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

• 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
• 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

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.

成功监测对新辅助化学疗法（NAC）的肿瘤反应可能会提供紧密的机会 针对乳腺癌患者量身定制的个性疗法。当前对乳腺癌的治疗通常适用 无论治疗成功如何，“一种尺寸适合所有人”。监视“治疗”响应的能力对于 1）具有完全反应并且可以从NAC减少以降低发病率和 2）对于未对当前NAC反应的患者提出了诱发更大的治疗的变化 抗肿瘤反应。这是可靠地监测基于成像治疗NAC治疗的肿瘤反应的能力 系统是迈向实现患者监管疗法的至关重要的一步，将使我们能够进一步脱离 乳房肿瘤学中的“一种尺寸适合所有人”。因此，我们建议开发一个新的基于Squarene 生物传感器（SAB）鉴定使用新成像技术可检测到的凋亡，多光谱光声 断层扫描（MSOT）。由于MSOT是一种新的成像技术，因此外源记者染料仅限于2 FDA 批准的染料，异硫化蓝色和吲哚纳因绿色，它们都无法将其缀合。我们的 目的是：（1）作为凋亡的一部分，开发一种新的光学优化的可共与记者染料 生物传感器和（2）在体内测试半凋亡生物传感器（SAB），以鉴定凋亡 体内化学疗法治疗。 我们建议建立我们最近使用多光谱光声断层扫描识别肿瘤的成功的基础 结合我们在NIR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 原型SAB，我们包括了一部分细胞穿透肽，该肽对细胞外反应 酸性pH。我们假设平方源凋亡生物传感器（SAB）的铅原型将具有 改善细胞穿透性肽（TS-CPP）和在凋亡序列Devd处的“打开”，以分离 QC1染料的Squaraine染料，最终鉴定出细胞凋亡。为了检验我们的假设，我们提出了 以下目的：1）开发和表征原型Squarine的衍生物，以作为记者 Squaraine凋亡生物传感器（SAB）； 2）评估优化的Squaraine和SAB作为光声的性能 体外代理； 3）评估优化的SAB，以促进使用体内乳腺肿瘤凋亡的检测 多光谱光声断层扫描。这些特定目标的成功完成将发展凋亡 最终可用于在体内和临床上鉴定凋亡的生物传感器以监测肿瘤反应和 使用光声成像可检测的新记者染料。最终，这种凋亡生物传感器会很好 适合用作多光谱对比剂鸡尾酒的一部分，以识别疾病的分子特征。