Delivery of chemotherapeutics across the blood-brain barrier: Challenges and advances

Nancy Doolittle, Leslie Muldoon, Aliana Y. Culp, Edward Neuwelt

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

The blood-brain barrier (BBB) limits drug delivery to brain tumors. We utilize intraarterial infusion of hyperosmotic mannitol to reversibly open the BBB by shrinking endothelial cells and opening tight junctions between the cells. This approach transiently increases the delivery of chemotherapy, antibodies, and nanoparticles to brain. Our preclinical studies have optimized the BBB disruption (BBBD) technique and clinical studies have shown its safety and efficacy. The delivery of methotrexate-based chemotherapy in conjunction with BBBD provides excellent outcomes in primary central nervous system lymphoma (PCNSL) including stable or improved cognitive function in survivors a median of 12 years (range 2-26 years) after diagnosis. The addition of rituximab to chemotherapy with BBBD for PCNSL can be safely accomplished with excellent overall survival. Our translational studies of thiol agents to protect against platinum-induced toxicities led to the development of a two-compartment model in brain tumor patients. We showed that delayed high-dose sodium thiosulfate protects against carboplatin-induced hearing loss, providing the framework for large cooperative group trials of hearing chemoprotection. Neuroimaging studies have identified that ferumoxytol, an iron oxide nanoparticle blood pool agent, appears to be a superior contrast agent to accurately assess therapy-induced changes in brain tumor vasculature, in brain tumor response to therapy, and in differentiating central nervous system lesions with inflammatory components. This chapter reviews the breakthroughs, challenges, and future directions for BBBD.

Original languageEnglish (US)
Pages (from-to)203-243
Number of pages41
JournalAdvances in Pharmacology
Volume71
DOIs
StatePublished - 2014

Fingerprint

Blood-Brain Barrier
Brain Neoplasms
Central Nervous System
Drug Therapy
Nanoparticles
Lymphoma
Ferrosoferric Oxide
Intra Arterial Infusions
Tight Junctions
Carboplatin
Mannitol
Platinum
Hearing Loss
Sulfhydryl Compounds
Neuroimaging
Methotrexate
Cognition
Contrast Media
Hearing
Survivors

Keywords

  • Blood-brain barrier
  • Blood-brain barrier disruption
  • Chemoprotection
  • Monoclonal antibody
  • Neuroimaging
  • Primary central nervous system lymphoma

ASJC Scopus subject areas

  • Pharmacology
  • Medicine(all)

Cite this

Delivery of chemotherapeutics across the blood-brain barrier : Challenges and advances. / Doolittle, Nancy; Muldoon, Leslie; Culp, Aliana Y.; Neuwelt, Edward.

In: Advances in Pharmacology, Vol. 71, 2014, p. 203-243.

Research output: Contribution to journalArticle

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