Breast cancer is not a single disease, but is instead a collection of diseases that have distinct histopathological features, genetic and genomic variability, and diverse prognostic outcomes. Thus, no individual model would be expected to completely recapitulate this complex disease. Here, the models commonly used to investigate breast cancer including cell lines, xenografts and genetically engineered mice, are discussed to help address the question: what is the most powerful way to investigate this heterogeneous disease?

We developed a rodent model that mimics the osteoblastic and osteolytic changes associated with human metastatic prostate cancer. Microarray analysis identified MMP-7, cathepsin-K, and apolipoprotein D as being upregulated at the tumor-bone interface. MMP-7, which was produced by osteoclasts at the tumor-bone interface, was capable of processing RANKL to a soluble form that promoted osteoclast activation. MMP-7-deficient mice demonstrated reduced prostate tumor-induced osteolysis and RANKL processing. This study suggests that inhibition of MMP-7 will have therapeutic benefit in the treatment of prostate cancer-induced osteolysis.

Computed tomography enables 3D anatomic imaging at a high spatial resolution, but requires delivery of an x-ray contrast agent to distinguish tissues with similar or low x-ray attenuation. Gold nanoparticles (AuNPs) have gained recent attention as an x-ray contrast agent due to exhibiting a high x-ray attenuation, nontoxicity and facile synthesis and surface functionalization for colloidal stability and targeted delivery. Potential diagnostic applications include blood pool imaging, passive targeting and active targeting, where actively targeted AuNPs could enable molecular imaging by computed tomography. This article summarizes the current state of knowledge for AuNP x-ray contrast agents within a paradigm of key structure-property-function relationships in order to provide guidance for the design of AuNP contrast agents to meet the necessary functional requirements in a particular application. Functional requirements include delivery to the site of interest (e.g., blood, tumors or microcalcifications), nontoxicity during delivery and clearance, targeting or localization at the site of interest and contrast enhancement for the site of interest compared with surrounding tissues. Design is achieved by strategically controlling structural characteristics (composition, mass concentration, size, shape and surface functionalization) for optimized properties and functional performance. Examples from the literature are used to highlight current design trade-offs that exist between the different functional requirements.

The high concentration of mineral present in bone and pathological calcifications is unique compared with all other tissues and thus provides opportunity for targeted delivery of pharmaceutical drugs, including radiosensitizers and imaging probes. Targeted delivery enables accumulation of a high local dose of a therapeutic or imaging contrast agent to diseased bone or pathological calcifications. Bisphosphonates (BPs) are the most widely utilized bone-targeting ligand due to exhibiting high binding affinity to hydroxyapatite mineral. BPs can be conjugated to an agent that would otherwise have little or no affinity for the sites of interest. This article summarizes the current state of knowledge and practice for the use of BPs as ligands for targeted delivery to bone and mineral deposits. The clinical history of BPs is briefly summarized to emphasize the success of these molecules as therapeutics for metabolic bone diseases. Mechanisms of binding and the relative binding affinity of various BPs to bone mineral are introduced, including common methods for measuring binding affinity in vitro and in vivo. Current research is highlighted for the use of BP ligands for targeted delivery of BP conjugates in various applications, including (1) therapeutic drug delivery for metabolic bone diseases, bone cancer, other bone diseases, and engineered drug delivery platforms; (2) imaging probes for scintigraphy, fluorescence, positron emission tomography, magnetic resonance imaging, and computed tomography; and (3) radiotherapy. Last, and perhaps most importantly, key structure-function relationships are considered for the design of drugs with BP ligands, including the tether length between the BP and drug, the size of the drug, the number of BP ligands per drug, cleavable tethers between the BP and drug, and conjugation schemes.