delivery to treat CNS disorders.