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Delivery Across the Blood-Brain Barrier



The blood-brain barrier (BBB) and the blood cerebrospinal fluid barrier (BCSFB) exist to protect the brain, stringently regulating the passage of substances in and out. This report examines the ways in which these natural barriers may be overcome or circumvented to ensure that drugs can reach their intended target in the brain.


  • Understand the functions of the blood-brain barrier and the reasons why it presents a significant challenge in development of CNS drugs.
  • Identify the five main strategies for maximizing the delivery of drugs to the brain.
  • Understand the scientific basis of the most promising and recent technology advances.
  • Identify the companies that are at the cutting edge of each type of delivery technology.
  • Assess which types of delivery technology are best suited to which types of drug and therapy area.


  • Increasingly, drug delivery specialists are harnessing endogenous BBB mechanisms such as receptor-mediated delivery pathways with nano-enabled platform technologies to improve the uptake and targeted delivery of substances into the brain.
  • Improvements in intranasal delivery devices and advances in formulation technologies have enabled researchers to deliver a wide range of substances in therapeutic doses into the olfactory regions. Medical device companies Kurve Technology, Impel NeuroPharma, and OptiNose have all developed devices that are compatible with intranasal delivery.
  • Chemical modification (e.g. lipidation and cationization) can be used to improve passive delivery across the blood-brain barrier but is rarely used in isolation. Permeability enhancers can be used to transiently disrupt the BBB to allow the passage of drugs into the CNS, but they have yet to be fully validated in the clinic.


  • Which delivery technologies can be considered for a drug that needs to achieve high CNS penetration?
  • What types of chemical modification have been applied and how successful have these been?
  • What role can nanotechnology play in CNS drug delivery?
  • How well validated are the delivery technologies and which are supported by data from human trials?
  • Are there in indications in which the problems of blood-brain barrier penetration can be circumvented by direct injection or implantation?

Table of Contents


  • Key findings

Why the blood-brain barrier matters in drug development

  • Summary
  • Introduction
  • Delivering drugs to the brain
  • The blood-brain barrier
  • The blood cerebrospinal fluid barrier
  • Transportation across the BBB
    • Neurosurgical
    • Pharmacological and physiological
  • CNS delivery issues
    • Oral and parenteral delivery
    • Intranasal delivery

Strategies for drug delivery to the brain

  • Summary
  • Delivery of drugs across the BBB
  • Direct injection and implantation
    • Conclusions on direct injection and implantation
  • Chemical modifications
    • Lipidation
    • Cationization
    • Prodrugs
    • CNS “locked” prodrugs
    • Carrier-mediated prodrugs
    • Receptor-mediated prodrugs
    • Conclusions on chemical modifications
  • Permeability enhancers
    • Efflux transporter inhibitors
    • Conclusions on permeability enhancers
  • Nano-enabled delivery technologies
    • Liposomes
    • Case study: G-Technology (to-BBB Technologies BV)
    • Bolaamphiphiles
    • Case study: V-Smart technology (Lauren Sciences)
    • Nanoparticles
  • Receptor-mediated delivery technologies
    • Case study: EPiC technology (Angiochem)
    • Other receptor-mediated delivery technologies
  • Conclusions on nano-enabled and receptor-mediated delivery technologies
  • Intranasal delivery
    • Mechanism of intranasal delivery
    • Intranasal delivery of biopharmaceuticals
    • Intranasal formulations
    • Intranasal devices
    • Case study: POD device (Impel NeuroPharma)
    • Intranasal conclusions
  • Overall conclusions

Future outlook

  • Summary
  • Challenges and opportunities
  • Stem cell and gene therapies
    • Diamyd Medical AB
    • NsGene A/S
    • Neurologix
    • Stem cell and gene therapy conclusions
  • Overall conclusions


  • Scope
  • Methodology
    • Acknowledgements
  • Abbreviations
  • Bibliography/references
    • Chapter 1 references
    • Chapter 2 references
    • Chapter 3 references


  • Table: Products approved for intrathecal delivery
  • Table: Inhibitors of blood-brain barrier efflux transporters
  • Table: Receptor-mediated targeting ligands


  • Figure: Schematic comparison of (A) brain capillary, (B) normal capillary, and (C) capillary in choroid plexus
  • Figure: Schematic of drug transport pathways into the brain
  • Figure: Delivery strategies for brain drug delivery
  • Figure: Oral and intravenous drug profiles
  • Figure: Enhancing lipophilicity may increase CNS delivery
  • Figure: Schematic of the prodrug approach for CNS delivery
  • Figure: Chemical structures of both exogenous and endogenous LAT substrates
  • Figure: Schematic of G-Technology
  • Figure: Schematic of nose-to-brain pathways for drugs
  • Figure: Intranasal delivery devices
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