Hydralazine augmented ultrasound hyperthermia for the treatment of hepatocellular carcinoma

This study investigates the use of hydralazine to enhance ultrasound hyperthermia for the treatment of hepatocellular carcinoma (HCC) by minimizing flow-mediated heat loss from the tumor. Murine HCC tumors were treated with a continuous mode ultrasound with or without an intravenous administration of hydralazine (5 mg/kg). Tumor blood flow and blood vessels were evaluated by contrast-enhanced ultrasound (CEUS) imaging and histology, respectively. Hydralazine markedly enhanced ultrasound hyperthermia through the disruption of tumor blood flow in HCC. Ultrasound treatment with hydralazine significantly reduced peak enhancement (PE), perfusion index (PI), and area under the curve (AUC) of the CEUS time-intensity curves by 91.9 ± 0.9%, 95.7 ± 0.7%, and 96.6 ± 0.5%, compared to 71.4 ± 1.9%, 84.7 ± 1.1%, and 85.6 ± 0.7% respectively without hydralazine. Tumor temperature measurements showed that the cumulative thermal dose delivered by ultrasound treatment with hydralazine (170.8 ± 11.8 min) was significantly higher than that without hydralazine (137.7 ± 10.7 min). Histological assessment of the ultrasound-treated tumors showed that hydralazine injection formed larger hemorrhagic pools and increased tumor vessel dilation consistent with CEUS observations illustrating the augmentation of hyperthermic effects by hydralazine. In conclusion, we demonstrated that ultrasound hyperthermia can be enhanced significantly by hydralazine in murine HCC tumors by modulating tumor blood flow. Future studies demonstrating the safety of the combined use of ultrasound and hydralazine would enable the clinical translation of the proposed technique.

Acoustic Remote Control of Bacterial Immunotherapy

Rapid advances in synthetic biology are driving the development of genetically engineered microbes as therapeutic agents for a multitude of human diseases, including cancer. In particular, the immunosuppressive microenvironment of solid tumors creates a favorable niche for systemically administered bacteria to engraft in the tumor and release therapeutic payloads. However, such payloads can be harmful if released in healthy tissues where the bacteria also engraft in smaller numbers. To address this limitation, we engineer therapeutic bacteria to be controlled by focused ultrasound, a form of energy that can be applied noninvasively to specific anatomical sites such as solid tumors. This control is provided by a temperature-actuated genetic state switch that produces lasting therapeutic output in response to briefly applied focused ultrasound hyperthermia. Using a combination of rational design and high-throughput screening we optimized the switching circuits of engineered cells and connected their activity to the release of immune checkpoint inhibitors. In a clinically relevant cancer model, ultrasound-activated therapeutic microbes successfully turned on in situ and induced a marked suppression of tumor growth. This technology provides a critical tool for the spatiotemporal targeting of potent bacterial therapeutics in a variety of biological and clinical scenarios.

Feasibility study of a 3D-printed personalized immobilization device integrating a patient-specific probe holder for prostate radiotherapy combined with adjuvant MR-guided transperineal ultrasound hyperthermia

The authors have requested that this preprint be removed from Research Square.

Activation Strategies in Image-Guided Nanotherapeutic Delivery

Therapeutic nanomaterials serve as an important platform for drug delivery under image guidance. Despite significant growth and broad applications, their design specifics remain a subject of continued interest primarily due to multifunctional factors involved, ranging from nanomaterial properties, imaging modalities, and therapeutic agents to activation strategies. This review article summarizes key findings on their design characteristics with a particular interest in strategies developed for therapeutic activation (release). First, their activation can be controlled using either an endogenous factor including low pH and glutathione or an external stimulation by light, ultrasound, or electromagnetic field. The former is passively controlled from a spatiotemporal aspect compared to the latter, which is otherwise actively controlled through drug linker photolysis, nanomaterial disassembly, or gate opening. Second, light stimulation serves a most notable strategy due to its essential role in controlled drug release, photothermal activation (hyperthermia), and photodynamic production of reactive oxygen species (ROS). Third, some of those activation strategies that rely on ultrasound, photothermal, photoacoustic, magnetic field, or X-ray radiation are dually functional due to their role in imaging modalities. In summary, this review article presents recent advances and new insights that pertain to nanotherapeutic delivery systems. It also addresses their technical limitations associated with tissue penetration (light), spatial resolution (ultrasound, hyperthermia), and occurrence of cellular resistance (ROS).