Molecularly guided multimodal theranostics for breast cancer

描述（由申请人提供）： 乳腺癌的主要治疗包括手术伴随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。使用曲他珠单抗等药物进行HER定向治疗仍然会失败，因为许多HER-2扩增的肿瘤都是如此，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，以通过替代治疗方法进行靶向。乳腺癌的另一个有希望的成像/治疗靶点是胰岛素样生长因子-I受体（IGF-IR）的过度表达，这可能会影响更大类别的患者。然而，尽管新兴的基于分子医学的癌症特异性细胞生长抑制剂的转变，细胞毒性化疗仍然被认为对广泛的患者群体更有效。因此，癌症纳米技术的早期推动力集中在开发用于提供诊断/治疗有效载荷的纳米载体，以改善常规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导致治疗失败，并且无法解决从头和获得性耐药性。基于金纳米结构的光热响应的替代癌症纳米治疗，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%的疗效：这是过去十年中纳米科学研究中出现的最有前途的新技术之一。我们最近报道了一类新的光热活性多功能纳米材料，其显著增强弱有机染料的近红外荧光（50倍），并提供强的T2加权MR对比度。我们证明了通过用痕量剂量的抗体靶向HER-2受体过表达，用这些磁荧光混合纳米颗粒（下文称为hNP）对乳腺癌细胞进行成功的双峰（NIR/MR）成像和治疗。在此，我们建议贝勒医学院和莱斯大学的部门之间建立跨学科的合作关系，以引入一种新的基于等离子体的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，在纳米医学时代，药剂可以被调整、定制和靶向到同时治疗和诊断（治疗诊断）的载体中，用于高度特异性的个性化医学。这个五年研究计划的具体目标是：1。制造和表征用于组合成像和治疗的混合磁荧光纳米颗粒的面板。2.开发和测试组合NIR/MRI断层成像和治疗仪器3.通过靶向HER-2和IGF-I受体过表达，验证了多模式治疗诊断仪器在裸鼠耐药异种移植瘤中的应用。4.研究Her-2/IGF-I过表达乳腺癌转移的图像引导光热治疗。 公共卫生相关性： 在本计画中，我们将发展一种近红外光学断层扫描仪，利用电浆增强萤光染料来进行分子影像。可调纳米壳的设计和制造将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基于猪的动物模型上进行验证，用于在微剂量皮内注射纳米壳缀合的荧光染料后检测三维淋巴结位置。此外，将进行临床前研究，以证明在原位动物模型中使用基于分子靶向抗体-纳米壳-荧光染料的试剂的胰腺癌的早期检测。

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.