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Translational Approaches for Brain Delivery of Biologics via Cerebrospinal Fluid.

ABSTRACT: Delivery of biologics via cerebrospinal fluid (CSF) has demonstrated potential to access the tissues of the central nervous system (CNS) by circumventing the blood-brain barrier and blood-CSF barrier. Developing an effective CSF drug delivery strategy requires optimization of multiple parameters, including choice of CSF access point, delivery device technology, and delivery kinetics to achieve effective therapeutic concentrations in the target brain region, whereas also considering the biologic modality, mechanism of action, disease indication, and patient population. This review discusses key preclinical and clinical examples of CSF delivery for different biologic modalities (antibodies, nucleic acid-based therapeutics, and gene therapy) to the brain via CSF or CNS access routes (intracerebroventricular, intrathecal-cisterna magna, intrathecal-lumbar, intraparenchymal, and intranasal), including the use of novel device technologies. This review also discusses quantitative models of CSF flow that provide insight into the effect of fluid dynamics in CSF on drug delivery and CNS distribution. Such models can facilitate delivery device design and pharmacokinetic/pharmacodynamic translation from preclinical species to humans in order to optimize CSF drug delivery to brain regions of interest.

SUBMITTER: Sadekar SS

PROVIDER: S-EPMC9305158 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionCerebrospinal fluid (CSF) outflow has been demonstrated along nasal lymphatics via olfactory nerve projections; flow may be increased by stimulating lymphatic contractility using agents such as noradrenaline and the thromboxane A2 analog U46619. Lymphatics elsewhere in the body show increased contractility upon exposure to the prostaglandin F2alpha analog isoprostane-8-epi-prostaglandin. We investigated the ability of ophthalmic prostaglandin F2alpha analogs to increase CSF outflow when applied to the nasal mucosa by inhalation.MethodsLatanoprost (0.1, 0.5, or 1mg/ml), bimatoprost (0.3 or 3mg/ml), travoprost (0.04 or 0.4mg/ml), latanoprostene bunod (0.24 or 2.4mg/ml), tafluprost (0.25 or 2.5mg/ml), or control vehicle (10% DMSO) was administered to awake adult C57B/6 mice by nasal inhalation of 2μl droplets. Multiday dosing (daily for 3 days) of latanoprost also was evaluated. A total of 81 animals were studied including controls. General anesthesia was induced by injection, and fluorescent tracer (AlexaFluor647-labelled ovalbumin) was injected under stereotaxic guidance into the right lateral ventricle. Nasal turbinate tissue was harvested and homogenized after 1 hour for tracer detection by ELISA and fluorometric analysis.ResultsInhalation of latanoprost 0.5mg/ml and 1mg/ml led to a 11.5-fold increase in tracer recovery from nasal turbinate tissues compared to controls (3312 pg/ml vs 288 pg/ml, p<0.001 for 0.5mg/ml; 3355 pg/ml vs 288 pg/ml, p<0.001 for 1mg/ml), while latanoprost 0.1 mg/ml enhanced recovery 6-fold (1713 pg/ml vs 288 pg/ml, p<0.01). Tafluprost 0.25mg/ml and bimatoprost 0.3mg/ml showed a modest (1.4x, p<0.05) effect, and the remaining agents showed no significant effect on tracer recovery. After 3 days of daily latanoprost treatment and several hours after the last dose, a persistently increased recovery of tracer was found.ConclusionsProstaglandin F2alpha analogs delivered by nasal inhalation resulted in increased nasal recovery of a CSF fluorescent tracer, implying increased CSF outflow via the nasal lymphatics. The greatest effect, partially dose-dependent, was observed using latanoprost. Further studies are needed to determine the efficacy of these agents in reducing ICP in short and long-term applications.

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Translational Approaches for Brain Delivery of Biologics via Cerebrospinal Fluid.

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