DDRE-49. TRANSIENT OPENING OF THE BLOOD-BRAIN BARRIER BY VASOACTIVE PEPTIDES TO INCREASE CNS DRUG DELIVERY: REALITY VERSUS WISHFUL THINKING?

BACKGROUND Drug delivery to treat neurologic disease and cancers of the central nervous system (CNS) is severely limited by the blood-brain barrier (BBB). Vasoactive peptides (VAPs) such as regadenoson, adenosine, and labradimil have been shown in animal studies to transiently open the BBB, and regadenoson is currently under investigation in humans to determine if it might improve CNS drug delivery. There is currently limited information regarding the potential for other VAPs to open the BBB transiently. METHODS We performed a review of the literature evaluating the physiologic effects of vasoactive peptides on the vasculature of the brain and systemic organs. To assess the likelihood that a vasoactive peptide might transiently disrupt the BBB, we devised a four-tier classification system to organize data available in the literature which factors in alterations in BBB integrity and effects on normal brain vasculature and systemic blood vessels. This data was further sorted based on whether it comes from humans, animals, or in vitro systems. RESULTS We identified 38 VAPs with potential BBB permeability-altering properties. To date, none of these has been shown to open the BBB in humans. Thirteen VAPs increased BBB permeability in rodents. The remaining 25 had favorable physiologic effects on blood vessels but lack specific information on permeability changes to the BBB. We ranked VAPs in a four-tier ranking system related to their known physiologic actions. CONCLUSION Rodent studies document that analogs of bradykinin and adenosine transiently disrupt the BBB leading to higher chemotherapy concentrations in the CNS. VAPs remain an understudied class of drugs with the potential to increase drug delivery to the CNS. Dozens of VAPs have yet to be formally evaluated for this important clinical effect. This retrospective review summarizes the available data on VAPs highlighting agents that deserve further in vitro and in vivo investigations.

Nanotechnology Approaches for Enhanced CNS Drug Delivery in the Management of Schizophrenia

Schizophrenia is a neuropsychiatric disorder mainly affecting the central nervous system, presented with auditory and visual hallucinations, delusion and withdrawal from society. Abnormal dopamine levels mainly characterise the disease; various theories of neurotransmitters explain the pathophysiology of the disease. The current therapeutic approach deals with the systemic administration of drugs other than the enteral route, altering the neurotransmitter levels within the brain and providing symptomatic relief. Fluid biomarkers help in the early detection of the disease, which would improve the therapeutic efficacy. However, the major challenge faced in CNS drug delivery is the blood-brain barrier. Nanotherapeutic approaches may overcome these limitations, which will improve safety, efficacy, and targeted drug delivery. This review article addresses the main challenges faced in CNS drug delivery and the significance of current therapeutic strategies and nanotherapeutic approaches for a better understanding and enhanced drug delivery to the brain, which improve the quality of life of schizophrenia patients.

Trial working groups for paediatric brain tumours

Aims Children's brain tumours are the biggest cancer killer in children and young adults. Several recent developments have the potential to change the treatment of brain tumours in children. These include intra-CSF chemotherapy, ultrasound-mediated blood-brain barrier disruption, convection enhanced delivery, polymer delivery systems and electric field therapy, as well as intra-arterial and intra-nasal chemotherapy. To date, there have been very few clinical trials to evaluate any of these. The science and technology underlying these developments is not traditionally embedded within the standard paediatric neuro-oncology network. In addition, custom-built hardware, novel surgical procedures and, in some cases, the testing and licensing of implantable devices, add difficulty at the regulatory level. Method The authors participated in an international workshop funded by the charity Children with Cancer UK in 2016, where different experimental techniques aimed at optimising CNS drug delivery were discussed. Following this workshop and two subsequent workshops run by the CBTDDC (Children’s Brain Tumour Drug Delivery Consortium) in 2018 and 2020, the CBTDDC and the recently developed ITCC (Innovative Therapies for Children with Cancer) brain tumour group started working together to set up a new initiative. Called the ‘Clinical Trials Working Group for Central Nervous System Drug Delivery’, this aims to accelerate clinical trials to assess the safety and effectiveness of drug delivery devices for the treatment of paediatric brain tumours. On March 1st, 2021, CBTDDC with guest chair, Mr Kristian Aquilina (Consultant Paediatric Neurosurgeon at Great Ormond Street Hospital), hosted the first virtual meeting of this group. Results We have assembled a prestigious steering group, comprising international researchers and clinicians with expertise in diverse aspects of translational and clinical research in CNS drug delivery. At our first group meeting on March 1st, 2021, 38 leading brain tumour research scientists and clinicians from the UK, EU and US tackled the challenges head-on, with commitment and a driving passion to identify and move forwards with the most effective ways of translating drug delivery modalities into clinical trials. Attendees were split into three break-out sessions based on distinct drug delivery systems, and lots of insightful comments were collated. Conclusion The ideas generated during the 1st March meeting will help form the basis of a CBTDDC ‘Clinical Trials’ workshop in the autumn of 2021. In particular, there was an agreed consensus that a key objective will be the creation of a ‘Roadmap’ document for pre-clinical to clinical translation which would be shared with the paediatric neuro-oncology research community. CBTDDC look forward to working with steering group as we act on their recommendations to address the current challenges faced by translational drug delivery research. We present this abstract to the BNOS Annual 2021 Meeting to raise awareness of this initiative with the large number of relevant stakeholders who will be attending the event.

