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

通过分解肿瘤细胞外羟基磷灰石来开发用于癌症治疗的纳米颗粒溶液：一个新范例

• 批准号: 10218793
• 负责人: Mohammed Noor Tantawy
• 金额: $ 47.3万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218793
• 关键词: 3-Dimensional; ANXA5 gene; Acidity; Acute; Adverse effects; Affinity; Alkaline Phosphatase; Alkalosis; Animals; Anions; Apoptosis; Binding; Biological; Breast; Breast Cancer Model; Calcium; Cancer Model; Cation Exchange Resins; Cell Death; Cell surface; Characteristics; Chelating Agents; Chronic; Clinic; Colon; Colon Carcinoma; Common Neoplasm; Crystallization; Data; Deposition; Detection; Development; Diphosphates; Drug Kinetics; Durapatite; Engineering; Excretory function; Exhibits; Extracellular Matrix; Extracellular Space; Extracellular Structure; FDA approved; Fluorescent Dyes; Formulation; Genetic; Genotype; Glioma; Goals; Growth; Half-Life; Healthcare; Histologic; Hour; Hydroxyapatites; Imaging Techniques; In Vitro; Industrialization; Injectable; Injections; Label; Lead; Lung; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mammary Neoplasms; Measures; Mediating; Metabolic; Metabolism; Metastatic Neoplasm to the Liver; Methodology; Modeling; Morphology; Mus; Ovarian; PSSO3; Patients; Photons; Physiological; Plant Resins; Plasma; Positron-Emission Tomography; Prostate; Radiation therapy; Resistance development; Rodent; SNARF dye; Safety; Signal Transduction; Sodium Fluoride; Solid; Specificity; Spectrum Analysis; Stains; Technetium Tc 99m Medronate; Testing; Therapeutic; Tissue Harvesting; Tissues; Toxic effect; Tuberculosis; Tumor Burden; Tumor Tissue; Work; X-Ray Computed Tomography; Xenograft procedure; absorption; bioimaging; bone; breast malignancies; cancer biomarkers; cancer therapy; cancer type; chelation; chemotherapeutic agent; design; extracellular; fluorodeoxyglucose; imaging biomarker; immunomodulatory therapies; in vivo; inorganic phosphate; insight; malignant breast neoplasm; malignant stomach neoplasm; mouse model; nanoparticulate; neoplastic cell; new therapeutic target; novel; prostate cancer model; radioligand; radiotracer; ratiometric; soft tissue; success; targeted treatment; therapeutically effective; treatment response; tumor; tumor growth; tumor metabolism; tumor microenvironment

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.

羟基磷灰石 (HAP)，Ca10(PO4)6OH2，曾经被认为是骨骼中唯一普遍存在的成分，但 不仅被证明是由乳腺恶性肿瘤直接产生的。我们扩大了肿瘤的研究 细胞外 HAP 的研究结果表明，它不仅存在于许多其他类型的恶性肿瘤中 例如前列腺癌、结肠癌、卵巢癌、神经胶质瘤、肺癌、胰腺癌和胃癌，也可用作 用于检测肿瘤负荷的成像生物标志物。此外，HAP 是一个潜在的新治疗靶点。来自肿瘤 从检测的角度来看，我们已经证明肿瘤细胞外 HAP 可以用结合的放射性配体进行检测 HAP 包括 18F 标记的氟化钠 (18F-NaF) 和 99mTc 标记的二磷酸甲酯 (99mTc-MDP)， 通过正电子发射断层扫描（PET）和单光子发射计算机断层扫描（SPECT）成像， 分别。由于正常软组织中不存在 HAP，因此肿瘤相关 HAP 的检测显示出高 特异性和高信号背景比。 由于 HAP 作为治疗癌症的潜在新靶点，我们假设如果 HAP 相关钙 肿瘤微环境内的肿瘤微环境可能在体内被耗尽，然后释放相关的(PO4)-+OH- 阴离子可能诱发肿瘤局部急性细胞外碱中毒，导致肿瘤细胞死亡。这样的重新 通过消耗 HAP 来改造肿瘤微环境可能为癌症提供新的范例 治疗。为了验证这一假设，我们开发了一种可注射的纳米颗粒磺化聚苯乙烯溶液 (NSPS) 专为体内递送而设计的配方。初步工作表明 NSPS 的体内给药 乳腺癌、前列腺癌和结肠癌的异种移植小鼠模型导致肿瘤代谢减少 并增加细胞凋亡，而没有明显的全身副作用。此外，根据我们的 假设，从 NSPS 处理的小鼠中收获的均质化肿瘤组织的整体酸度（宏观 pH） 发现显着高于接受载体注射或未注射载体的小鼠的肿瘤 注射。在这项工作中，我们的目的是通过直接测试 NSPS 导致肿瘤细胞外碱中毒的假设 使用比例 pH 指示剂 5-(and-6)-Carboxy SNARF-5 在体外测量肿瘤细胞外 pH 在肿瘤球体和体内，使用 3-氨基丙基膦酸酯 (3-APP) 的局部 31P 光谱 NSPS 治疗后通过磁共振成像 (MRI) 进行量化。我们将关联变化 细胞外 pH 值随肿瘤生长、代谢活动和细胞凋亡的变化而变化（目标 1）。此外，我们 将测量小鼠 NSPS 的药代动力学 (PK) 参数以及小鼠毒性的潜在标志物 模型（目标 2）。计划中的研究将深入了解 NSPS 相对于肿瘤细胞的功效机制 在多种癌症类型中，推测是通过细胞外基质酸度降低介导的 肿瘤微环境。目标是对 NSPS 作为小说的潜力进行全面评估 副作用最小的癌症治疗范例。