Observation of non-glandular gastritis associated with Doxil chemotherapy treatment in NSG™ mice.

NSG™ mice are highly immunocompromised thus demonstrate high efficiency engraftment of patient-derived xenografts (PDXs) for pre-clinical oncology research. It has previously been reported that NSG™ mice are hyper-sensitive to doxorubicin due to the impairment of DNA damage repair mechanisms. As such, doxorubicin causes a wide spectrum of toxicities including cardiotoxicity, hepatotoxicity and intestinal toxicity in NSG™ mice. Doxil is an alternative clinical formulation of doxorubicin, where doxorubicin is encapsulated within pegylated liposomes and displays improved toxicity profiles compared to conventional doxorubicin. Doxil was substituted for doxorubicin in our study to determine its toxicity profile in female NSG™ mice. The mice that were treated with Doxil developed dose-dependent histopathological alterations associated with non-glandular gastritis, with non-Helicobacter spp. bacterial infiltrates, as well as oesophagitis. Of note, a study using a dose of 2 mg/kg Doxil was terminated early due to significant weight loss while the use of Doxil at 1 mg/kg allowed for repeated treatment of twice a week for a duration of three weeks. A dose optimised treatment regimen has now been established and can be applied to assess Doxil-related anti-tumour efficacy in a range of PDX-bearing NSG™ mice.

A switch in mechanism of action prevents doxorubicin-mediated cardiac damage.

Cancer patients treated with doxorubicin are at risk of congestive heart failure due to doxorubicin-mediated cardiotoxicity via topoisomerase IIß poisoning. Acute cardiac muscle damage occurs in response to the very first dose of doxorubicin, however, cardioprotection has been reported after co-treatment of doxorubicin with acyloxyalkyl ester prodrugs. The aim of this study was to examine the role played by various forms of acute cardiac damage mediated by doxorubicin and determine a mechanism for the cardioprotective effect of formaldehyde-releasing prodrug AN-9 (pivaloyloxymethyl butyrate). Doxorubicin-induced cardiac damage in BALB/c mice bearing mammary tumours was established with a single dose of doxorubicin (4 or 16 mg/kg) administered alone or in combination with AN-9 (100 mg/kg). AN-9 protected the heart from doxorubicin-induced myocardial apoptosis and also significantly reduced dsDNA breaks, independent from the level of doxorubicin biodistribution to the heart. Covalent incorporation of [14C]doxorubicin into DNA showed that the combination treatment yielded significantly higher levels of formaldehyde-mediated doxorubicin-DNA adducts compared to doxorubicin alone, yet this form of damage was associated with cardioprotection from apoptosis. The cardiac transcriptomic analysis indicates that the combination treatment initiates inflammatory response signalling pathways. Doxorubicin and AN-9 combination treatments were cardioprotective, yet preserved doxorubicin-mediated anti-tumour proliferation and apoptosis in mammary tumours. This was associated with a switch in doxorubicin action from cardiac topoisomerase IIß poisoning to covalent-DNA adduct formation. Co-administration of doxorubicin and formaldehyde-releasing prodrugs, such as AN-9, may be a promising cardioprotective therapy while maintaining doxorubicin activity in primary mammary tumours.

Self-Organizing Map and Relational Perspective Mapping for the Accurate Visualization of High-Dimensional Hyperspectral Data.

We present an optimization of the toroidal self-organizing map (SOM) algorithm for the accurate visualization of hyperspectral data. This represents a significant advancement on our previous work, in which we demonstrated the use of toroidal SOMs for the visualization of time-of-flight secondary ion mass spectrometry (ToF-SIMS) imaging data. We have previously shown that the toroidal SOM can be used, unsupervised, to produce a multicolor similarity map of the analysis area, in which pixels with similar mass spectra are assigned a similar color. Here, we use an additional algorithm, relational perspective mapping (RPM), to produce more accurate visualizations of hyperspectral data. The SOM output is used as an input for the RPM algorithm, which is a nonlinear dimensionality reduction technique designed to produce a two-dimensional map of high-dimensional data. Using the topological information provided by the SOM, RPM provides complementary distance information. The result is a color scheme that more accurately reflects the local spectral distances between pixels in the data. We exemplify SOM-RPM using ToF-SIMS imaging data from a mouse tumor tissue section. The similarity maps produced are compared with those produced by two leading hyperspectral visualization techniques in the field of mass spectrometry imaging: t-distributed stochastic neighborhood embedding (t-SNE) and uniform manifold approximation and projection (UMAP). We evaluate the performance of each technique both qualitatively and quantitatively, investigating the correlations between distances in the models and distances in the data. SOM-RPM is demonstrably highly competitive with t-SNE and UMAP, according to our evaluations. Furthermore, the use of a neural network offers distinct advantages in data characterization, which we discuss. We also show how spectra extracted from regions of interest identified by SOM-RPM can be further analyzed using linear discriminant analysis for the validation and characterization of the surface chemistry.

Encapsulation of Mitoxantrone within Cucurbit[8]uril Decreases Toxicity and Enhances Survival in a Mouse Model of Cancer.

Mitoxantrone was efficiently encapsulated within cucurbit[8]uril in a 2:1 complex where the two mitoxantrone molecules were symmetrically located through both portals of a cucurbit[8]uril cage. The novel complex facilitates increased mitoxantrone uptake in mouse breast cancer cells and decreases the toxicity of the drug in healthy mice. In an orthotopic mouse model of metastatic breast cancer the complex still maintains in vivo anticancer activity compared to the free drug, yet provides a statistically significant increase in the survival of these mice compared to conventional mitoxantrone treatment. This new low toxicity formulation offers the possibility to increase mitoxantrone dose and thus maximize efficacy while managing the dose limiting side effects.