Real-Time Visualization and Quantitation of Vascular Permeability In Vivo: Implications for Drug Delivery

The leaky, heterogeneous vasculature of human tumors prevents the even distribution of systemic drugs within cancer tissues. However, techniques for studying vascular delivery systems in vivo often require complex mammalian models and time-consuming, surgical protocols. The developing chicken embryo is a well-established model for human cancer that is easily accessible for tumor imaging. To assess this model for the in vivo analysis of tumor permeability, human tumors were grown on the chorioallantoic membrane (CAM), a thin vascular membrane which overlays the growing chick embryo. The real-time movement of small fluorescent dextrans through the tumor vasculature and surrounding tissues were used to measure vascular leak within tumor xenografts. Dextran extravasation within tumor sites was selectively enhanced an interleukin-2 (IL-2) peptide fragment or vascular endothelial growth factor (VEGF). VEGF treatment increased vascular leak in the tumor core relative to surrounding normal tissue and increased doxorubicin uptake in human tumor xenografts. This new system easily visualizes vascular permeability changes in vivo and suggests that vascular permeability may be manipulated to improve chemotherapeutic targeting to tumors

Simultaneous High-Frame-Rate Acoustic Plane-Wave and Optical Imaging of Intracranial Cavitation in Polyacrylamide Brain Phantoms during Blunt Force Impact

Blunt and blast impacts occur in civilian and military personnel, resulting in traumatic brain injuries necessitating a complete understanding of damage mechanisms and protective equipment design. However, the inability to monitor in vivo brain deformation and potential harmful cavitation events during collisions limits the investigation of injury mechanisms. To study the cavitation potential, we developed a full-scale human head phantom with features that allow a direct optical and acoustic observation at high frame rates during blunt impacts. The phantom consists of a transparent polyacrylamide material sealed with fluid in a 3D-printed skull where windows are integrated for data acquisition. The model has similar mechanical properties to brain tissue and includes simplified yet key anatomical features. Optical imaging indicated reproducible cavitation events above a threshold impact energy and localized cavitation to the fluid of the central sulcus, which appeared as high-intensity regions in acoustic images. An acoustic spectral analysis detected cavitation as harmonic and broadband signals that were mapped onto a reconstructed acoustic frame. Small bubbles trapped during phantom fabrication resulted in cavitation artifacts, which remain the largest challenge of the study. Ultimately, acoustic imaging demonstrated the potential to be a stand-alone tool, allowing observations at depth, where optical techniques are limited

Mechanical characterization data of polyacrylamide hydrogel formulations and 3D printed PLA for application in human head phantoms

To study human traumatic brain injury (TBI) mechanics, a realistic surrogate must be developed for testing in impact experiments. In this data brief, materials used to simulate brain tissue and skull are characterized for application in a full-scale human head phantom. Polyacrylamide hydrogels are implemented as tissue scaffolds and tissue mimics because they are bioinert and tunable. These properties make them ideal for use as brain tissue in studies that simulate head impacts. The objective is to modify hydrogel formulations to have minimal swelling and optical clarity while maintaining properties that mimic brain tissue, such as density, viscoelastic properties, and rheological properties. Secondly, polylactic acid (PLA) polymers are 3D printed to create biomimetic skulls to enclose the hydrogel brain tissue mimic or brain phantom. PLA samples are printed and tested to determine their mechanical strength with the intention of roughly matching human skull properties. Hydrogel data was obtained with an oscillatory rheometer, while PLA samples were tested using a mechanical tester with a 3-point bend setup. The present data brief highlights several hydrogel formulations and compares them to identify the benefits of each formula and reports mechanical values of 3D printed PLA samples with 100% grid infill patterns applied in a skull model

Ultrasound-Mediated Drug/Gene Delivery in Solid Tumor Treatment

Ultrasound is an emerging modality for drug delivery in chemotherapy. This paper reviews this novel technology by first introducing the designs and characteristics of three classes of drug/gene vehicles, microbubble (including nanoemulsion), liposomes, and micelles. In comparison to conventional free drug, the targeted drug-release and delivery through vessel wall and interstitial space to cancerous cells can be activated and enhanced under certain sonication conditions. In the acoustic field, there are several reactions of these drug vehicles, including hyperthermia, bubble cavitation, sonoporation, and sonodynamics, whose physical properties are illustrated for better understanding of this approach. In vitro and in vivo results are summarized, and future directions are discussed. Altogether, ultrasound-mediated drug/gene delivery under imaging guidance provides a promising option in cancer treatment with enhanced agent release and site specificity and reduced toxicity

Noninvasive imaging of nanomedicines and nanotheranostics: principles, progress, and prospects

Noninvasive imaging is used for many different (pre)clinical purposes, ranging from disease diagnosis, disease staging, and treatment monitoring to the visualization and quantification of nanomedicine-mediated drug targeting and (triggered) drug release. Noninvasive imaging can be employed to visualize and quantify how efficient passive or active drug targeting is in individual patients and, on this basis, to preselect patients likely to respond to nanomedicine-based chemotherapeutic interventions. In addition, it can be used to visualize the off-target localization of nanomedicines, e.g., in potentially endangered healthy tissues, which under certain circumstances might lead to exclusion from targeted treatment. Moreover, by systematically integrating imaging also during follow-up and by closely monitoring therapeutic responses upon nanomedicine treatment, clinical decision making can be facilitated and improved, as decisions on whether or not to (dis)continue treatment and on whether or not to adjust drug doses can be made relatively early on. Noninvasive imaging may be particularly useful in the case of metastatic disease. By subsequently performing PET or SPECT scans with radionuclide-labeled nanomedicines, information can be obtained on the accumulation of these formulations in both primary tumors and metastases, and treatment protocols can be adapted accordingly