From breast cancer cell homing to the onset of early bone metastasis: The role of bone (re)modeling in early lesion formation.

Breast cancer often metastasizes to bone, causing osteolytic lesions. Structural and biophysical changes are rarely studied yet are hypothesized to influence metastasis. We developed a mouse model of early bone metastasis and multimodal imaging to quantify cancer cell homing, bone (re)modeling, and onset of metastasis. Using tissue clearing and three-dimensional (3D) light sheet fluorescence microscopy, we located enhanced green fluorescent protein-positive cancer cells and small clusters in intact bones and quantified their size and spatial distribution. We detected early bone lesions using in vivo microcomputed tomography (microCT)-based time-lapse morphometry and revealed altered bone (re)modeling in the absence of detectable lesions. With a new microCT image analysis tool, we tracked the growth of early lesions over time. We showed that cancer cells home in all bone compartments, while osteolytic lesions are only detected in the metaphysis, a region of high (re)modeling. Our study suggests that higher rates of (re)modeling act as a driver of lesion formation during early metastasis.

In vivo microCT-based time-lapse morphometry reveals anatomical site-specific differences in bone (re)modeling serving as baseline parameters to detect early pathological events.

The bone structure is very dynamic and continuously adapts its geometry to external stimuli by modeling and remodeling the mineralized tissue. In vivo microCT-based time-lapse morphometry is a powerful tool to study the temporal and spatial dynamics of bone (re)modeling. Here an advancement in the methodology to detect and quantify site-specific differences in bone (re)modeling of 12-week-old BALB/c nude mice is presented. We describe our method of quantifying new bone surface interface readouts and how these are influenced by bone curvature. This method is then used to compare bone surface (re)modeling in mice across different anatomical regions to demonstrate variations in the rate of change and spatial gradients thereof. Significant differences in bone (re)modeling baseline parameters between the metaphyseal and epiphyseal, as well as cortical and trabecular bone of the distal femur and proximal tibia are shown. These results are validated using conventional static in vivo microCT analysis. Finally, the insights from these new baseline values of physiological bone (re)modeling were used to evaluate pathological bone (re)modeling in a pilot breast cancer bone metastasis model. The method shows the potential to be suitable to detect early pathological events and track their spatio-temporal development in both cortical and trabecular bone. This advancement in (re)modeling surface analysis and defined baseline parameters according to distinct anatomical regions will be valuable to others investigating various disease models with site-distinct local alterations in bone (re)modeling.

Engineering hairy cellulose nanocrystals for chemotherapy drug capture.

Cancer is one of the leading causes of death worldwide, affecting millions of people every year. While chemotherapy remains one of the most common cancer treatments in the world, the severe side effects of chemotherapy drugs impose serious concerns to cancer patients. In many cases, the chemotherapy can be localized to maximize the drug effects; however, the drug systemic circulation induces undesirable side effects. Here, we have developed a highly efficient cellulose-based nanoadsorbent that can capture more than 6000 mg of doxorubicin (DOX), one of the most widely used chemotherapy drugs, per gram of the adsorbent at physiological conditions. Such drug capture capacity is more than 3200% higher than other nanoadsorbents, such as DNA-based platforms. We show how anionic hairy cellulose nanocrystals, also known as electrosterically stabilized nanocrystalline cellulose (ENCC), bind to positively charged drugs in human serum and capture DOX immediately without imposing any cytotoxicity and hemolytic effects. We elucidate how ENCC provides a remarkable platform for biodetoxification at varying pH, ionic strength, ion type, and protein concentration. The outcome of this research may pave the way for developing the next generation in vitro and in vivo drug capture additives and devices.

Magnetite-binding proteins from the magnetotactic bacterium Desulfamplus magnetovallimortis BW-1.

Magnetite-binding proteins are in high demand for the functionalization of magnetic nanoparticles. Binding analysis of six previously uncharacterized proteins from the magnetotactic Deltaproteobacterium Desulfamplus magnetovallimortis BW-1 identified two new magnetite-binding proteins (Mad10, Mad11). These proteins can be utilized as affinity tags for the immobilization of recombinant fusion proteins to magnetite.