Chemotherapy of glioblastoma by targeted liposomal platinum compounds with focused ultrasound.

Giloblastoma multiforme (GBM) is the most aggressive brain neoplasm, and patients have a poor prognosis after radiation and chemotherapy. The chemotherapy protocols still marginally improve the anti-tumor effect of patients with glioblastoma because the therapeutic dosage of many drugs is impeded by the blood-brain barrier (BBB). The use of liposomal drugs to GBM treatment might benefit from a more crossing of the BBB due to the lipid nature achieving higher doses of drug at the tumor sites. Human GBM-bearing mice were injected intravenously with cisplatin encapsulated in atherosclerotic plaque-specific peptide-1 (AP-1)-conjugated liposomes or unconjugated liposome. Moreover, the administration of AP-1 liposomal cisplatin (lipoplatin) followed by focused ultrasound (FUS)-induced BBB disruption. Tumor progression was monitored by biophotonic imaging. The preliminary data demonstrated that the GBM chemotherapy with AP-1 lipoplatin followed by pulsed FUS showed a modest improvement of tumor growth in the brain compared to the group treated with lipoplatin alone. Further investigations are needed to use this new targeted lipoplatin in treatment of malignancies.

Memetic algorithm for real-time combinatorial stochastic simulation optimization problems with performance analysis.

A three-phase memetic algorithm (MA) is proposed to find a suboptimal solution for real-time combinatorial stochastic simulation optimization (CSSO) problems with large discrete solution space. In phase 1, a genetic algorithm assisted by an offline global surrogate model is applied to find N good diversified solutions. In phase 2, a probabilistic local search method integrated with an online surrogate model is used to search for the approximate corresponding local optimum of each of the N solutions resulted from phase 1. In phase 3, the optimal computing budget allocation technique is employed to simulate and identify the best solution among the N local optima from phase 2. The proposed MA is applied to an assemble-to-order problem, which is a real-world CSSO problem. Extensive simulations were performed to demonstrate its superior performance, and results showed that the obtained solution is within 1% of the true optimum with a probability of 99%. We also provide a rigorous analysis to evaluate the performance of the proposed MA.

Evaluation of dose distribution of molecular delivery after blood-brain barrier disruption by focused ultrasound with treatment planning.

The permeability of the blood-brain barrier (BBB) can be enhanced by focused ultrasound (FUS) in localized regions with applications of ultrasound contrast agent (UCA). The purpose of this study was to evaluate the dose distribution of Evans blue (EB) in the targeted brain by sonication with treatment strategy. FUS exposure was applied with an ultrasound frequency of 1 MHz, a 5% duty cycle and a repetition frequency of 1 Hz. Single sonication with two doses of UCA and two sonications at the same location or an interval of 3 mm to induce BBB disruption for assessing dose distribution. The permeability of the BBB was measured quantitatively based on EB extravasation. Gadolinium deposition was monitored by contrast enhanced MR imaging for dose distribution of the focal plane. Hematoxylin and eosin staining was performed for histologic observation. No significant difference was found for EB in the focal regions between the single sonication with UCA at a dose of 300 µL/kg and repeated sonication with UCA at a lower dose of 150 µL/kg. There was a sharper dose distribution in the brain with repeated sonication at the same location, compared with the brain receiving two sonications at an interval of 3 mm. Compared with a single sonication with UCA at a dose of 150 µL/kg, the histologic evaluation of the sonicated regions indicated that more erythrocytes were seen in the brain treated with single sonication at a higher dose of 300 µL/kg or repeated sonication at a dose of 150 µL/kg. This study demonstrated that the dose distribution of molecular delivery could be regulated by sonication with treatment planning.

Prenatal exposure to diagnostic ultrasound impacts blood-brain barrier permeability in rats.

The central nervous system vasculature consists of a tightly sealed endothelium that forms the blood-brain barrier (BBB); these blood vessels are impermeable to large-molecular-size agents. The aim of this study was to determine the influence of prenatal ultrasound exposure on blood-brain barrier (BBB) integrity as measured by the permeation of Evans blue (EB) through the BBB during the postnatal development of the rat. Diagnostic levels of ultrasound (2.89 MHz, mechanical index = 1.1, acoustic output power = 70.5 mW) for 1 h and 2 h per day, for 9 consecutive days were used on Sprague-Dawley rats. Offspring were assessed postnatally on days 10, 17, 24 and 38. Our analysis of over 139 animals reveals that, when exposed to diagnostic levels of ultrasound during embryonic development, a statistically significant amount of EB extravasation into the cerebrum and cerebellum could be detected on postnatal day 10 but not later. In addition, small changes in pup body weight, cerebrum weight and cerebellum weight were observed after relatively prolonged ultrasound exposure on all postnatal days. Taken together, these results emphasize the need for further investigation of the effects of ultrasound exposure during the potentially vulnerable period of intense BBB development in the human fetus.

Microbubble-enhanced functional changes in arteries induced by pulsed high-intensity focused ultrasound exposure.

The purpose of this study is to investigate the dose-dependent effects of ultrasound contrast agent (UCA) on the changes of peak systolic velocity (PSV) and pulsatility index (PI) in the arteries of 24 male Sprague-Dawley rats. The rats were sonicated with 1.0-MHz pulsed high-intensity focused ultrasound (HIFU) at two acoustic powers, 15 W and 30 W, with UCA present at four concentrations (0, 150, 300, and 450 µL/kg). Ultrasound imaging was used to localize and to monitor the pulsed-HIFU exposure. The mean PSV of blood flow, as measured by Doppler ultrasound imaging, increased immediately in the arteries where UCA has been administrated at all four doses after pulsed-HIFU at 15 W. However, the normalized PSV change decreased with each injected dose of UCA at 30 W. Furthermore, the normalized pulsatility index changes increased as the injected dose of UCA increased at two acoustic powers. No obvious changes were found in terms of histological structures and temperature rise at the vessel wall. Our results demonstrated that the response of the artery to pulsed-HIFU was dependent on UCA dose at the same acoustic power. The value of normalized PSV change was minimal and the normalized PI change reached a maximum when the UCA dose was at the highest dose of UCA (450 µL/kg) with the two acoustic powers.

