Molecularly guided multimodal theranostics for breast cancer

分子引导乳腺癌多模式治疗诊断

• 批准号: 8204843
• 负责人: AMIT JOSHI
• 金额: $ 33.46万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-12 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204843
• 关键词: Address; Adverse effects; Affect; Animal Model; Antibodies; Breast Cancer Cell; Breast Cancer Treatment; Cancer cell line; Cytostatics; Cytotoxic Chemotherapy; Detection; Development; Diagnostic; Dimensions; Disease remission; Dose; Drug Delivery Systems; Drug Kinetics; Drug resistance; Dyes; ERBB2 gene; Equation; Exhibits; Family suidae; Fluorescence; Fluorescent Dyes; Frequencies; Gold; Heating; Hybrids; Image; In Vitro; Injection of therapeutic agent; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Light; Location; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of pancreas; Medicine; Methods; Modeling; Molecular Medicine; Molecular Profiling; Multi-Drug Resistance; Nanostructures; Nanotechnology; Neoplasm Metastasis; Nude Mice; Operative Surgical Procedures; Optical Tomography; Optics; Particle Size; Patients; Pharmaceutical Preparations; Radiation; Reporting; Research; Resistance; Rice; Silicon Dioxide; Staging; Surface Properties; System; Technology; Temperature; Testing; Therapeutic; Time; Tissues; Toxic effect; Treatment Failure; Universities; Validation; Weight; Xenograft Model; base; chemotherapy; clinically relevant; college; cytotoxic; design; dosage; improved; in vivo; instrumentation; intradermal injection; iron oxide; lymph nodes; malignant breast neoplasm; mathematical model; molecular imaging; nanocarrier; nanomaterials; nanomedicine; nanoparticle; nanoscience; nanoshell; nanotherapeutic; new technology; novel; patient population; plasmonics; preclinical study; programs; public health relevance; receptor; response; theranostics; therapeutic target; therapy resistant; tumor; tumor xenograft

DESCRIPTION (provided by applicant): Primary treatment for breast cancer includes surgery accompanied with systemically cytotoxic chemotherapy and/or locally cytotoxic radiation treatment. In recent years multiple molecular signatures of breast cancer have been identified. HER directed therapies with drugs like trastazumab can still fail as many HER-2 amplified tumors are, or become resistant to therapy. However, even the resistant tumors may still continue expressing the HER-2 receptor for targeting by alternative therapeutic methods. Another promising imaging/therapeutic target for breast cancer is the over expression of Insulin like growth factor-I receptor (IGF-IR), which can potentially affect a much larger class of patients. However, despite the emerging molecular medicine-based shift towards cancer-specific cytostatic agents, cytotoxic chemotherapy is still considered more effective against broad patient populations. Hence, the early thrust of cancer nanotechnology was focused towards the development of nanocarriers for delivering diagnostic/therapeutic payloads to improve conventional chemotherapy and minimize side effects. These approaches are not externally controlled: the inability to guarantee intracellular drug delivery often results in treatment failure and it cannot address de novo and acquired drug resistance. Alternative cancer nanotherapeutics based on the photothermal response of gold nanostructures designed to absorb near-infrared (NIR), tissue-penetrating light has exhibited near 100% efficacy in the remission of tumors: this stands as one of the most promising new technologies to emerge from nanoscience research in the past decade. We recently reported a new class of photothermally active multifunctional nanomaterials, which dramatically enhance the NIR fluorescence of weak organic dyes (50X), and provide a strong T2 weighted MR contrast. We demonstrated successful bimodal (NIR/MR) imaging and therapy of breast cancer cells with these magneto-fluorescent hybrid nanoparticles (hereafter referred as hNPs) by targeting the HER-2 receptor over-expression with trace dosage of antibody. Herein, we propose an interdisciplinary partnership between the departments within the Baylor College of Medicine and Rice University to introduce a novel plasmonics based molecularly targeted theranostic technology for the treatment of drug resistant breast cancer. The convergence of nanotechnology, bio-imaging, and medicine bring the promise of an era of nanomedicine in which agents can be tuned, tailored and targeted into simultaneous therapeutic and diagnostic (theranostic) vehicles for highly specific, personalized medicine. The specific aims of this five-year research program are: 1. Fabricate and characterize a panel of hybrid magneto-fluorescent nanoparticles for combined imaging and therapy. 2. Develop and test instrumentation for combined NIR/MRI tomographic imaging and therapy 3. Validate the multimodal theranostic instrumentation on drug resistant xenograft tumors in nude mice by targeting the HER-2 and IGF-I receptor over-expression. 4. Investigate the treatment of Her-2/IGF-I over-expressing breast cancer metastasis with image guided photothermal therapy.)) PUBLIC HEALTH RELEVANCE: In this project we will develop a near infrared optical tomography scanner to exploit plasmonically enhanced fluorescent dyes for molecular imaging. Tunable nanoshells will be designed and manufactured to enhance the yield and lifetime contrast of near infrared fluorescent dyes. The developed system and methods will be validated on a clinically relevant Swine based animal model for detecting lymph node locations in three dimensions, following microdose intradermal injections of nanoshell conjugated fluorescent dyes. In addition, a preclinical study will be conducted to demonstrate early stage detection of pancreatic cancer in an orthotopic animal model with a molecularly targeting antibody-nanoshell-fluorescent dye based agent.

