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Patients with brain cancers including medulloblastoma lack treatments that are effective long‐term and without side effects. In this study, a multifunctional fluoropolymer‐engineered iron oxide nanoparticle gene‐therapeutic platform is presented to overcome these challenges. The fluoropolymers are designed and synthesized to incorporate various properties including robust anchoring moieties for efficient surface coating, cationic components to facilitate short interference RNA (siRNA) binding, and a fluorinated tail to ensure stability in serum. The blood‐brain barrier (BBB) tailored system demonstrates enhanced BBB penetration, facilitates delivery of functionally active siRNA to medulloblastoma cells, and delivers a significant, almost complete block in protein expression within an in vitro extracellular acidic environment (pH 6.7) – as favored by most cancer cells. In vivo, it effectively crosses an intact BBB, provides contrast for magnetic resonance imaging (MRI), and delivers siRNA capable of slowing tumor growth without causing signs of toxicity – meaning it possesses a safe theranostic function. The pioneering methodology applied shows significant promise in the advancement of brain and tumor microenvironment‐focused MRI‐siRNA theranostics for the better treatment and diagnosis of medulloblastoma. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an autoimmune disease involving demyelination and axonal damage in the central nervous system (CNS). In this study, we investigated pathological changes in the lumbar spinal cord of C57BL/6 mice induced with progressive experimental autoimmune encephalomyelitis (EAE) disease using 9.4‐T magnetic resonance imaging (MRI). Multiparametric MRI measurements including MR spectroscopy, diffusion tensor imaging (DTI) and volumetric analyses were applied to detect metabolic changes in the CNS of EAE mice. Compared with healthy mice, EAE mice showed a significant reduction in N‐acetyl aspartate and increases in choline, glycine, taurine and lactate. DTI revealed a significant reduction in fractional anisotropy and axial diffusivity and an increase in radial diffusivity in the lumbar spinal cord white matter (WM), while in the grey matter (GM), fractional anisotropy increased. High‐resolution structural imaging also revealed lumbar spinal cord WM hypertrophy and GM atrophy. Importantly, these MRI changes were strongly correlated with EAE disease scoring and pathological changes in the lumbar (L2–L6), particularly WM demyelination lesions and aggregation of immune cells (microglia/macrophages and astrocytes) in this region. This study identified changes in MRI biomarker signatures that can be useful for evaluating the efficacy of novel drugs using EAE models in vivo. [ABSTRACT FROM AUTHOR]

Background: Descriptions of the radiological appearance of the craniovertebral ligaments often lack detail. This study aimed to provide an accurate description of the morphology and radiological appearance of the alar and cruciform ligaments with confirmation of findings by fine dissection. Materials and Methods: Six embalmed human cadaveric specimens were reduced to an osseoligamentous arrangement spanning the C2/3 disc to the occiput. Specimens were imaged on a 4.6T Bruker magnetic resonance (MR) system using a 3D RARE multiple SE sequence with acquisition time 18 h 24 min. Acquired images were viewed in three planes, and detailed descriptions and morphometric measurement of the ligaments were obtained. Specimens were then examined and described using fine dissection. Direct comparison of the descriptions of each method was undertaken. Results: From imaging, detailed features of all alar ligaments could be identified in all specimens. Consistency in shape, orientation, and attachments is described. Attachment to the medial aspect of the atlantooccipital joints was evident in all specimens. Five of six alar ligament pairs contained fibers that traversed the dens without attachment. Ascending cruciform ligaments could be clearly identified in four of six specimens. No descending cruciform ligaments could be clearly delineated. Detailed features of the transverse ligaments could be identified and described in all planes. Dissection findings were mostly consistent with descriptions obtained from MR images. Conclusion: 4.6T MR images provide accurate detail of the structure, dimensions, and attachments of the craniovertebral ligaments. The morphology of the craniovertebral ligaments assessed radiologically was consistent with findings on gross dissection. