Development of nanoparticulate solution for cancer treatment by breakup of tumor extracellular hydroxyapatite: a new paradigm

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Hydroxyapatite (HAP), Ca10(PO4)6OH2, once thought to be solely an ubiquitous component of bone, has not only been shown to be directly produced by breast malignancies. We have expanded the study of tumor extracellular HAP and present results showing that not only is it present in many other types of malignancies such as prostate, colon, ovarian, glioma, lung, pancreatic, and gastric cancers but also can be used as an imaging biomarker for detecting tumor burden. Further, HAP is a potential novel target for therapy. From tumor detection perspective, we have shown that tumor extracellular HAP can be detected with radioligands that bind to HAP including 18F-labeled sodium fluoride (18F-NaF) and 99mTc-labeled methyl diphosphate (99mTc-MDP), imaged by positron emission tomography (PET) and single photon emission computer tomography (SPECT), respectively. As HAP is absent from normal soft tissue, detection of tumor-associated HAP exhibited both high specificity and a high signal-to-background ratio. With HAP as a potential novel target for treating cancer, we postulated that if HAP-associated calcium within the tumor microenvironment could be depleted in vivo, then the release of the associated (PO4) - + OH- anions might induce localized acute extracellular alkalosis in the tumor leading to tumor cell death. Such re- engineering of the tumor microenvironment by depleting HAP may provide a novel paradigm for cancer treatment. To test this hypothesis, we developed an injectable nanoparticulate sulfonated polystyrene solution (NSPS) formulation designed for in vivo delivery. Preliminary work shows that in vivo administration of NSPS in xenograft mouse models of breast, prostate and colon cancer resulted in the reduction of tumor metabolism and increased cellular apoptosis without evident systemic adverse effects. Furthermore, in accord with our hypothesis, the overall acidity (macro pH) of homogenized tumor tissue harvested from NSPS-treated mice was found to be significantly higher than in tumors from mice that received either vehicle injections or no injection. In this work, we aim to test the postulate that NSPS leads to tumor extracellular alkalosis by directly measuring tumor extracellular pH both in vitro, using the ratiometric pH indicator 5-(and-6)-Carboxy SNARF-5 in tumor spheroids, and in vivo with localized 31P spectroscopy of 3-aminopropylphosphonate (3-APP) quantified by magnetic resonance imaging (MRI) following NSPS treatment. We will correlate changes in extracellular pH with changes in tumor growth, metabolic activity and cellular apoptosis (Aim 1). In addition, we will measure the pharmacokinetic (PK) parameters of NSPS in mice and potential markers of toxicity in mouse models (Aim 2). Planned studies will provide insight into the mechanism for NSPS efficacy versus tumor cells in a broad range of cancer types, postulated to be mediated via reduction in acidity of the extracellular matrix in the tumor microenvironment. The goal is to initiate a full assessment of the potential of NSPS as a novel cancer treatment paradigm with minimal adverse effects.