Molecularly guided multimodal theranostics for breast cancer

描述(由申请人提供)： 乳腺癌的主要治疗方法包括手术配合全身细胞毒性化疗和/或局部细胞毒性放射治疗。近年来，乳腺癌的多个分子标记已被鉴定出来。她用曲他珠单抗等药物进行的定向治疗仍然可能像许多HER-2扩增肿瘤一样失败，或者对治疗产生抗药性。然而，即使是耐药的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。另一个有希望的乳腺癌成像/治疗靶点是胰岛素样生长因子-I受体(IGF-IR)的过度表达，这可能会影响到更多的患者。然而，尽管新兴的基于分子医学的药物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泛的患者群体更有效。因此，癌症纳米技术的早期重点是开发纳米载体，用于提供诊断/治疗有效载荷，以改进传统化疗并将副作用降至最低。这些方法不受外部控制：无法保证细胞内药物输送往往导致治疗失败，也无法解决从头开始和获得性耐药问题。替代癌症纳米疗法基于金纳米结构的光热响应，旨在吸收近红外(NIR)，组织穿透光在缓解肿瘤方面显示出近100%的效率：这是过去十年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型的光热活性多功能纳米材料，它显著增强了弱有机染料(50X)的近红外荧光，并提供了强大的T2加权磁共振对比度。我们通过用微量抗体靶向HER-2受体的过度表达，成功地展示了这些磁-荧光杂化纳米颗粒(以下简称hNPs)对乳腺癌细胞的双峰(NIR/MR)成像和治疗。在此，我们建议贝勒医学院和莱斯大学的院系之间建立跨学科的合作伙伴关系，以引入一种基于等离子体的分子靶向治疗耐药乳腺癌的新技术。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，试剂可以被调整、定制和靶向进入同时治疗和诊断(治疗)的载体，以实现高度特异性和个性化的药物。这项为期五年的研究计划的具体目标是：1.制备和表征一组用于联合成像和治疗的杂化磁-荧光纳米粒子。3.以HER-2和IGF-I受体的高表达为靶点，验证多模式热疗治疗耐药裸鼠移植瘤的有效性。4.探讨图像引导光热疗法对HER-2/IGF-I高表达乳腺癌转移的治疗作用。) 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层析扫描仪，以开发用于分子成像的等离子体增强荧光染料。可调纳米壳层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。开发的系统和方法将在临床相关的猪为基础的动物模型上进行验证，以检测在皮内注射微量纳米壳结合荧光染料后的三维淋巴结位置。此外，还将进行一项临床前研究，以证明使用基于分子靶向抗体-纳米壳-荧光染料的试剂在原位动物模型中早期检测胰腺癌。

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.