Pulsed high-intensity focused ultrasound enhances the relative permeability of the blood-tumor barrier in a glioma-bearing rat model.

The use of pulsed high-intensity focused ultrasound (HIFU) with an ultrasound contrast agent (UCA) has been shown to disrupt the blood-brain barrier (BBB) noninvasively and reversibly in the targeted regions. This study evaluated the relative permeability of the blood-tumor barrier (BTB) after sonication by pulsed HIFU. Entry into the brain of chemotherapeutic agents is impeded by the BBB even though the permeability of this barrier may be partially reduced in the presence of a brain tumor. F98 glioma-bearing rats were injected intravenously with Evans blue (EB) with or without BTB disruption induced by pulsed HIFU. Sonication was applied at an ultrasound frequency of 1 MHz with a 5% duty cycle, and a repetition frequency of 1 Hz. The accumulation of EB in brain tumor and the tumor-to-contralateral brain ratio of EB were highest after pulsed HIFU exposure. Sonication followed by EB injection showed a tumor-to-contralateral brain ratio in the target tumors which was about 2 times that of the control tumors. This research demonstrates that pulsed HIFU enhances the relative permeability of the BTB in glioma- bearing rats. The results of this pilot study support the idea that further evaluation of other treatment strategies, such as HIFU exposure in addition to combined chemotherapy or repeated pulsed HIFU exposure to increase delivery of drugs into brain tumors, might be useful.

Ultrasound enhanced delivery of macromolecular agents in brain tumor rat model.

The purpose of this study was to evaluate the permeability of the blood-brain barrier (BBB) after focused ultrasound (FUS) exposure and to investigate if such an approach increases the tumor-to-ipsilateral brain permeability ratio. Normal rats and F98 glioma-bearing rats were injected intravenously with Evans blue (EB); these treatments took place with or without BBB disruption induced by transcranial FUS of one hemisphere of the brain. Sonication was applied at an ultrasound frequency of 1 MHz with a 5% duty cycle, and a repetition frequency of 1 Hz. The permeability of the BBB was quantitatively assessed by means of the extravasation of EB. Contrast-enhanced MR images were used to monitor the gadolinium deposition path associated with transcranial FUS and the influence of size and location was also investigated. Furthermore, whole brain histological analysis was performed. The results were compared by two-tailed unpaired t test. The accumulation of EB in brains and the tumor-to-ipsilateral brain permeability ratio of EB were significantly increased after FUS exposure. EB injection followed by sonication showed an increase in the tumor-to-ipsilateral brain ratio of the target tumors of about two-fold compared with the control tumors on day 8 after tumor implantation. MR images showed that FUS locally enhances the permeability of the BBB in the glioma-bearing rats. The BBB can be locally disrupted with FUS in the presence of microbubbles. This technology may offer new opportunities that will allow enhanced synergistic effects with respect to other brain tumor treatment regimens.

Association between contrast-enhanced MR images and blood-brain barrier disruption following transcranial focused ultrasound.

PURPOSE: To investigate the correlation between the contrast-enhanced magnetic resonance imaging (MRI) signal and the duration of blood-brain barrier (BBB) disruption induced by focused ultrasound (FUS). MATERIALS AND METHODS: FUS was applied to 45 rat brains in the presence of microbubbles, and these rats were scanned on a 3T MRI system at several timepoints. The rat brains were then studied using contrast-enhanced spin echo T1-weighted images. At the same time, BBB disruption was evaluated based on Evans blue (EB) extravasation. The relationship between the normalized signal intensity change of the MRI and EB extravasation was analyzed by least-squares linear regression and the calculation of correlation coefficients. RESULTS: When MRI enhancement was quantitatively evaluated by EB extravasation, a strong correlation between the normalized signal intensity change of the MRI and EB extravasation was identified during BBB disruption after sonication. However, the correlation coefficient decreased as BBB closure occurred after sonication ended. CONCLUSION: The contrast-enhanced MRI signal can potentially be used to evaluate the amount of chemotherapeutic agents entering the targeted tissue, but the accuracy of the assessment will be affected by the time interval since sonication.

Real-time ultrasound image-monitored focal changes of the vascular function in rats by pulsed HIFU.

It has been shown that B-mode ultrasound can be useful for the real-time visualization of high-intensity focused ultrasound (HIFU) treatment. The aim of this study is to demonstrate the real-time ultrasound observation of functional changes when a vessel is exposed to pulsed-HIFU in the presence of preformed microbubbles. Using in vivo experiments, 12 male Sprague-Dawley rats were sonicated by 1-MHz pulsed-HIFU in the presence of ultrasound contrast agent (UCA) at four doses (0, 150, 300, and 450 microL/kg). The microbubbles passing through the aorta can be discerned with B-mode imaging. The mean peak systolic velocity (PSV) of the blood flow, as measured by Doppler ultrasound imaging, increased in arteries when the low-dose UCA groups (0 and 150 microL/kg) were examined after pulsed-HIFU at 45 W, but decreased when the high-dose UCA groups (300 and 450 microL/ kg) were examined. Additionally, the normalized pulsatility index (PI) changes increased with the injected dose of UCA. The interactions between ultrasound and the microbubbles can be seen to change the tissue permeability of the drug. Thus, monitoring of PSV or PI might be useful as an online method to ensure the correct sonicated position and to indicate when drug delivery has occurred.