Novel magnetic/ultrasound focusing system enhances nanoparticle drug delivery for glioma treatment

Abstract

Malignant glioma is a common and severe primary brain tumor with a high recurrence rate and an extremely high mortality rate within 2 years of diagnosis, even when surgical, radiological, and chemotherapeutic interventions are applied. Intravenously administered drugs have limited use because of their adverse systemic effects and poor blood-brain barrier penetration. Here, we combine 2 methods to increase drug delivery to brain tumors. Focused ultrasound transiently permeabilizes the blood-brain barrier, increasing passive diffusion. Subsequent application of an external magnetic field then actively enhances localization of a chemotherapeutic agent immobilized on a novel magnetic nanoparticle. Combining these techniques significantly improved the delivery of 1,3-bis(2-chloroethyl)-1-nitrosourea to rodent gliomas. Furthermore, the physicochemical properties of the nanoparticles allowed their delivery to be monitored by magnetic resonance imaging (MRI). The resulting suppression of tumor progression without damaging the normal regions of the brain was verified by MRI and histological examination. This noninvasive, reversible technique promises to provide a more effective and tolerable means of tumor treatment, with lower therapeutic doses and concurrent clinical monitoring.

In vivo MR quantification of superparamagnetic iron oxide nanoparticle leakage during low‐frequency‐ultrasound‐induced blood–brain barrier opening in swine

“…Also, because SPIO nanoparticles respond to external magnetic forces, magnetic targeting can actively enhance their deposition at the target site, increasing the therapeutic dose delivered beyond that obtainable by passive diffusion into BBB-disrupted regions. It has been demonstrated that conjugating SPIO with a chemotherapeutic agent can treat brain tumors in rodents (34,35). SPIO proved effective both as an image indicator (to identify distribution of chemotherapeutic drugs after BBB disruption) and as a means of increasing treatment efficacy when used in conjunction with magnetic targeting.…”

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

“…Similar conclusions were found when using BCNU. 10 , significance not reported). Results from low-and high-dose MNPs demonstrated that this effect was dose dependent.…”

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

“…6). 8 However, for groups receiving high-dose therapeutic MNPs (equivalent to 5 mg/kg of BCNU), tumor volumes were suppressed in the 1st week, both with and without applying FUS/magnetic targeting (-52% and -97%, respectively). The medium dose (equivalent to 1 mg/kg BCNU) appeared to represent the critical dose for suppression of tumor growth when FUS/magnetic targeting is applied (-79%), but tumors progressed in the sham group (296%).…”

“…2A) for treatment of gliomas has also been investigated to determine the optimal enhancement conditions. 8 Normal/ glioma rats were subjected to various treatments to compare their efficacy in delivering localized concentrations of nanoparticles to a specific region of the brain. Quantitative inductively coupled plasma optical emission spectrometry analysis of Fe content revealed that FUS alone or magnetic targeting alone only increased therapeutic MNP concentrations by 2-fold relative to the untreated brain.…”

“…These findings suggested that MNPs alone do not cause severe immune activity, but the cytotoxic effect of the therapeutic MNPs causes tumor cell death and induces increased macrophage infiltration for the clearance of the necrotic tumor debris as well as the Fe particles. 8 When summarizing the dosing comparison (Fig. 6), treatment with an effective BCNU dose of 5 mg/kg even without FUS/magnetic targeting was more effective at shrinking tumors than treatment with unbound BCNU at a dose of 13.5 mg/kg, 8 showing an enhanced permeability and retention effect for immobilized chemotherapy drugs on MNPs.…”