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Additionally, acidosis in the TME has been reported to play a key role in selecting for a more aggressive tumor phenotype, drug resistance and desensitization to immunotherapy for many types of cancers. TME\u2010HAP is an attractive target for tumor detection and treatment development since HAP is generally absent from normal soft tissue. We provide strong evidence that dissolution of hydroxyapatite (HAP) within the tumor microenvironment (TME\u2010HAP) using a novel therapeutic can be used to kill cancer cells both\u2009in vitro<\/jats:italic>\u2009and\u2009in vivo<\/jats:italic>\u2009with minimal adverse effects.<\/jats:p><\/jats:sec>Methods<\/jats:title>We developed\u2009an injectable cation exchange nano particulate sulfonated polystyrene solution (NSPS) that we engineered to dissolve TME\u2010HAP, inducing localized acute alkalosis and inhibition of tumor growth and glucose metabolism.\u2009This was evaluated in cell culture using 4T1, MDA\u2010MB\u2010231 triple negative breast cancer cells, MCF10 normal breast cells, and H292 lung cancer cells, and\u2009in vivo<\/jats:italic>\u2009using orthotopic mouse models of cancer that contained detectable microenvironment HAP including breast (MMTV\u2010Neu, 4T1, and MDA\u2010MB\u2010231), prostate (PC3) and colon (HCA7) cancer using\u200918<\/jats:sup>F\u2010NaF for HAP and\u200918<\/jats:sup>F\u2010FDG for glucose metabolism with PET imaging. On the other hand, H292 lung tumor cells that lacked detectable microenvironment HAP and MCF10a normal breast cells that do not produce HAP served as negative controls. Tumor microenvironment pH levels following injection of NSPS were evaluated via Chemical Exchange Saturation (CEST) MRI and via\u2009ex vivo<\/jats:italic>\u2009methods.<\/jats:p><\/jats:sec>Results<\/jats:title>Within 24 h of adding the small concentration of 1X of NSPS (~7\u2009\u03bcM), we observed significant tumor cell death (~\u200910%, p\u2009<\u20090.05) in 4T1 and MDA\u2010MB\u2010231 cell cultures that contain HAP\u2009but \u27e82% in H292 and MCF10a cells that lack detectable HAP and in controls. Using CEST MRI, we found extracellular pH (pHe) in the 4T1 breast tumors, located in the mammary fat pad, to increase by nearly 10% from baseline before gradually receding back to baseline during the first hour post NSPS administration. in the tumors that contained TME\u2010HAP in mouse models, MMTV\u2010Neu, 4T1, and MDA\u2010MB\u2010231, PC3, and HCA7,\u2009there was a significant reduction (p<\/jats:italic><0.05) in\u200918<\/jats:sup>F\u2010Na Fuptake post NSPS treatment as expected;\u200918<\/jats:sup>F\u2010<\/jats:sup>\u2009uptake in the tumor\u2009=\u20093.8\u2009\u00b1\u20090.5 %ID\/g (percent of the injected dose per gram) at baseline\u2009compared to\u20091.8 \u00b10.5 %ID\/g following one\u2010time treatment with 100 mg\/kg NSPS. Of similar importance, is that\u200918<\/jats:sup>F\u2010FDG uptake in the tumors was reduced by more than 75% compared to baseline within 24 h of treatment with one\u2010time NSPS which persisted for at least one week. Additionally, tumor growth was significantly slower (p<\/jats:italic>\u2009<\u20090.05) in the mice treated with one\u2010time NSPS.\u2009Toxicity showed\u2009no evidence of any adverse effects, a finding attributed to the absence of HAP in normal soft tissue and to our therapeutic NSPS having limited penetration to access HAP within skeletal bone.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>Dissolution of TME\u2010HAP using our novel NSPS has the potential to provide a new treatment paradigm to enhance the management of cancer patients with poor prognosis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.6812","type":"journal-article","created":{"date-parts":[[2024,1,19]],"date-time":"2024-01-19T06:56:34Z","timestamp":1705647394000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Tumor therapy by targeting extracellular hydroxyapatite using novel drugs: A paradigm shift"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5975-7540","authenticated-orcid":false,"given":"Mohammed N.","family":"Tantawy","sequence":"first","affiliation":[{"name":"Vanderbilt University Institute of Imaging Science Vanderbilt University Medical Center Nashville Tennessee USA"},{"name":"Departments of Radiology and Radiological Sciences Vanderbilt Univerity Medical Center Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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