Biology subjects

Babayemi, O.

Publications and source records attributed to Babayemi, O..

3 recordsLinked to original sources

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↗