Targeted brain delivery of methotrexate by glutathione PEGylated liposomes: How can the formulation make a difference?

The purpose of this study was to quantitatively investigate how conjugation of GSH to different liposomal formulations influence the brain delivery of methotrexate (MTX) in rats. GSH-PEG liposomal MTX based on hydrogenated soy phosphatidylcholine (HSPC) or egg yolk phosphatidylcholine (EYPC) and their corresponding PEG control liposomes were prepared. The brain delivery of MTX after intravenously administering free MTX, four liposomal formulations or free MTX + empty GSH-PEG-HSPC liposomes was evaluated by performing microdialysis in brain interstitial fluid and blood.

Drug delivery to retinal photoreceptors.

The photoreceptors of the retina are afflicted by diseases that still often lack satisfactory treatment options. Although suitable drugs might be available in some cases, the delivery of these compounds into the eye and across the blood-retinal barrier remains a significant challenge for therapy development. Here, we review the routes of drug administration to the retina and highlight different options for drug delivery to the photoreceptor cells.

In Vivo Quantitative Understanding of PEGylated Liposome's Influence on Brain Delivery of Diphenhydramine.

Despite the promising features of liposomes as brain drug delivery vehicles, it remains uncertain how they influence the brain uptake in vivo. In order to gain a better fundamental understanding of the interaction between liposomes and the blood-brain barrier (BBB), it is indispensable to test if liposomes affect drugs with different BBB transport properties (active influx or efflux) differently. The aim of this study was to quantitatively evaluate how PEGylated (PEG) liposomes influence brain delivery of diphenhydramine (DPH), a drug with active influx at the BBB, in rats.

Correction to: Current research into brain barriers and the delivery of therapeutics for neurological diseases: a report on CNS barrier congress London, UK, 2017.

After publication of the article [1], it has been brought to our attention that there are some errors in the formatting of names in the final version of the article.

Current research into brain barriers and the delivery of therapeutics for neurological diseases: a report on CNS barrier congress London, UK, 2017.

This is a report on the CNS barrier congress held in London, UK, March 22-23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers consisted of invited academic researchers studying the brain barriers in relation to neurological diseases and industry researchers studying new methods to deliver therapeutics to treat neurological diseases.

Treatment with penicillin G and hydrocortisone reduces ALS-associated symptoms: a case series of three patients.

Three male Caucasian patients with ALS were admitted to the hospital due to progressive dysphagia and dysarthria. During two 21-day courses of penicillin G and hydrocortisone, these patients' dysphagia and dysarthria resolved. The patient's other ALS-associated symptoms also improved, including respiratory function, coordination, walking, and muscle strength.

The Impact of Liposomal Formulations on the Release and Brain Delivery of Methotrexate: An In Vivo Microdialysis Study.

The impact of liposomal formulations on the in vivo release and brain delivery of methotrexate (MTX) was quantitatively assessed in rats. Two PEGylated liposomal MTX formulations based on hydrogenated soy phosphatidylcholine (HSPC) or egg-yolk phosphatidylcholine (EYPC) were prepared. The drug release and uptake into the brain after intravenous administration of both formulations were compared with unformulated MTX by determining the released, unbound MTX in brain and plasma using microdialysis.

Preclinical evaluation of convection-enhanced delivery of liposomal doxorubicin to treat pediatric diffuse intrinsic pontine glioma and thalamic high-grade glioma.

OBJECTIVE Pediatric high-grade gliomas (pHGGs) including diffuse intrinsic pontine gliomas (DIPGs) are primary brain tumors with high mortality and morbidity. Because of their poor brain penetrance, systemic chemotherapy regimens have failed to deliver satisfactory results; however, convection-enhanced delivery (CED) may be an alternative mode of drug delivery. Anthracyclines are potent chemotherapeutics that have been successfully delivered via CED in preclinical supratentorial glioma models.

