69 research outputs found
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
Targeted microbubbles carrying lipid-oil-nanodroplets for ultrasound-triggered delivery of the hydrophobic drug, Combretastatin A4
The hydrophobicity of a drug can be a major challenge in its development and prevents the clinical translation of highly potent anti-cancer agents. We have used a lipid-based nanoemulsion termed Lipid-Oil-Nanodroplets (LONDs) for the encapsulation and in vivo delivery of the poorly bioavailable combretastatin A4 (CA4). Drug delivery with CA4 LONDs was assessed in a xenograft model of colorectal cancer. LC–MS/MS analysis revealed that CA4 LONDs, administered at a drug dose four times lower than drug control, achieved equivalent concentrations of CA4 intratumorally. We then attached CA4 LONDs to microbubbles (MBs) and targeted this construct to VEGFR2. A reduction in tumor perfusion was observed in CA4 LONDs-MBs treated tumors. A combination study with irinotecan demonstrated a greater reduction in tumor growth and perfusion (P = 0.01) compared to irinotecan alone. This study suggests that LONDs, either alone or attached to targeted MBs, have the potential to significantly enhance tumor-specific hydrophobic drug delivery
Control over Silica Particle Growth and Particle–Biomolecule Interactions Facilitates Silica Encapsulation of Mammalian Cells with Thickness Control
Over
the past 20 years, many strategies utilizing sol–gel
chemistry to integrate biological cells into silica-based materials
have been reported. One such strategy, Sol-Generating Chemical Vapor
into Liquid (SG-CViL) deposition, shows promise as an efficient encapsulation
technique due to the ability to vary the silica encapsulation morphology
obtained by this process through variation of SG-CViL reaction conditions.
In this report, we develop SG-CViL as a tunable, multi-purpose silica
encapsulation strategy by investigating the mechanisms governing both
silica particle generation and subsequent interaction with phospholipid
assemblies (liposomes and living cells). Using Dynamic Light Scattering
(DLS) measurements, linear and exponential silica particle growth
dynamics were observed which were dependent on deposition buffer ion
constituents and ion concentration. Silica particle growth followed
a cluster–cluster growth mechanism at acidic pH, and a monomer-cluster
growth mechanism at neutral to basic pH. Increasing silica sol aging
temperature resulted in higher rates of particle growth and larger
particles. DLS measurements employing PEG-coated liposomes and cationic
liposomes, serving as model phospholipid assemblies, revealed that
electrostatic interactions promote more stable liposome–silica
interactions than hydrogen bonding and facilitate silica coating on
suspension cells. However, continued silica reactivity leads to aggregation
of silica-coated suspension cells, revealing the need for cell isolation
to tune deposited silica thickness. Utilizing these mechanistic study
insights, silica was deposited onto adherent HeLa cells under biocompatible
conditions with micrometer-scale control over silica thickness, minimal
cell manipulation steps, and retained cell viability over several
days
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
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