Microbubbles (MBs) serve as a critical catalyst to amplify local cavitation in CNS capillary lumen to facilitate focused ultrasound (FUS) to transiently open the blood-brain barrier (BBB). However, limited understanding is available regarding the effect of different microbubbles to induce BBB opening. The aim of this study is to characterize different MBs on their effect in FUS-induced BBB opening. Three MBs, SonoVue, Definity, and USphere, were tested, with 0.4-MHz FUS exposure at 0.62–1.38 of mechanical index (MI) on rats. Evans blue, dynamic contrast-enhanced (DCE) MRI and small-animal ultrasound imaging were used as surrogates to allow molecule-penetrated quantification, BBB-opened observation, and MBs circulation/persistence. Cavitation activity was measured via the passive cavitation detection (PCD) setup to correlate with the exposure level and the histological effect. Under given and identical MB concentrations, the three MBs induced similar and equivalent BBB-opening effects and persistence. In addition, a treatment paradigm by adapting exposure time is proposed to compensate MB decay to retain the persistence of BBB-opening efficiency in multiple FUS exposures. The results potentially improve understanding of the equivalence among MBs in focused ultrasound CNS drug delivery, and provide an effective strategy for securing persistence in this treatment modality.

Glioblastoma multiforme (GBM) continues to have a dismal prognosis and significant efforts are being made to develop more effective treatment methods. Sonodynamic therapy (SDT) is an emerging modality for cancer treatment which combines ultrasound with sonosensitizers to produce a localized cytotoxic effect. It has long been known that ultrasound exposure can cause both thermal and non-thermal bioeffects and it remains an open question to what degree does temperature impact the efficacy of SDT. In order to optimize the ultrasound parameters of SDT, transcranial MRI-guided focused ultrasound (MRgFUS) and real-time MRI thermometry were used to monitor the therapy in a rat brain tumor model. Experiments were performed using a C6 intracranial glioma tumor model in 37 male Sprague Dawley rats. Treatments were performed about 7 days following tumor implantation when the tumor reached 1–3 mm in diameter as determined by MRI. 5-aminolevulinic acid (5-ALA) was injected at a dose of 60 mg/kg six hours before sonication. MRgFUS at 1.06 MHz was delivered continuously at an in situ spatial-peak temporal-average intensity of 5.5 W/cm² for 20 min. MR thermometry was acquired to monitor the temperature change in the brain during sonication. The tumor growth response for animals receiving 5-ALA alone, FUS alone, 5-ALA + FUS and a sham control group were evaluated with MRI every week following treatment. During 20 min of MRgFUS at 5.5 W/cm², the temperature within the targeted brain tumor was elevated from 32.3 ± 0.5 °C and 37.2 ± 0.7 °C to 33.2 ± 0.9 °C and 38.4 ± 1.1 °C, respectively. Both the tumor growth inhibition and survival were significantly improved in the 5-ALA + FUS group with 32 °C or 37 °C as the starting core body (rectal) temperature. 5-ALA alone and FUS alone did not improve survival. These promising results indicate that relatively low power continuous wave transcranial MRgFUS in conjunction with 5-ALA can produce an inhibitory effect on rat brain tumor growth in the absence of thermal dose. Further investigation of the ultrasound parameters is needed to improve the therapeutic efficacy of MRgFUS and 5-ALA.

The use of photodynamic therapy (PDT) in the treatment of brain cancer has produced exciting results in clinical trials over the past decade. PDT is based on the concept that a photosensitizer exposed to a specific light wavelength produces the predominant cytotoxic agent, to destroy tumor cells. However, delivering an efficient light source to the brain tumor site is still a challenge. The light source should be delivered by placing external optical fibers into the brain at the time of surgical debulking of the tumor. Consequently, there exists the need for a minimally invasive treatment for brain cancer PDT. In this study, we investigated an attractive non-invasive option on glioma cell line by using Tb3+-doped LaF3 scintillating nanoparticles (LaF3:Tb) in combination with photosensitizer, meso-tetra(4-carboxyphenyl)porphyrin (MTCP), followed by activation with soft X-ray (80 kVp). Scintillating LaF3:Tb nanoparticles, with sizes of approximately 25 nm, were fabricated. The particles have a good dispersibility in aqueous solution and possess high biocompatibility. However, significant cytotoxicity was observed in the glioma cells while the LaF3:Tb nanoparticles with MTCP were exposed under X-ray irradiation. The study has demonstrated a proof of concept as a non-invasive way to treat brain cancer in the future.

Leptomeningeal metastases (LM) are a serious complication of cancer in the central nervous system (CNS) and are diagnosed in approximately 5% of patients with solid tumors. Effective treatment using systemically administered therapeutics is hindered by the barriers of the CNS. Ultrasound can mediate delivery of drugs through these barriers. The goal of this study was to test the feasibility of using ultrasound-mediated drug delivery to improve the treatment of LM. LM was induced in the spinal cord of athymic rats by injecting HER2-expressing breast cancer cells into the subarachnoid space of the thoracic spine. Animals were divided into three groups: no treatment (n = 5), trastuzumab only (n = 6) or trastuzumab + focused ultrasound + microbubbles (FUS + MBs) (n = 7). Animals in groups 2 and 3 were treated weekly with intravenous trastuzumab +/− FUS + MBs for three weeks. Suppression in tumor growth was qualitatively observed by MRI in the group receiving ultrasound, and was confirmed by a significant difference in the tumor volume measured from the histology data (25 ± 17 mm³ vs 8 ± 5 mm³, p = 0.04 in the trastuzumab-only vs trastuzumab + FUS + MBs). This pilot study demonstrates the potential of ultrasound-mediated drug delivery as a novel treatment for LM. Future studies will extend this work to larger cohorts and the investigation of LM arising from other cancers.

Erythropoietin (EPO) is a neuroprotective agent against cerebral ischemia/reperfusion (I/R)-induced brain injury. However, its crossing of blood-brain barrier is limited. Focused ultrasound (FUS) sonication with microbubbles (MBs) can effectively open blood-brain barrier to boost the vascular permeability. In this study, we investigated the effects of MBs/FUS on extending the therapeutic time window of EPO and its neuroprotective effects in both acute and chronic phases. Male Wistar rats were firstly subjected to two common carotid arteries and right middle cerebral artery occlusion (three vessels occlusion, 3VO) for 50 min, and then the rats were treated with hEPO (human recombinant EPO, 5000 IU/kg) with or without MBs/FUS at 5 h after occlusion/reperfusion. Acute phase investigation (I/R, I/R+MBs/FUS, I/R+hEPO, and I/R+hEPO+MBs/FUS) was performed 24 h after I/R; chronic tests including cylinder test and gait analysis were performed one month after I/R. The experimental results showed that MBs/FUS significantly increased the cerebral content of EPO by bettering vascular permeability. In acute phase, both significant improvement of neurological score and reduction of infarct volume were found in the I/R+hEPO+MBs/FUS group, as compared with I/R and I/R+hEPO groups. In chronic phase, long-term behavioral recovery and neuronal loss in brain cortex after I/R injury was significantly improved in the I/R+hEPO+MBs/FUS group. This study indicates that hEPO administration with MBs/FUS sonication even at 5 h after occlusion/reperfusion can produce a significant neuroprotection.