Evaluation of permeability, doxorubicin delivery, and drug retention in a rat brain tumor model after ultrasound-induced blood-tumor barrier disruption

Abstract

Drug delivery in brain tumors is challenging because of the presence of blood-brain barrier (BBB) and the blood-tumor barrier (BTB). Focused ultrasound (FUS) combined with microbubbles can enhance the permeability of the BTB in brain tumors, as well as disrupting the BBB in the surrounding tissue. In this study, dynamic contrast-enhanced Magnetic Resonance Imaging (DCE-MRI) was used to characterize FUS-induced permeability changes in a rat glioma model and in the normal brain and to investigate the relationship between these changes and the resulting concentration of the chemotherapy agent doxorubicin (DOX). 9L gliosarcoma cells were implanted in both hemispheres in male rats. At day 10–12 after implantation, FUS-induced BTB disruption using 690 kHz ultrasound and Definity microbubbles was performed in one of the tumors and in a normal brain region in each animal. After FUS, DOX was administered at a dose of 5.67 mg kg−1. The resulting DOX concentration was measured via fluorometry at 1 or 24 hours after FUS. The transfer coefficient Ktrans describing extravasation of the MRI contrast agent Gd-DTPA was significantly increased in both the sonicated tumors and in the normal brain tissue (P<0.001) between the two DCE-MRI acquisitions obtained before and after FUS, while no significant difference was found in the controls (non-sonicated tumor/normal brain tissue). DOX concentrations were also significantly larger than controls in both the sonicated tumors and in the normal tissue volumes at 1 and 24 hours after sonication. The DOX concentrations were significantly larger (P<0.01) in the control tumors harvested 1 hour after FUS than in those harvested at 24 hours, when the tumor concentrations were not significantly different than in the non-sonicated normal brain. In contrast, there was no significant difference in the DOX concentrations between the tumors harvested at 1 and 24 hours after FUS or in the concentrations measured in the brain at these time points. The transfer coefficient Ktrans for Gd-DTPA and the drug concentrations showed a good linear correlation (R2 = 0.56). Overall, these data suggest that FUS and microbubbles can not only increase DOX delivery across the BBB and BTB, but that it is retained in the tissue at significantly enhanced levels for at least 24 hours. Such enhanced retention may increase the potency of this chemotherapy agent and allow for reduced systemic doses. Furthermore, MRI-based estimates of Gd-DTPA transport across these barriers might be useful to estimate local DOX concentrations in the tumor and in the surrounding normal tissue.

Blood–brain barrier opening with focused ultrasound in experimental models of Parkinson's disease

“…This intervention has shown efficacy in delivering various compounds of different molecular weights into the brain parenchyma, including contrast agents, sugars, antibodies, chemotherapeutics, and neurotrophic factors . Aside from the direct delivery of the pharmacological agent, FUS‐facilitated viral and nonviral vector‐based gene delivery has been proven feasible to promote the long‐term expression of endogenous proteins …”

A review of potential applications of MR-guided focused ultrasound for targeting brain tumor therapy

“…The BBB and BTB may respond differently to the same dose equivalent of MRgFUS depending on the systemic treatment or tumor. In the study by Park et al, 47 DOX was able to cross the BTB at higher rates than the healthy BBB, but in another study using a similar model with BCNU, the BTB was more challenging to disrupt with MRgFUS than the BBB. 29 MRgFUS at the same dose equivalent increased delivery of BCNU into normal brain tissue by 340% in normal rats, but by only 202% in the tumor-implanted rats (p < 0.05).…”

“…29,47,59 In a rat brain glioma model of intravenous doxorubicin (DOX), Park et al reported that MRgFUS increased DOX concentrations in gliomas by more than 2.5 times at 1 hour posttreatment compared with gliomas not receiving MRg-FUS (p < 0.01). 47 At 24 hours posttreatment, DOX concentrations in gliomas with MRgFUS were almost 14 times higher than those without MRgFUS (p < 0.001). The authors also found that gliomas with MRgFUS had no sig- nificant change in DOX concentration between 1 hour and 24 hours posttreatment.…”

“…31 A risk of hemorrhage has been documented in animal models, but it is uncertain how this will translate to humans. 25,47 The only relevant study in humans is a nonrandomized, single-arm Phase 1 clinical trial (registration no. NCT02986932, clinicaltrials.gov) evaluating the safety of BBB opening with FUS in 6 patients with Alzheimer's disease.…”

Developing a Roadmap for Interventional Oncology

“…High‐intensity focused ultrasound ablation is another emerging therapeutic modality wherein noninvasive, pinpoint ablations can be performed . This modality also allows tumor regional increases in drug delivery through either selective opening of the vascular barrier or nanoparticle disruption .…”