描述（由申请人提供）： 乳腺癌的主要治疗包括手术结合全身细胞毒性化疗和/或局部细胞毒性放射治疗。近年来，已经确定了乳腺癌的多种分子特征。使用曲他单抗等药物进行 HER 定向治疗仍然可能会失败，就像许多 HER-2 扩增肿瘤一样，或者对治疗产生耐药性。然而，即使是耐药肿瘤也可能继续表达 HER-2 受体，以供替代治疗方法靶向。乳腺癌的另一个有前景的成像/治疗靶点是胰岛素样生长因子-I 受体 (IGF-IR) 的过度表达，它可能会影响更多的患者。然而，尽管新兴的基于分子医学的转向癌症特异性细胞抑制剂，细胞毒性化疗仍然被认为对广大患者群体更有效。因此，癌症纳米技术的早期重点是开发用于提供诊断/治疗有效负载的纳米载体，以改善传统化疗并最大限度地减少副作用。这些方法不受外部控制：无法保证细胞内药物递送通常会导致治疗失败，并且无法解决从头和获得性耐药问题。基于金纳米结构光热响应的替代癌症纳米疗法，旨在吸收近红外 (NIR)、组织穿透光，在缓解肿瘤方面表现出接近 100% 的功效：这是最有前途的新技术之一过去十年的纳米科学研究。我们最近报道了一种新型光热活性多功能纳米材料，它可以显着增强弱有机染料的近红外荧光 (50X)，并提供强大的 T2 加权 MR 对比度。我们通过用微量抗体靶向 HER-2 受体过度表达，证明了使用这些磁荧光混合纳米粒子（以下称为 hNP）成功地对乳腺癌细胞进行双峰 (NIR/MR) 成像和治疗。在此，我们建议贝勒医学院和莱斯大学各部门之间建立跨学科合作伙伴关系，推出一种基于等离激元的新型分子靶向治疗诊断技术，用于治疗耐药乳腺癌。纳米技术、生物成像和医学的融合带来了纳米医学时代的希望，在这个时代，药剂可以被调整、定制和靶向到同步治疗和诊断（治疗诊断）工具中，以实现高度特异性、个性化的医学。这个为期五年的研究计划的具体目标是： 1. 制造并表征一组用于组合成像和治疗的混合磁荧光纳米颗粒。 2. 开发和测试用于组合 NIR/MRI 断层成像和治疗的仪器 3. 通过针对 HER-2 和 IGF-I 受体过度表达，验证多模式治疗诊断仪器对裸鼠耐药异种移植肿瘤的作用。 4. 研究图像引导光热疗法治疗 Her-2/IGF-I 过表达乳腺癌转移。）） 公共卫生相关性： 在这个项目中，我们将开发一种近红外光学断层扫描仪，以利用等离子体增强荧光染料进行分子成像。将设计和制造可调谐纳米壳，以提高近红外荧光染料的产量和寿命对比度。所开发的系统和方法将在临床相关的猪动物模型上进行验证，用于在微剂量皮内注射纳米壳共轭荧光染料后检测淋巴结的三维位置。此外，还将进行一项临床前研究，以证明使用分子靶向抗体-纳米壳-荧光染料基剂在原位动物模型中对胰腺癌进行早期检测。