Personalized Cancer Therapy Guided by Photoacoustic Chemical Imaging (PACI) of Tumor Microenvironment (TME)

肿瘤微环境（TME）光声化学成像（PACI）引导的个性化癌症治疗

• 批准号: 10452531
• 负责人: Raoul Kopelman
• 金额: $ 61.08万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-08 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10452531
• 关键词: Acidosis; Affect; Aftercare; Animal Model; Cancer Patient; Chemicals; Clinical Management; Complex; Correlation Studies; Early treatment; Ecosystem; Ensure; Funding; Health Personnel; Hypoxia; Image; Imaging technology; Immuno-Chemotherapy; Immunotherapy; Individual; Lasers; Light; Malignant Neoplasms; Maps; Medicine; Metabolic; Modeling; Modification; Molecular Biology; Mus; Neoplasm Metastasis; Outcomes Research; Oxygen; Patient imaging; Patient-Focused Outcomes; Patient-derived xenograft models of breast cancer; Patients; Penetration; Pharmaceutical Preparations; Physiological; Play; Potassium; Publications; Radio; Research; Resistance; Resolution; Shapes; Signal Transduction; Solid Neoplasm; Spatial Distribution; Speed; System; T cell therapy; Technology; Testing; Tissues; Translational Research; Treatment outcome; Triad Acrylic Resin; Warburg Effect; base; cancer imaging; cancer therapy; chemical property; clinical translation; experience; hyperkalemia; image guided; in vivo; malignant breast neoplasm; member; mouse model; nanomedicine; nanoprobe; nanosensors; novel; optimal treatments; patient derived xenograft model; personalized cancer therapy; photoacoustic imaging; response; spatiotemporal; tool; treatment planning; treatment response; tumor; tumor heterogeneity; tumor microenvironment; tumor xenograft; ultrasound

Title: Personalized Cancer Therapy Guided by Photoacoustic Chemical Imaging (PACI) of Tumor Microenvironment (TME) Abstract: Tumors are often found in an altered metabolic state, which leads to anomalous chemical composition, such as hypoxia (low oxygen level), acidosis (low pH level), and hyperkalemia (high potassium concentration). These three form a “therapy resistance triad (O2, pH, and K+)”, suppressing cancer’s responses to radio-, chemo-, and immuno-therapy. As each triad member’s concentration is strongly relevant to cancer progress and response to therapy, a non-invasive, sensitive, and reliable approach for evaluating their temporal and spatial distributions in the tumor microenvironment (TME) in vivo, non-invasively, is highly desirable. To fill this serious and long-standing gap in technology, we introduce a novel set of O2, pH, and K+ sensing nanoprobes that, in combination with the emerging photoacoustic imaging technology, enables quantitative mapping of the O2, pH, and K+ levels in solid tumors in vivo. The central hypothesis of this proposed research is that, enabled by our photoacoustic chemical imaging (PACI) powered with sensitive chemical indicator nanoprobes, we can image and quantitatively evaluate the spatio-temporal distributions of the TME’s therapy resistance triad (O2, pH, and K+), at depths of up to a few centimeters, in vivo and in a non-invasive fashion, and then correlate with cancer responses to treatments via radio-, chemo-, and immuno-therapy. This hypothesis will be examined rigorously using orthotopic patient derived xenograft (PDX) breast cancer mouse models. To enable a comprehensive understanding of the technology’s capabilities, as well as limitations, the imaging results from PACI of the TME will be compared for a wide variety of PDX tumor models and treatment situations. To examine the central hypothesis, our research will focus on three specific aims: Aim 1. Understand tumor response to radio-therapy by PACI of the TME; Aim 2. Understand tumor response to chemo-therapy by PACI of the TME; and Aim 3. Understand tumor response to immuno-therapy by PACI of the TME. Potential impact: As the orthotopic PDX tumors faithfully resemble the original tumors in cancer patients, including their TME, chemical imaging of these PDX tumors, combined with studying the correlations of the imaging findings with the cancer responses to therapies, could have a large impact on translational research and clinical management of breast cancer, e.g. helping to discriminate the most suitable treatment plan or alternative plan for individual cancer patients. By the end of this funding period, we will objectively test and thoroughly verify whether the novel PACI technology powered by sensitive nanoprobes can image the TME’s chemical properties of PDX mouse tumors in vivo, non-invasively, for predicting the cancer responses to radio- , chemo-, and immuno-therapy. Once successfully validated, the proposed strategy could shed new light on imaging-guided personalized cancer medicine, so as to hopefully ensure an optimal treatment outcome.

标题：光声化学成像（PACI）引导的个性化癌症治疗 肿瘤微环境（TME） 摘要： 肿瘤通常被发现处于改变的代谢状态，这导致异常的化学成分，例如 缺氧（低氧水平）、酸中毒（低pH水平）和高钾血症（高钾浓度）。这些 三种形成“治疗抗性三联体（O2，pH和K+）"，抑制癌症对放射性，化学， 和免疫疗法。由于每个三元组成员的浓度与癌症进展密切相关， 对治疗的反应，一种非侵入性的，敏感的，可靠的方法来评估他们的时间和空间 因此，非常需要在体内非侵入性地在肿瘤微环境（TME）中分布。为了填补这个严重的 和长期存在的技术差距，我们介绍了一套新的O2，pH值和K+传感纳米探针， 与新兴的光声成像技术相结合，能够定量绘制O2，pH， 和体内实体瘤中的K+水平。这项研究的中心假设是，通过我们的研究， 光声化学成像（PACI）与敏感的化学指示剂纳米探针供电，我们可以成像 并定量评估TME的治疗抗性三联体（O2、pH和 K+），在体内以非侵入性方式在高达几厘米的深度处，然后与癌症相关 通过放射治疗、化学治疗和免疫治疗的反应。这一假设将受到严格的检验 使用原位患者来源的异种移植物（PDX）乳腺癌小鼠模型。为了实现全面的 了解该技术的能力，以及限制，从TME的PACI成像结果 将针对各种PDX肿瘤模型和治疗情况进行比较。检查中央 假设，我们的研究将集中在三个具体目标：目标1。了解肿瘤对放射治疗的反应 《易经》云：“二。通过TME的PACI了解肿瘤对化疗的反应;和目的3. 了解肿瘤对TME的PACI免疫治疗的反应。 潜在影响：由于原位PDX肿瘤与癌症患者的原始肿瘤非常相似， 包括他们的TME，这些PDX肿瘤的化学成像，结合研究这些肿瘤的相关性， 成像结果与癌症对治疗的反应，可能对转化研究产生重大影响。 和乳腺癌的临床管理，例如帮助区分最合适的治疗计划， 为个别癌症患者提供替代方案。到本融资期结束时，我们将客观地测试和 彻底验证由敏感的纳米探针驱动的新型PACI技术是否可以对TME成像 PDX小鼠肿瘤在体内的化学性质，非侵入性，用于预测癌症对放射性的反应， 化疗和免疫治疗。一旦成功验证，拟议的战略可以揭示新的光 成像引导的个性化癌症药物，从而有望确保最佳治疗结果。