Combining Microbubbles and Ultrasound for Drug Delivery to Brain Tumors: Current Progress and Overview

Abstract

Malignant glioma is one of the most challenging central nervous system (CNS) diseases, which is typically associated with high rates of recurrence and mortality. Current surgical debulking combined with radiation or chemotherapy has failed to control tumor progression or improve glioma patient survival. Microbubbles (MBs) originally serve as contrast agents in diagnostic ultrasound but have recently attracted considerable attention for therapeutic application in enhancing blood-tissue permeability for drug delivery. MB-facilitated focused ultrasound (FUS) has already been confirmed to enhance CNS-blood permeability by temporally opening the blood-brain barrier (BBB), thus has potential to enhance delivery of various kinds of therapeutic agents into brain tumors. Here we review the current preclinical studies which demonstrate the reports by using FUS with MB-facilitated drug delivery technology in brain tumor treatment. In addition, we review newly developed multifunctional theranostic MBs for FUS-induced BBB opening for brain tumor therapy.

Acoustic Cluster Therapy (ACT) — pre-clinical proof of principle for local drug delivery and enhanced uptake

“…In brief, local US insonation of a pathologic condition (e.g. tumor) containing microbubbles in vascular compartments induces bubble oscillations (stable or inertial cavitation) which lead to a variety of biomechanical effects that enhance extravasation and distribution of drug molecules to target tissue [9][10][11][12][13][14]. This approach may hence be explored to improve on the local specificity of a drug, either co-injected with, or attached to microbubbles.…”

“…In addition, the circulation or lifetime of most microbubbles is typically on the order of 2-3 min, limiting the exposure time. Furthermore, the oscillating bubbles need to be close to the endothelial wall to maximize their biomechanical effects [14]. However, regular contrast microbubbles are quite small, and in a free flowing situation, the average distance between microbubbles and vessel wall may be too large to produce an optimal effect.…”

Acoustic Cluster Therapy (ACT) enhances the therapeutic efficacy of paclitaxel and Abraxane® for treatment of human prostate adenocarcinoma in mice

“…In recent years, several concepts for ultrasound (US) mediated, targeted drug delivery have been investigated, some with quite encouraging results [7][8][9][10][11][12]. Many of the these approaches explore the use of regular US contrast microbubbles such as Sonovue™ (Bracco Imaging S.p.A, Italy) or Optison™ (GE Healthcare AS, Norway) co-injected with various drug formulations.…”

Optimization of low-frequency low-intensity ultrasound-mediated microvessel disruption on prostate cancer xenografts in nude mice using an orthogonal experimental design

“…Although there are certain studies that have investigated microbubble parameters, including size or shell properties or ultrasound pulse parameters, including the fundamental transmission frequency, pulse repetition frequency, duty cycle, pulse length, mechanical index and acoustic peak negative acoustic pressure (8,(10)(11)(12)(13), these studies investigated few parameters simultaneously and did not investigate the different combinations of various levels of parameters. In addition, these studies focused only on the therapeutic effects of USMB, and seldom considered the damage to the skin induced by USMB.…”