Biology subjects

Wilson, M. G.

Publications and source records attributed to Wilson, M. G..

6 recordsLinked to original sources

bioRxiv2023

Remotely controlled drug release in deep brain regionsof non-human primates

Many areas of science and medicine would benefit from selective release of drugs in specific regions of interest. Nanoparticle drug carriers activated by focused ultrasound--remotely applied, depth-penetrating energy--may provide such selective interventions. Here, we developed stable, ultrasound-responsive nanoparticles that can be used to release drugs effectively and safely in non-human primates. The nanoparticles were used to release propofol in deep brain visual regions. The release reversibly modulated the subjects visual choice behavior and was specific to the targeted region and to the released drug. Gadolinium-enhanced MRI imaging suggested an intact blood-brain barrier. Blood draws showed normal clinical chemistry and hematology. In summary, this study provides a safe and effective approach to release drugs on demand in selected deep brain regions at levels sufficient to modulate behavior. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=61 SRC="FIGDIR/small/561539v3_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1c4c3acorg.highwire.dtl.DTLVardef@10a5e6borg.highwire.dtl.DTLVardef@1bce636org.highwire.dtl.DTLVardef@adf9a8_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2022

Controlled delivery of ultrasound through the head for effective and safe therapies of the brain

Transcranial focused ultrasound provides noninvasive and reversible approaches for precise and personalized manipulations of brain circuits, with the potential to transform our understanding of brain function and treatments of brain dysfunction. However, the effectiveness and safety of these approaches have been limited by the human head, which attenuates and distorts ultrasound strongly and unpredictably. To address this lingering barrier, we have developed a "Relative Through-Transmit" (RTT) approach that directly measures and compensates for the attenuation and distortion of a given skull and scalp. We have implemented RTT in hardware and demonstrated that it accurately restores the operators intended intensities inside ex-vivo human skulls. Moreover, this functionality enabled effective and intensity-dependent transcranial modulation of nerves and effective release of defined doses of propofol inside the skull. RTT was essential for these new applications of transcranial ultrasound; when not applied, there were no significant differences from sham conditions. Moreover, RTT was safely applied in humans and accounted for all intervening obstacles including hair and ultrasound coupling. This method and hardware unlock the potential of ultrasound-based approaches to provide effective, safe, and reproducible precision therapies of the brain.

neuroscience↗

bioRxiv2022

Noninvasive, Systematic, and Sustained Modulation of Deep Brain Circuits in Awake Subjects

Transcranial focused ultrasound has the potential to noninvasively and systematically modulate deep brain circuits and impart sustained, neuroplastic effects in awake subjects. The intersection of these properties is critical for effective treatments of brain disorders, yet remains to be shown. Harnessing the full potential of transcranial ultrasound, we delivered 30-second stimuli into deep brain targets (left/right lateral geniculate nucleus) of non-human primates while they performed a visual discrimination task. This brief stimulation induced sustained and target-specific behavioral preference that persisted up to 15 minutes following the ultrasound offset. The polarity of the behavioral and neural effects suggested that ultrasound excited the stimulated circuits. The ultrasound was delivered into the deep brain daily for a period of more than 6 months, which enabled us to evaluate the safety of longterm stimulation. There were no detrimental effects on the animals discrimination accuracy over the course of this stimulation regimen. This study demonstrates ultrasounds capacity to condition deep brain circuits in a safe and treatment-relevant manner in awake subjects, and provides a basis for effective and safe translations into humans. HighlightsO_LITranscranial ultrasound induces effective and sustained modulation of deep brain circuits. C_LIO_LIThe deep brain modulation biases choice behavior of non-human primates. C_LIO_LIThe deep brain modulation produces sustained elevation of high gamma activity. C_LIO_LIThe stimulation, applied daily for several months, is safe. C_LI

