Tumor therapy by targeting extracellular hydroxyapatite using novel drugs: A paradigm shift
Year: 2024
Type: article
Abstract: Background It has been shown that tumor microenvironment (TME) hydroxyapatite (HAP) is typically associated with many malignancies and plays a role in tumor progression and growth. 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‐HAP 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‐HAP) using a novel therapeutic can be used to kill cancer cells both in vitro and in vivo with minimal adverse effects. Methods We developed an injectable cation exchange nano particulate sulfonated polystyrene solution (NSPS) that we engineered to dissolve TME‐HAP, inducing localized acute alkalosis and inhibition of tumor growth and glucose metabolism. This was evaluated in cell culture using 4T1, MDA‐MB‐231 triple negative breast cancer cells, MCF10 normal breast cells, and H292 lung cancer cells, and in vivo using orthotopic mouse models of cancer that contained detectable microenvironment HAP including breast (MMTV‐Neu, 4T1, and MDA‐MB‐231), prostate (PC3) and colon (HCA7) cancer using 18F‐NaF for HAP and 18F‐FDG 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 ex vivo methods. Results Within 24 h of adding the small concentration of 1X of NSPS (~7 μM), we observed significant tumor cell death (~ 10%, p < 0.05) in 4T1 and MDA‐MB‐231 cell cultures that contain HAP but ⟨2% 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‐HAP in mouse models, MMTV‐Neu, 4T1, and MDA‐MB‐231, PC3, and HCA7, there was a significant reduction (p<0.05) in 18F‐Na Fuptake post NSPS treatment as expected; 18F‐ uptake in the tumor = 3.8 ± 0.5 %ID/g (percent of the injected dose per gram) at baseline compared to 1.8 ±0.5 %ID/g following one‐time treatment with 100 mg/kg NSPS. Of similar importance, is that 18F‐FDG uptake in the tumors was reduced by more than 75% compared to baseline within 24 h of treatment with one‐time NSPS which persisted for at least one week. Additionally, tumor growth was significantly slower (p < 0.05) in the mice treated with one‐time NSPS. Toxicity showed no 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. Conclusion Dissolution of TME‐HAP using our novel NSPS has the potential to provide a new treatment paradigm to enhance the management of cancer patients with poor prognosis.
Source: Cancer Medicine
DOI: 10.1002/cam4.6812
Language: English
Subfield: Biomedical Engineering
Field: Engineering
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $4,270
Funders: U.S. Department of Defense, U.S. Department of Veterans Affairs, Vanderbilt University, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, National Institutes of Health, Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources
Awards: G1275244077, G1339403715, Novel ultrahigh resolution microCT imaging system, G2268269956, Development of nanoparticulate solution for cancer treatment by breakup of tumor extracellular hydroxyapatite: a new paradigm, G3269002440, G344109072, G3703967407, G4119534169, G5613659379, G5673529183, G5850682332, G6360502121, G6569741389, G7247264053, G725763919, G7382571767, G7642566612, Upgrade of a 7T Small Animal MRI/MRS System, PET System for Preclinical Research, G8953775245, G9000064184, G9000076948, G9000089795, Molecular and Cellular Basis for Digestive Diseases
OpenAlex ID: W4391034020