Permeation Challenges of Drugs for Treatment of Neurological Tuberculosis and HIV and the Application of Magneto-Electric Nanoparticle Drug Delivery Systems

The anatomical structure of the brain at the blood–brain barrier (BBB) creates a limitation for the movement of drugs into the central nervous system (CNS). Drug delivery facilitated by magneto-electric nanoparticles (MENs) is a relatively new non-invasive approach for the delivery of drugs into the CNS. These nanoparticles (NPs) can create localized transient changes in the permeability of the cells of the BBB by inducing electroporation. MENs can be applied to deliver antiretrovirals and antibiotics towards the treatment of human immunodeficiency virus (HIV) and tuberculosis (TB) infections in the CNS. This review focuses on the drug permeation challenges and reviews the application of MENs for drug delivery for these diseases. We conclude that MENs are promising systems for effective CNS drug delivery and treatment for these diseases, however, further pre-clinical and clinical studies are required to achieve translation of this approach to the clinic.

Glioblastoma therapeutic approaches were established utilizing contemporary discoveries in delivering medicines to the brain as smart nanoparticles for focused therapy

The blood-brain barrier (primary) and the blood-brain tumor barrier (secondary) are the main barriers for Glioblastoma (GBM) treatment options. Brain design is connected to a critical barrier that restricts medicine delivery to a specific brain region, leaving the rest of the brain without therapeutic chemicals. This requires moving to a different treatment strategy to reach effective therapeutic concentration in brain tumor tissue. Due to more accurate controlled release of medication to the affected area, a continual shift from standard treatment to targeted administration of medication to the brain is attracting more attention these days. GBM's therapeutic approach was established utilizing contemporary discoveries in delivering medicines to the brain as smart nanoparticles for focused therapy. Better knowledge of molecular mechanisms involved in brain targeting and receptor-based therapeutic potential can boost the therapy results. Nonetheless, the most promising technology is still under development, and continual attempts to infer the fundamental process involved in medication delivery will assist hasten nanoparticles' translation into clinical application. Furthermore, numerous complex nanoparticles, including multifunctional smart nanoparticles, have been created to overcome such challenges for CNS drug delivery and their prospective application has been clinically demonstrated or is in the trial phase.

EPCT-08. TRIAL WORKING GROUPS FOR PAEDIATRIC BRAIN TUMOURS

Introduction Brain tumours are the biggest cancer killer in children and young adults. Several recent developments have the potential to change the treatment of brain tumours in children. These include ultrasound-mediated blood-brain barrier disruption, convection enhanced delivery, polymer delivery systems and electric field therapy, as well as intra-arterial, intra-CSF and intra-nasal chemotherapy. To date, there have been very few clinical trials to evaluate any of these. The science and technology underlying these developments is not traditionally embedded within the standard paediatric neuro-oncology network. In addition, custom-built hardware, novel surgical procedures and, in some cases, the testing and licensing of implantable devices, add difficulty at the regulatory level. Methods The authors participated in an international workshop funded by the charity Children with Cancer UK in 2016, where different experimental techniques aimed at optimising CNS drug delivery were discussed. Following this workshop and two subsequent workshops run by the CBTDDC (Children’s Brain Tumour Drug Delivery Consortium) in 2018 and 2020, the CBTDDC and the recently developed ITCC (Innovative Therapies for Children with Cancer) brain tumour group started working together to set up a new initiative. This aims to develop CNS-delivery-focused trial working groups for paediatric brain tumours. Results We have assembled a prestigious steering group, comprising international researchers and clinicians with expertise in diverse aspects of translational and clinical research in CNS drug delivery. At our first group meeting in March, participants will discuss the most effective ways of translating the emerging drug delivery modalities into clinical trials. Prioritised actions will be taken forward and the group will reconvene to discuss developments and next steps at a workshop in the Autumn. Conclusion We present this abstract to the SNO Paediatric conference to raise awareness of this initiative with the large number of relevant stakeholders who will be attending the event.

Shortcut Approaches to Substance Delivery into the Brain Based on Intranasal Administration Using Nanodelivery Strategies for Insulin

The direct delivery of central nervous system (CNS) drugs into the brain after administration is an ideal concept due to its effectiveness and non-toxicity. However, the blood–brain barrier (BBB) prevents drugs from penetrating the capillary endothelial cells, blocking their entry into the brain. Thus, alternative approaches must be developed. The nasal cavity directly leads from the olfactory epithelium to the brain through the cribriform plate of the skull bone. Nose-to-brain drug delivery could solve the BBB-related repulsion problem. Recently, it has been revealed that insulin improved Alzheimer’s disease (AD)-related dementia. Several ongoing AD clinical trials investigate the use of intranasal insulin delivery. Related to the real trajectory, intranasal labeled-insulins demonstrated distribution into the brain not only along the olfactory nerve but also the trigeminal nerve. Nonetheless, intranasally administered insulin was delivered into the brain. Therefore, insulin conjugates with covalent or non-covalent cargos, such as AD or other CNS drugs, could potentially contribute to a promising strategy to cure CNS-related diseases. In this review, I will introduce the CNS drug delivery approach into the brain using nanodelivery strategies for insulin through transcellular routes based on receptor-mediated transcytosis or through paracellular routes based on escaping the tight junction at the olfactory epithelium.