Glutathione conjugation dose-dependently increases brain-specific liposomal drug delivery in vitro and in vivo.

The blood-brain barrier (BBB) represents a major obstacle for the delivery and development of drugs curing brain pathologies. However, this biological barrier presents numerous endogenous specialized transport systems that can be exploited by engineered nanoparticles to enable drug delivery to the brain. In particular, conjugation of glutathione (GSH) onto PEGylated liposomes (G-Technology) showed to safely enhance delivery of encapsulated drugs to the brain.

Patient-reported adverse effects of high-dose intravenous methylprednisolone treatment: a prospective web-based multi-center study in multiple sclerosis patients with a relapse.

In a prospective multi-center observational study, we evaluated the frequency, severity, and impact on activities of daily living (ADL) of adverse effects (AEs) of high-dose intravenous methylprednisolone (IVMP) in relapsing remitting multiple sclerosis (MS) patients with a relapse. Online self-report questionnaires stating IVMP's most common AEs were completed at baseline, the 2nd day of treatment, and 1 day and 1 week after treatment. Eighty-five patients were included, 66 completed the baseline questionnaire, and 59 completed at least one post-baseline questionnaire.

In vivo Functional Evaluation of Increased Brain Delivery of the Opioid Peptide DAMGO by Glutathione-PEGylated Liposomes.

Purpose: The purpose of this study was to evaluate formulation factors causing improvement in brain delivery of a small peptide after encapsulation into a targeted nanocarrier in vivo.

Methods: The evaluation was performed in rats using microdialysis, which enabled continuous sampling of the released drug in both the brain (striatum) and blood. Uptake in brain could thereby be studied in terms of therapeutically active, released drug.

Enhanced glutathione PEGylated liposomal brain delivery of an anti-amyloid single domain antibody fragment in a mouse model for Alzheimer's disease.

Treatment of neurodegenerative disorders such as Alzheimer's disease is hampered by the blood-brain barrier (BBB). This tight cerebral vascular endothelium regulates selective diffusion and active transport of endogenous molecules and xenobiotics into and out of the brain parenchyma. In this study, glutathione targeted PEGylated (GSH-PEG) liposomes were designed to deliver amyloid-targeting antibody fragments across the BBB into the brain.

Glutathione PEGylated liposomal methylprednisolone (2B3-201) attenuates CNS inflammation and degeneration in murine myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis.

Methylprednisolone (MP) pulses are the mainstay for relapse therapy in multiple sclerosis (MS). To improve the efficacy of treatment and reduce the side effects of MP, a long circulating brain-targeted formulation was developed; glutathione polyethylene glycol (PEG)ylated liposomal MP (2B3-201). Here we investigate the efficacy of 2B3-201 in murine myelin oligodendrocyte induced experimental autoimmune encephalomyelitis (MOG-EAE), an animal model mimicking inflammatory features and neurodegenerative aspects of MS.

CNS-targeted glucocorticoid reduces pathology in mouse model of amyotrophic lateral sclerosis.

Background: Hallmarks of CNS inflammation, including microglial and astrocyte activation, are prominent features in post-mortem tissue from amyotrophic lateral sclerosis (ALS) patients and in mice overexpressing mutant superoxide dismutase-1 (SOD1G93A). Administration of non-targeted glucocorticoids does not significantly alter disease progression, but this may reflect poor CNS delivery. Here, we sought to discover whether CNS-targeted, liposomal encapsulated glucocorticoid would inhibit the CNS inflammatory response and reduce motor neuron loss.

Enhanced doxorubicin delivery to the brain administered through glutathione PEGylated liposomal doxorubicin (2B3-101) as compared with generic Caelyx,(®)/Doxil(®)--a cerebral open flow microperfusion pilot study.

