Biology subjects

Sirianni, R. W.

Publications and source records attributed to Sirianni, R. W..

6 recordsLinked to original sources

bioRxiv2026

The ultrastructure of subarachnoid trabeculae in non-human primates varies by tissue region within the central nervous system

The subarachnoid space (SAS) plays an important role in central nervous system (CNS) physiology, housing cerebrospinal fluid (CSF), providing nutrients, clearing waste, and protecting CNS tissues from injury. The SAS also contains an intricate arrangement of collagenous fibers, known as subarachnoid trabeculae, which serve as biomechanical support for the subarachnoid space and modulate the flow of CSF. Despite their myriad of roles in health and disease, the ultrastructure of trabeculae is incompletely described, with a specific gap in understanding how fiber structure varies across different regions of the CNS. In this work, we used optimized fixation techniques and scanning electron microscopy (SEM) imaging to study ultrastructural differences in trabeculae that were obtained from different regions of the nonhuman primate (NHP) brain and spinal cord. Qualitative assessments included evaluation of the relative prevalence of different kinds of fiber networks by region, leading us to a redefinition of terminology for fiber morphology. Quantitative measurements yielded dramatic differences in fiber diameter, density, and network porosity between different regions of the CNS. Broadly, trabeculae supporting cauda equina, cervical spinal cord, and exiting nerve roots were observed to have a very high density of small diameter fibers, whereas larger fibers and more complex arrangements were observed in other regions of the CNS. These data contribute to a growing field understanding of CNS-region specific differences in tissue ultrastructure.

neuroscience↗

bioRxiv2026

Solvent-free Nanoparticle Assembly Protocol (SNAP): one-pot formulation of drug loaded polyester nanoparticles and their vessel size-dependent perivascular transport

This work describes a new approach for rapid and reproducible formulation of drug loaded biodegradable nanoparticles based on polyester copolymers, including poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) and poly(caprolactone)-poly(ethylene glycol) (PCL-PEG). The new approach, termed Solvent-free Nanoparticle Assembly Protocol (SNAP), carries several advantages over conventional polyester formulation strategies, including very rapid formulation (minutes) and the ability to use nanoparticles immediately without lengthy solvent evaporation or washing steps. Altering polyester molecular weight and concentration, alongside the introduction of specific functional groups yielded precise control of nanoparticle properties, including size, shape, surface charge, drug release and loading. We examined loading of multiple therapeutic compounds, including diclofenac, loperamide, bortezomib, CT179, panobinostat, docetaxel, methotrexate, and camptothecin. The SNAP protocol facilitated the rapid production of stable, drug-loaded nanoparticles with a narrow size distribution and generally good drug loading. Using Fluorescence Resonance Energy Transfer (FRET) and size exclusion chromatography (SEC) with a focus on the model agent Rhodamine B, we were able to carefully examine stability of the nanoparticle and assess the distribution of small molecules within the polymer as well as nanoparticle stability. In vivo evaluation of fluorescently labeled nanoparticles using real-time, intravital microscopy showed that, after direct administration to cerebrospinal fluid (CSF) via the intrathecal cisterna magna (IT-CM) route, the dynamic accumulation of nanoparticles within the perivascular space (PVS) depends on the size of the vessel that is imaged. Nanoparticles accumulated steadily within the PVS of large vessels, while accumulating more slowly and exhibiting clearance from medium-sized and smaller vessels over the course of several hours. In sum, these studies present a new platform for facile production of polyester nanoparticles, demonstrate their ability to encapsulate a variety of hydrophobic small molecules, and expand our knowledge on the development of nanocarriers for intrathecal administration. Taken together, these data open new opportunities for development safer and more effective nanoparticle-based therapies.

bioengineering↗

bioRxiv2026

Ang2 and TAT targeting of leptomeningeal disease by the intravenous and intrathecal routes: a comparative analysis

Leptomeningeal disease (LD) refers to the metastasis of cells to the leptomeningeal membranes in the central nervous system (CNS), and it is a deadly complication of several different types of cancer, including breast cancer (BC) and pediatric medulloblastoma (MB). Angiopep-2 (Ang2) and transactivating transcriptional activator (TAT) peptides have been reported to transport therapeutic cargos into the CNS. Here, compared the LD-targeting capability of Ang2 vs TAT by intrathecal (intracisternal magna, ICM) vs intravenous (IV) routes of administration. We first generated two xenograft models of LD by directly infusing breast cancer cells (MDA-MB231) or medulloblastoma cells (HDMB03) via the ICM route, characterizing models for survival, tumor growth patterns, and presence of hydrocephalus. Second, we administered fluorescently labeled Ang2 or TAT peptides either IV or ICM into tumor bearing mice to examine ligand localization. We discovered that the median survival of both models was negatively related to the number of the cells infused. While HDMB03 cells tended to metastasize preferentially to the brain region, MDA-MB231 cells tended to metastasize preferentially to the spinal cord. Compared to the healthy control, MB-LD yielded a 7.3-fold increase and BC-LD a 26.5-fold increase in ventricular volume. Furthermore, targeting achieved by TAT was significantly higher than targeting achieved by Ang2 in thoracic spine for the MB-LD model. For BC-LD, TAT targeting was superiot to Ang2 in the olfactory bulbs, brain stem, thoracic spine, and lumbar spine regions. Significantly, these data provide evidence that ICM will be a preferable route of administration over IV for maximally targeting LD.

