Image-Guided Focused-Ultrasound CNS Molecular Delivery: An Implementation via Dynamic Contrast-Enhanced Magnetic-Resonance Imaging.

Wen-Yen Chai,Hung-Wei Yang,Hsin-Yi Lai,Po-Chun Chu,Chung-Yin Lin,Hao-Li Liu,Chih-Hung Tsai

doi:10.1038/s41598-018-22571-8

Abstract

Focused ultrasound (FUS) exposure with microbubbles can transiently open the blood-brain barrier (BBB) to deliver therapeutic molecules into CNS tissues. However, delivered molecular distribution/concentration at the target need to be controlled. Dynamic Contrast-Enhanced Magnetic-Resonance Imaging (DCE-MRI) is a well-established protocol for monitoring the pharmacokinetic/pharmacodynamic behavior of FUS-BBB opening. This study investigates the feasibility of using DCE-MRI to estimate molecular CNS penetration under various exposure conditions and molecule sizes. In the 1st stage, a relationship among the imaging index Ktrans, exposure level and molecular size was calibrated and established. In the 2nd stage, various exposure levels and distinct molecules were applied to evaluate the estimated molecular concentration discrepancy with the quantified ones. High correlation (r2 = 0.9684) between Ktrans and transcranial mechanical index (MI) implies Ktrans can serve as an in vivo imaging index to mirror FUS-BBB opening scale. When testing various molecules with the size ranging 1–149 kDa, an overall correlation of r2 = 0.9915 between quantified and predicted concentrations was reached, suggesting the established model can provide reasonably accurate estimation. Our work demonstrates the feasibility of estimating molecular penetration through FUS-BBB opening via DCE-MRI and may facilitate development of FUS-induced BBB opening in brain drug delivery.

Highlights

Concentrations of therapeutic agents for delivery into the CNS
Many studies have discussed the relation between mechanical index (MI) and blood-brain barrier (BBB) opening, but so far none have addressed the feasibility of using MI as a gauge to measure concentrations of molecular substances with various molecular weights delivered into the brain following Focused ultrasound (FUS)-induced BBB opening
BBB kinetic change induced by FUS exposure was observed by dynamic contrast enhanced Magnetic resonance imaging (MRI) (DCE-MRI) image indexs, Ktrans in Fig. 2 and

Summary

Introduction

Concentrations of therapeutic agents for delivery into the CNS. This technology has recently been adopted to be applied clinically to enhance chemotherapeutic agent (Doxorubicin, Cisplatin, or Carboplatin) delivery for human malignant brain tumor treatment, and preliminarily demonstrate its feasibility[12,13,14]. Liposomal-Dox delivery with FUS significantly inhibited tumor growth compared with chemotherapy alone and improved animal survival by nearly 100% in three weekly treatment sessions[28,29] Other chemotherapeutic agents, such as 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU), Temozolomide (TMZ), Bevacizumab have been evaluated. The relationship of exposure conditions to therapeutic agent size has been largely overlooked and in-vivo MRI based predictions of the penetration rates of various molecular substances into the CNS cannot be made without sacrificing the subject animal. This study investigates the feasibility to establish a CNS drug delivery approach to estimate in vivo molecular penetration at various sizes of therapeutic agents based on DCE-MRI. Relationships between DCE-MRI index (Ktrans), ultrasound exposure level (transcranial MI), and delivered molecular concentration (molecules including Gd-DTPA (1 kDa) and Trypan blue-albumin complex (~70 kDa)) was calibrated in the 1st stage.

Methods

Results

Conclusion