The neuroprotective blood-brain barrier (BBB) keeps many drug candidates below therapeutic levels in the central nervous system. Glutathione PEGylated liposomal doxorubicin (2B3-101) has been developed to safely enhance the delivery of doxorubicin to brain tumors. However, doxorubicin concentration in extracellular brain fluid cannot yet be reliably measured using conventional techniques.

Systemic treatment with glutathione PEGylated liposomal methylprednisolone (2B3-201) improves therapeutic efficacy in a model of ocular inflammation.

Purpose: Ocular inflammation is associated with the loss of visual acuity and subsequent blindness. Since their development, glucocorticoids have been the mainstay of therapy for ocular inflammatory diseases. However, the clinical benefit is limited by side effects due to the chronic use and generally high dosage that is required for effective treatment.

Glutathione pegylated liposomal methylprednisolone administration after the early phase of status epilepticus did not modify epileptogenesis in the rat.

It has been reported that glucocorticoids (GCs) can effectively control seizures in pediatric epilepsy syndromes, possibly by inhibition of inflammation. Since inflammation is supposed to be involved in epileptogenesis, we hypothesized that treatment with GCs would reduce brain inflammation and thereby modify epileptogenesis in a rat model for temporal lobe epilepsy, in which epilepsy gradually develops after electrically induced status epilepticus (SE). To prevent the severe adverse effects that are inevitable with long-term GC treatment, we used liposome nanotechnology (G-Technology(®)) to enhance the sustained delivery to the brain.

Glutathione PEGylated liposomes: pharmacokinetics and delivery of cargo across the blood-brain barrier in rats.

Partly due to poor blood-brain barrier drug penetration the treatment options for many brain diseases are limited. To safely enhance drug delivery to the brain, glutathione PEGylated liposomes (G-Technology®) were developed. In this study, in rats, we compared the pharmacokinetics and organ distribution of GSH-PEG liposomes using an autoquenched fluorescent tracer after intraperitoneal administration and intravenous administration.

Pharmacokinetics, brain delivery, and efficacy in brain tumor-bearing mice of glutathione pegylated liposomal doxorubicin (2B3-101).

Brain cancer is a devastating disease affecting many people worldwide. Effective treatment with chemotherapeutics is limited due to the presence of the blood-brain barrier (BBB) that tightly regulates the diffusion of endogenous molecules but also xenobiotics. Glutathione pegylated liposomal doxorubicin (2B3-101) is being developed as a new treatment option for patients with brain cancer.

Targeted blood-to-brain drug delivery --10 key development criteria.

Drug delivery to the brain remains challenging due to the presence of the blood-brain barrier. In this review, 10 key development criteria are presented that are important for successful drug development to treat CNS diseases by targeted drug delivery systems. Although several routes of delivery are being investigated, such as intranasal delivery, direct injections into the brain or CSF, and transient opening of the blood-brain barrier, the focus of this review is on physiological strategies aiming to target endogenous transport mechanisms.

Enhanced brain delivery of the opioid peptide DAMGO in glutathione pegylated liposomes: a microdialysis study.

Glutathione PEGylated (GSH-PEG) liposomes were evaluated for their ability to enhance and prolong blood-to-brain drug delivery of the opioid peptide DAMGO (H-Tyr-d-Ala-Gly-MePhe-Gly-ol). An intravenous loading dose of DAMGO followed by a 2 h constant rate infusion was administered to rats, and after a washout period of 1 h, GSH-PEG liposomal DAMGO was administered using a similar dosing regimen. DAMGO and GSH-PEG liposomal DAMGO were also administered as a 10 min infusion to compare the disposition of the two formulations.

Case study: to-BBB's G-Technology, getting the best from drug-delivery research with industry-academia partnerships.

To-BBB aims to develop efficacious treatments for patients with devastating neurological conditions based on to-BBB's proprietary G-Technology that safely enhances the delivery of drugs across the blood-brain barrier. Through strategic research collaborations, a small company such as to-BBB is able to deliver the high-quality research necessary to develop these novel treatments.