bioengineering↗

bioRxiv2026

Intrathecal infusion of hypertonic fluid enables CSF Flow Enhancement (CFE) to facilitate nanoparticle delivery to the brain and spinal cord

Intrathecal (IT) drug delivery, i.e., the infusion of substances directly into cerebrospinal fluid (CSF) by lumbar, ventricular, or cisternal access points, is one method that can be used to bypass the blood brain barrier (BBB), however, IT-administered substances also suffer from rapid turnover and poor tissue penetration. Although nanoparticles and colloids can circulate within the subarachnoid space to sustain the levels of encapsulated drug in CSF, their access to deep tissue regions remains incomplete. Here, we present a new method for enhancing CNS delivery of IT-administered nanoparticles. CSF Flow Enhancement (CFE) refers to the manipulation of CSF production, distribution, and clearance for therapeutic purposes. We tested the overarching hypothesis that infusion of hypertonic fluid adjacent to the choroid plexus would enhance fluid production and movement to improve the CNS delivery of IT-administered nanoparticles. Model polystyrene nanoparticles (100nm) were solubilized in aCSF of increasing tonicity (1-9X tonicity) and infused into the cisterna magna, after which tissues were removed to examine delivery to CNS tissues and peripheral organs. Our results demonstrate that an infusion of up to 4X hypertonic aCSF in 10uL is well tolerated and yields significant improvements in CNS localization of co-administered nanoparticles, more than doubling the delivery of nanoparticles to the ventral surfaces of the brain and sometimes dramatic (up to 10-fold) increases in delivery to specific tissue regions and surfaces of the CNS. Significantly, we provide early evidence that modulation of tonicity can define the parenchymal fate of IT administered colloids: while nanoparticles were not detected in the brain parenchyma of mice that received a standard infusion, parenchymal delivery was observed for the 2X condition, and extensive perivascular infiltration of nanoparticles was observed for the 4X condition. Lastly, we show that the delivery improvements achieved by CFE are generalizable across multiple sizes of polystyrene nanoparticle (20, 40, or 100nm). Collectively, this work describes a tonicity-based approach for achieving CFE by the intrathecal route, which we posit is a useful and potentially generalizable approach for improving CNS drug delivery.

bioengineering↗

bioRxiv2026

Nanoparticle encapsulation enhances spatial distribution of Panobinostat to treat metastatic medulloblastoma via the intrathecal route

Medulloblastoma (MB) is an aggressive central nervous system (CNS) malignancy that primarily affects children and frequently exhibits metastasis to the leptomeninges of the brain and spinal cord. We developed a {beta}-Cyclodextrin-poly({beta}-Amino Ester) nanoparticle system to deliver the histone deactylase inhibitor (HDACi) Panobinostat to MB by the intrathecal route. Various imaging methods were utilized to study nanoparticle and payload fate following infusion into the cerebrospinal fluid (CSF) of mice via cisterna magna or lumbar access points. Nanoparticles dramatically improved penetration of hydrophobic small molecules into distal regions of the spinal cord. Panobinostat-loaded nanoparticles were effective at treating patient-derived MB, activating pharmacodynamic targets, slowing growth of the primary tumor, decreasing incidence of metastasis at the time of death, and ultimately prolonging survival. These studies provide insight into the mechanisms mediating transport of colloids and therapeutic molecules in the subarachnoid space and highlight new approaches for treating metastatic disease in the CNS.

bioengineering↗

bioRxiv2026

Differential sex-dependent responses of circulating steroid hormones and cortical gene expression in a preclinical traumatic brain injury model

Accumulating evidence supports sex differences in traumatic brain injury (TBI) outcomes, however the underlying processes that lead to sex differences are not well understood. TBI results in the initiation of molecular and cellular responses that facilitate the progression of neurodegeneration. Importantly, little is known about how the circulating hormone profile is altered in response to TBI, and whether sex differences in endocrine responses might shape secondary injury pathologies. Using intact male and female mice in a preclinical TBI model, we assessed changes in plasma hormone concentrations and cortical gene expression at 24 and 72 hours after TBI. We demonstrate that males and females exhibit sex-specific alterations in circulating levels of progesterone, testosterone, androstenedione, estradiol and dehydroepiandrosterone (DHEA) in response to TBI. We also identified sex differences in the expression of genes that are involved in immune responses and tissue remodeling after injury. Moreover, we report divergent circulating hormone and gene expression correlations between sexes.

neuroscience↗