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with extremely limited therapeutic options. One key pathological feature of ALS is the abnormal accumulation of misfolded proteins within motor neurons. Hence, reducing the burden of misfolded protein has emerged as a promising therapeutic approach. Antisense oligonucleotides (ASOs) have the potential to effectively silence proteins with gain-of-function mutations, such as superoxide dismutase 1 (SOD1). However, ASO delivery to the central nervous system (CNS) is hindered by poor blood-brain barrier (BBB) penetration and the invasiveness of intrathecal administration. In the current study, we demonstrate effective systemic delivery of a next-generation SOD1 ASO (Tofersen) into the brain of wildtype and G93A-SOD1 transgenic C57BL/6 mice using calcium phosphate lipid nanoparticles (CaP lipid NPs). We show that transcranial focused ultrasound (FUS) with intravenously administered microbubbles can significantly enhance ASO-loaded nanoparticle delivery into the mouse brain. Magnetic resonance imaging (MRI) and immunohistological analysis showed reduced SOD1 expression in the FUS-exposed brain regions and increased motor neuron count in the spinal cord of treated mice suggesting decreased motor neuron degeneration. Importantly, the BBB opening was transient without evidence of structural changes, neuroinflammation or damage to the brain tissue, indicating that the treatment is well tolerated. Overall, our results highlight FUS-assisted nanoparticle delivery of ASOs as a promising non-invasive therapeutic strategy for the treatment of ALS and CNS diseases more broadly., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

We explored the feasibility of a self-assembled chitosan nanocomposite incorporating cerium oxide/nanoceria and superparamagnetic iron oxide nanoparticles (Chit-IOCO NPs), conjugated with methotrexate (MTX) and Cy5 dye, as an integrated cancer theranostic nanosystem (Chit-IOCO-MTX-Cy5). In this system, nanoceria serves as an anti-cancer agent, while the superparamagnetic iron oxide nanoparticles function as a negative contrast agent for MR imaging. This dual metal oxide nanocomposite is conjugated with MTX which is a structural analogue of folate, serving both as a targeting mechanism for folate receptors on cancer cells and as a chemotherapeutic drug. Chit-IOCO-MTX-Cy5 exhibited exceptional negative contrast in T2 and T2∗-weighted MRI, achieving a high relaxivity of 409.5 mM⁻ 1  s⁻ 1 which is superior to clinically approved agents. The nanocomposite demonstrated both pro-oxidative and antioxidative properties, significantly increasing reactive oxygen species (ROS) production in U87MG cells (1.4-fold change), which triggered apoptosis in these cancer cells. Simultaneously, it exhibited ROS scavenging activity in non-malignant endothelial cells (0.8-fold change). Intravenous infusion of Chit-IOCO-MTX-Cy5 (5 mg/kg MTX) led to significant tumor growth inhibition, indicating a synergistic enhancement of anti-cancer effects when combining MTX and nanoceria, compared to free MTX or nanoceria without MTX conjugation. Importantly, after treatment cessation, tumours in the nanocomposite group did not re-grow, while those in the free MTX group rapidly did. In vivo MR and fluorescence imaging revealed improved uptake and retention of Chit-IOCO-MTX-Cy5 in tumours compared to nanoceria without MTX. Notably, biosafety and biochemical analyses in mice showed no significant differences between the Chit-IOCO-MTX-Cy5 treatment group and control groups., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Hang Thu Ta reports financial support was provided by 10.13039/501100000925National Health and Medical Research Council. Hang Thu Ta reports financial support was provided by 10.13039/501100001030National Heart Foundation of Australia. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Multimodal imaging provides rich biological information, which can be exploited to study drug activity, disease associated phenotypes, and pharmacological responses. Here we show discovery and validation of a new probe targeting the endocannabinoid α/β-hydrolase domain 6 (ABHD6) enzyme by utilizing positron emission tomography (PET) and matrix-assisted laser desorption/ionization (MALDI) imaging. [ 18 F]JZP-MA-11 as the first PET ligand for in vivo imaging of the ABHD6 is reported and specific uptake in ABHD6-rich peripheral tissues and major brain regions was demonstrated using PET. A proof-of-concept study in nonhuman primate confirmed brain uptake. In vivo pharmacological response upon ABHD6 inhibition was observed by MALDI imaging. These synergistic imaging efforts used to identify biological information cannot be obtained by a single imaging modality and hold promise for improving the understanding of ABHD6-mediated endocannabinoid metabolism in peripheral and central nervous system disorders.