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，曾被认为是唯一普遍存在的骨骼成分，具有 不仅被证明是由乳腺癌直接产生的。我们扩大了对肿瘤的研究 细胞外HAP和目前的结果表明，它不仅存在于许多其他类型的恶性肿瘤中 如前列腺癌、结肠癌、卵巢癌、胶质瘤、肺癌、胰腺癌和胃癌，但也可用作 用于检测肿瘤负荷的成像生物标志物。此外，HAP是一种潜在的治疗新靶点。来自肿瘤 从检测的角度来看，我们已经证明，肿瘤细胞外的HAP可以通过结合的放射性配体来检测 对HAP包括18F标记氟化钠(18F-NaF)和99mTc标记二磷酸甲酯(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， 分别进行了分析。由于正常软组织中不存在HAP，与肿瘤相关的HAP的检测率既高又高 特异性和高信号背景比。 由于HAP是治疗癌症的潜在新靶点，我们推测如果HAP相关的钙 肿瘤内的微环境可在体内耗尽，然后释放相关的(PO4)-+OH- 阴离子可诱导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- 通过去除HAP来改造肿瘤微环境可能为癌症提供一种新的范例 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)为体内给药而设计的制剂。初步工作表明，NSPS在小鼠体内给药 乳腺癌、前列腺癌和结肠癌小鼠异种移植模型导致肿瘤代谢减慢 细胞凋亡率增加，无明显全身不良反应。此外，根据我们的 假设，从NSPS处理的小鼠获取的匀浆肿瘤组织的总酸度(宏观pH) 被发现明显高于接受或不接受赋形剂注射的小鼠的肿瘤 注射。在这项工作中，我们旨在验证NSPS通过直接导致肿瘤细胞外碱中毒的假设 用比值pH指示剂5-(和-6)-Carboxy snarf-5在体外测定肿瘤细胞外pH 3-氨基丙基膦(3-APP)在肿瘤球体和活体内的~(31)P谱定位 在NSPS治疗后通过磁共振成像(MRI)进行量化。我们将关联以下方面的变化 细胞外pH与肿瘤生长、代谢活性和细胞凋亡的变化(目标1)。此外，我们 将测量NSPS在小鼠体内的药代动力学(PK)参数和潜在的小鼠毒性标志物 模型(目标2)。计划中的研究将深入了解NSPS相对于肿瘤细胞的疗效机制 在广泛的癌症类型中，推测是通过减少细胞外基质的酸度来调节的 肿瘤微环境。目标是启动对NSPS作为一种小说的潜力的全面评估 副作用最小的癌症治疗范例。