Development of an apoptosis biosensor for monitoring of breast cancer

开发用于监测乳腺癌的细胞凋亡生物传感器

基本信息

批准号：
10719415
负责人：
Maged M Henary
金额：
$ 49.51万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10719415
关键词：
Adjuvant Chemotherapy Antitumor Response Apoptosis Biodistribution Biopsy Biosensor Breast Cancer Patient Breast Cancer Treatment Breast Oncology Cancer Patient Cell Death Cells Chemistry Chemotherapy-Oncologic Procedure Clinical Computer Models Contrast Media Detection Development Disease Dose Drug Kinetics Dyes Engineering Extinction FDA approved Goals Human Image Imaging technology In Vitro In complete remission Induction of Apoptosis Investigation Ionizing radiation Lead Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Molecular Molecular Biology Monitor Morbidity - disease rate Neoadjuvant Therapy Non-Malignant Operative Surgical Procedures Optics Pathway interactions Patients Penetration Peptides Performance Pharmaceutical Preparations Property Reporter Sampling Schedule Sensitivity and Specificity Signal Transduction Specificity System Techniques Testing Time Tissue Sample Tissues Toxic effect Visit Visualization Work cancer care cancer therapy chemotherapy clinical decision-making clinical examination extracellular improved in vivo individualized medicine malignant breast neoplasm near infrared dye neoplastic cell novel novel therapeutics optoacoustic tomography personalized medicine photoacoustic imaging pre-clinical prototype quantum rational design response squaraine success treatment response tumor uptake

项目摘要

Successful monitoring tumor response to neo-adjuvant chemotherapy (NAC) could offer the opportunity to tightly- tailored individualized therapy in patients with breast cancer. Current treatment of breast cancer generally applies a “one-size fits all” regardless of treatment success. The ability to monitor “on-treatment” response is critical for both 1) the patients that have complete response and could benefit from reduced NAC to reduce morbidity and 2) to the patients who are not responding to current NAC to suggest a change in treatments which induce greater anti-tumor response. Thus, the ability to reliably monitor tumor response to NAC treatment via an imaging-based system is a vital step toward realizing patient-tailored therapy and would enable us to further move away from a “one size fits all” paradigm in breast oncology. Therefore, we propose to develop a new Squaraine-based biosensor (SAB) to identify apoptosis detectable using a new imaging technology, Multispectral Optoacoustic Tomography (MSOT). As MSOT is a new imaging technology, exogenous reporter dyes are limited to 2 FDA approved dyes, isosulfane blue and indocynaine green, neither of which can be conjugated to peptides. Our objective is to: (1) develop a new optoacoustically optimized conjugatable reporter dye as part of the apoptosis biosensor and (2) test the Squaraine apoptosis biosensor (SAB) in vivo to identify apoptosis following chemotherapy treatment in vivo. We propose to build upon our recent success of identifying tumors using multispectral optoacoustic tomography combined with our expertise in NIR dye chemistry and molecular biology. To improve specificity of cell uptake of the prototype SAB, we have included a portion of a cell penetrating peptide that is responsive to extracellular acidic pH. We hypothesize that our lead prototype for the Squaraine Apoptosis Biosensor (SAB) will have improved cell penetrating peptide (TS-CPP) and “turn on” at the apoptosis sequence, DEVD, to separate the Squaraine dye from the QC1 dye, ultimately identifying apoptosis. To test our hypothesis, we propose the following aims: 1) develop and characterize derivatives of prototype Squaraine to serve as the reporter for the Squaraine apoptosis biosensor (SAB); 2) assess performance of optimized Squaraine and SAB as optoacoustic agents in vitro; and 3) assess optimized SAB to facilitate detection of apoptosis in breast tumors in vivo using multispectral optoacoustic tomography. Successful completion of these specific aims will develop an apoptosis biosensor that ultimately could be used to identify apoptosis in vivo and clinically to monitor tumor response and a new reporter dye detectable using optoacoustic imaging. Ultimately, this apoptosis biosensor would be well suited for use as part of a multispectral contrast agent cocktail for identifying molecular features of disease.

成功监测肿瘤对新辅助化疗（NAC）的反应可能会提供密切关注的机会。乳腺癌患者的个体化治疗目前普遍适用。无论治疗是否成功，“一刀切”的能力对于“治疗中”的反应至关重要。 1) 完全缓解并可受益于减少 NAC 来降低发病率的患者，以及 2) 对当前 NAC 没有反应的患者建议改变治疗方法，从而引起更大的效果因此，能够通过基于成像的方法可靠地监测肿瘤对 NAC 治疗的反应。系统是实现患者定制治疗的重要一步，将使我们能够进一步远离因此，我们建议开发一种新的基于 Squareine 的方法。生物传感器（SAB）可使用新的成像技术多光谱光声来识别可检测的细胞凋亡由于MSOT是一种新的成像技术，外源报告染料仅限于2 FDA。批准的染料，异硫烷蓝和吲哚青绿，这两种染料都不能与肽结合。目标是：(1) 开发一种新的光声优化可缀合报告染料作为细胞凋亡的一部分生物传感器和 (2) 体内测试 Squaraine 细胞凋亡生物传感器 (SAB) 以识别细胞凋亡体内化疗治疗。我们建议以我们最近使用多光谱光声断层扫描识别肿瘤的成功为基础结合我们在近红外染料化学和分子生物学方面的专业知识，提高细胞摄取的特异性。在原型 SAB 中，我们加入了细胞穿透肽的一部分，该肽对细胞外物质有反应我们追求我们的方酸细胞凋亡生物传感器 (SAB) 的主要原型具有酸性 pH 值。改进的细胞穿透肽 (TS-CPP) 并在凋亡序列 DEVD 处“开启”，以分离来自 QC1 染料的方酸菁染料，最终鉴定细胞凋亡为了检验我们的假设，我们提出了以下目标：1) 开发并表征原型 Squaraine 的衍生物，作为报告基因 Squaraine 细胞凋亡生物传感器 (SAB)；2) 评估优化的 Squaraine 和 SAB 作为光声传感器的性能体外试剂；3) 评估优化的 SAB，以促进体内乳腺肿瘤细胞凋亡的检测多光谱光声断层扫描的成功完成这些特定目标将导致细胞凋亡。最终可用于识别体内细胞凋亡和临床监测肿瘤反应和最终，这种细胞凋亡生物传感器将会很好地利用光声成像进行检测。适合用作多光谱造影剂混合物的一部分，用于识别疾病的分子特征。