Modeling localized delivery of Doxorubicin to the brain following focused ultrasound enhanced blood-brain barrier permeability

• Published in: Physics in medicine & biology 2014-10, Vol.59 (20), p.5987-6004
• Main Authors: Nhan, Tam, Burgess, Alison, Lilge, Lothar, Hynynen, Kullervo
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; BBB opening; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - radiation effects; Capillary Permeability; doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - pharmacokinetics; Drug Delivery Systems - methods; focused ultrasound; Humans; modeling; Models, Biological; Sonication - methods
• ISSN: 0031-9155; 1361-6560
• DOI: 10.1088/0031-9155/59/20/5987

Doxorubicin (Dox) is a well-established chemotherapeutic agent, however it has limited efficacy in treating brain malignancies due to the presence of the blood-brain barrier (BBB). Recent preclinical studies have demonstrated that focused ultrasound induced BBB disruption (BBBD) enables efficient delivery of Dox to the brain. For future treatment planning of BBBD-based drug delivery, it is crucial to establish a mathematical framework to predict the effect of transient BBB permeability enhancement on the spatiotemporal distribution of Dox at the targeted area. The constructed model considers Dox concentrations within three compartments (plasma, extracellular, intracellular) that are governed by various transport processes (e.g. diffusion in interstitial space, exchange across vessel wall, clearance by cerebral spinal fluid, uptake by brain cells). By examining several clinical treatment aspects (e.g. sonication scheme, permeability enhancement, injection mode), our simulation results support the experimental findings of optimal interval delay between two consecutive sonications and therapeutically-sufficient intracellular concentration with respect to transfer constant Ktrans range of 0.01-0.03 min−1. Finally, the model suggests that infusion over a short duration (20-60 min) should be employed along with single-sonication or multiple-sonication at 10 min interval to ensure maximum delivery to the intracellular compartment while attaining minimal cardiotoxicity via suppressing peak plasma concentration.