neuroscience↗

bioRxiv2021

Effective drug release from safe ultrasound-triggered nanocarriers

Targeted delivery of medication has the promise of increasing the effectiveness and safety of current systemic drug treatments. Focused ultrasound is emerging as noninvasive and practical energy for targeted drug release. However, it has yet to be determined which nanocarriers and ultrasound parameters can provide both effective and safe release. Perfluorocarbon nanodroplets have the potential to achieve these goals, but current approaches have either been effective or safe, but not both. We found that nanocarriers with highly stable perfluorocarbon cores mediate effective drug release so long as they are activated by ultrasound of sufficiently low frequency. We demonstrate a favorable safety profile of this formulation in a non-human primate. To facilitate translation of this approach into humans, we provide an optimized method for manufacturing the nanocarriers. This study provides a recipe and release parameters for effective and safe drug release from nanoparticle carriers in the body part specified by focused ultrasonic waves.

bioengineering↗

bioRxiv2021

Gram-negative bacterial infection increases lung cancer metastasis via Toll-like receptor 1 activation and increased cancer cell proliferation post-tumor adhesion

BackgroundLung cancer is a leading cause of death partially due to high recurrence rates after surgical resection. Clinical data suggest that post-operative infections may increase the risk of recurrence. Our previous work indicated that increased adhesion of circulating tumors in the context of infection is partially responsible for this phenotype. However, cancer metastasis is a multi-step process, and it is likely that other events following tumor adhesion also play a role. MethodsIn vivo intrasplenic injection of murine lung cancer cells into wild type (WT) and Toll-like receptor 4 knockout (TLR4-/-) mice followed by cecal-ligation and puncture (CLP) as a model of post-operative infection or sham surgery were used. H&E staining and immunohistochemistry analysis of Ki67+ cells in the livers of those mice were performed. In vitro proliferation assays were performed on human lung cancer cells using combinations of TLR blockade. ResultsWe found a 5-fold increase in hepatic metastases in WT CLP mice compared to WT sham mice. TLR4-/- CLP mice had a significant decreased tumor burden compared to WT CLP mice. This indicated an important mechanistic role for the TLR4-initiated host response to gram negative infection post-tumor cell adhesion. By analyzing the livers of those mice, we observed an increase in proliferation of tumor micrometastases in vivo in WT CLP mice as compared to WT sham mice. Here again, CLP TLR4 -/- mice had significantly fewer replicating micrometastases than CLP WT mice. Indeed, we found that direct stimulation of lung cancer cells with heat-inactivated E.Coli resulted in increased proliferation of tumor growth in vitro. These effects were partially abrogated by tumor TLR4 blockade; combined TLR2, 4 and 5 blockades led to a more prominent decrease. Conditioned media from bronchoalveolar epithelial cells treated with lipopolysaccharide lead to increased lung cancer proliferation; these changes were reversed with TLR blockade, indicating that the host response to infection is TLR mediated. ConclusionsOverall, these results imply a more complex mechanistic role of post-operative infection in metastasis. From a clinical standpoint, this evidence strengthens the case for the use of TLR blockade as a potential therapeutic target in the prevention of metastasis.

cancer biology↗

bioRxiv2021

Platform for Incisionless, Focal, and Multisite Brain Interventions

MotivationTranscranial focused ultrasound brings personalized medicine to the human brain. Ultrasound can modulate neural activity or release drugs in specific neural circuits but this personalized approach requires a system that delivers ultrasound into specified targets flexibly and on command. SummaryWe developed a remote ultrasound system (Remus) that programmatically targets deep brain regions with high spatiotemporal precision and in a multi-focal manner. We validated these functions by safely modulating two deep brain nuclei--the left and right lateral geniculate nucleus-in a task-performing non-human primate. This flexible system will enable researchers and clinicians to diagnose and treat specific deep brain circuits in a noninvasive yet targeted manner, thus embodying the promise of personalized treatments of brain disorders. Animated graphical abstract: onetarget.us/download/rem.

neuroscience↗