Focused ultrasound delivery of Raman nanoparticles across the blood-brain barrier: Potential for targeting experimental brain tumors

Abstract OBJECTIVE In neuro-oncology, it is believed that one major obstacle to effective chemotherapy is the high vascularity and heterogenous permeability of brain tumors. Focused ultrasound (FUS) exposure with the microbubbles has been shown to transiently open the blood-brain barrier (BBB) without depositing thermal energy, and thus may enhance the delivery of various therapeutic drugs into brain tumors. The aim of this study was to evaluate the BBB opening using 220-kHz transcranial MRI-guided FUS (TcMRgFUS) device and microbubbles in mouse and rat. METHODS The experiments were performed with the 220-kHz ExAblate Neuro TcMRgFUS system (InSightec) and novel lipid bubbles (LB, Teikyo Univ.). Normal mouse and rat brains were irradiated with TcMRgFUS (output power, 5W; duration of irradiation, 30 s; duty cycle 100%) following intravenous injection of 6x107 LB per mouse and rat, respectively. On irradiation, target temperature rise & cavitation signal were monitored by MR thermometry and cavitation receiver, respectively. Immediately after irradiation, BBB opening and complications were detected based on T1, T2, T2*, and Gadolinium (Gd) enhanced T1-weighted images. RESULTS The maximum temperature of brain tissue was under 42 C. There were no risky-cavitation signals causing hemorrhage. The FUS-LB exposure induced successful BBB opening effect in both mouse and rat, confirmed by Gd enhancement in the target region, lateral ventricles, and sulcus. In addition, there were no complications such as edema, coagulation, and hemorrhage. CONCLUSIONS Although there remain many conditions to be optimized, BBB opening using a 220-kHz TcMRgFUS device and LB can offer a non-invasive and feasible drug delivery for brain malignancies.

Download Full-text

Focused Ultrasound-Mediated Blood-Brain Barrier Disruption for Enhanced Drug Delivery to Brain Tumors

Neuromethods - Nanotherapy for Brain Tumor Drug Delivery ◽

10.1007/978-1-0716-1052-7_8 ◽

2020 ◽

pp. 205-223

Author(s):

Pavlos Anastasiadis ◽

Jeffrey A. Winkles ◽

Anthony J. Kim ◽

Graeme F. Woodworth

Keyword(s):

Drug Delivery ◽

Brain Tumors ◽

Blood Brain Barrier ◽

Focused Ultrasound ◽

Brain Barrier ◽

Barrier Disruption ◽

Blood Brain Barrier Disruption ◽

Blood Brain ◽

Brain Barrier Disruption

Download Full-text

Enhanced therapeutic agent delivery through magnetic resonance imaging–monitored focused ultrasound blood-brain barrier disruption for brain tumor treatment: an overview of the current preclinical status

Neurosurgical FOCUS ◽

10.3171/2011.10.focus11238 ◽

2012 ◽

Vol 32 (1) ◽

pp. E4 ◽

Cited By ~ 23

Author(s):

Hao-Li Liu ◽

Hung-Wei Yang ◽

Mu-Yi Hua ◽

Kuo-Chen Wei

Keyword(s):

Drug Delivery ◽

Brain Tumor ◽

Brain Tumors ◽

Blood Brain Barrier ◽

Focused Ultrasound ◽

Therapeutic Agent ◽

Brain Barrier ◽

Term Survival ◽

Blood Brain ◽

The Brain

Malignant glioma is a severe primary CNS cancer with a high recurrence and mortality rate. The current strategy of surgical debulking combined with radiation therapy or chemotherapy does not provide good prognosis, tumor progression control, or improved patient survival. The blood-brain barrier (BBB) acts as a major obstacle to chemotherapeutic treatment of brain tumors by severely restricting drug delivery into the brain. Because of their high toxicity, chemotherapeutic drugs cannot be administered at sufficient concentrations by conventional delivery methods to significantly improve long-term survival of patients with brain tumors. Temporal disruption of the BBB by microbubble-enhanced focused ultrasound (FUS) exposure can increase CNS-blood permeability, providing a promising new direction to increase the concentration of therapeutic agents in the brain tumor and improve disease control. Under the guidance and monitoring of MR imaging, a brain drug-delivery platform can be developed to control and monitor therapeutic agent distribution and kinetics. The success of FUS BBB disruption in delivering a variety of therapeutic molecules into brain tumors has recently been demonstrated in an animal model. In this paper the authors review a number of critical studies that have demonstrated successful outcomes, including enhancement of the delivery of traditional clinically used chemotherapeutic agents or application of novel nanocarrier designs for actively transporting drugs or extending drug half-lives to significantly improve treatment efficacy in preclinical animal models.

Download Full-text

Focused ultrasound disruption of the blood-brain barrier: a new frontier for therapeutic delivery in molecular neurooncology

Neurosurgical FOCUS ◽

10.3171/2011.10.focus11252 ◽

2012 ◽

Vol 32 (1) ◽

pp. E3 ◽

Cited By ~ 73

Author(s):

Arnold B. Etame ◽

Roberto J. Diaz ◽

Christian A. Smith ◽

Todd G. Mainprize ◽

Kullervo Hynynen ◽

...

Keyword(s):

Brain Tumors ◽

Blood Brain Barrier ◽

Focused Ultrasound ◽

Brain Barrier ◽

Therapeutic Delivery ◽

Blood Brain ◽

Dismal Prognosis ◽

New Frontier ◽

Novel Strategy ◽

The Brain

Recent advances in molecular neurooncology provide unique opportunities for targeted molecular-based therapies. However, the blood-brain barrier (BBB) remains a major limitation to the delivery of tumor-specific therapies directed against aberrant signaling pathways in brain tumors. Given the dismal prognosis of patients with malignant brain tumors, novel strategies that overcome the intrinsic limitations of the BBB are therefore highly desirable. Focused ultrasound BBB disruption is emerging as a novel strategy for enhanced delivery of therapeutic agents into the brain via focal, reversible, and safe BBB disruption. This review examines the potential role and implications of focused ultrasound in molecular neurooncology.

Download Full-text