Novel Nano-Constructs to Target and Destroy Tumor Neovasculature

描述（由申请人提供）：破坏与肿瘤相关的内皮血管结构可影响肿瘤生长。传统设计的药物抑制血管生成或对肿瘤血管内皮细胞具有细胞毒性，但效力和特异性有限，阻碍了它们的临床应用。我们假设可以设计纳米级碳纳米管结构，以增强传统放射性药物结构的内在靶向性、结合性和治疗属性，从而提高治疗指数。这些新型合成纳米结构将被设计成由生物制剂、放射性核素和碳纳米管组成的杂交分子，并应具有新兴的抗癌特性。碳纳米管提供了一个平台来扩增这些片段并将其传递到血管内皮细胞。因此，相对于目前的治疗方法，靶向、结合和治疗部分的化学计量学扩增应该提高效力、特异性和疗效。本项目的目标是靶向和选择性照射肿瘤血管生成内皮，破坏血管生成，有效抑制肿瘤进一步生长或根除肿瘤。已经研究了抑制血管生成或对肿瘤血管内皮细胞具有细胞毒性的药物，但尽管可快速获得，但它们的效力低，特异性低，结合相互作用弱，清除速度快，每个细胞的靶分子数量有限。为了克服这些与低特异性和/或弱结合相关的问题，我们将研究一种策略来综合增强针对肿瘤新生血管内皮的药物结构的有效性和效力。将合成具有多个靶向部分以增加活性和多个治疗性α粒子发射放射性核素以增加比活性的结构体。在提出的模型系统中，将研究针对肿瘤血管整合素表位的RGD肽靶向分子，并提出有效的α发射放射性核素作为治疗方式。具体目标是：1。合成并表征了放射性靶向碳纳米管结构体和2。研究构建物在合适血管模型小鼠体内的药代动力学和生物分布，探讨特异性构建物与对照构建物对肿瘤小鼠的治疗效果。血管生成包括现有血管系统的新血管增殖，是一个高度调控的过程。血管生成在伤口愈合、胚胎发育和滋养细胞植入等生理过程中起着至关重要的作用。然而，它也在异常生理过程中发挥作用，如糖尿病视网膜病变、类风湿关节炎、许多侵袭性实体瘤和转移性疾病的生长。多种细胞过程及其各自的调控分子协同作用，调节细胞外基质重塑、侵袭、迁移和增殖事件。干扰异常血管生成可能减轻视网膜病变、关节炎和肿瘤发生的症状。我们假设，基于由生物制剂、放射性核素和碳纳米管组成的混合分子的新型纳米器件将具有新兴的抗癌特性，并且这种纳米器件的内在靶向性、结合性和治疗特性的扩增将因此提高相对于传统抗血管生成药物的效力、特异性和疗效。

DESCRIPTION (provided by applicant): Disrupting the endothelial vascular architecture associated with tumor can impact tumor growth. Conventionally designed drugs have been investigated which inhibit angiogenesis or are cytotoxic to tumor vascular endothelial cells, but have limited potency and specificity, impeding their clinical utility. We hypothesize that nano-scale carbon nanotube constructs can be designed which amplify the intrinsic targeting, binding, and therapeutic attributes of a conventional radiolabled drug construct and thereby improve the therapeutic index. These novel synthetic nanostructures will be designed as hybrid molecules consisting of biologics, radionuclides and carbon nanotubes and should have emergent anti-cancer properties. The carbon nanotube provides a platform to amplify these moieties and deliver to vascular endothelial cells. The stoichiometric amplification of targeting, binding, and therapeutic moieties should therefore improve potency, specificity, and efficacy relative to current therapeutics. The goal of this project is to target and selectively irradiate angiogenic endothelium in tumor, disrupt angiogenesis, and potently inhibit further tumor growth or eradicate tumor. Drugs have been investigated which inhibit angiogenesis or are cytotoxic to tumor vascular endothelial cells, but despite rapid accessibility they suffer from low potency and minimal specificity, weak binding interaction, rapid clearance, and a limited number of target molecules per cell. In order to overcome those issues related to low specificity and/or weak binding, a strategy will be investigated to synthetically amplify the avidity and potency of drug constructs directed against tumor neovascular endothelium. Constructs will be synthesized which have both multiple targeting moieties to increase avidity and multiple therapeutic alpha particle emitting radionuclides to increase the specific activity. In the proposed model systems, RGD peptide targeting molecules directed against tumor vasculature integrin epitopes will be examined and potent alpha emitting radionuclides are proposed as the therapeutic modality. The specific aims are: 1. To synthesize and characterize the radiolabled, targeting carbon nanotube constructs and 2. To investigate the pharmacokinetics and biodistribution of constructs in appropriate vascular models in mice and explore the therapeutic efficacy of specific constructs versus control constructs in tumored mice. Angiogenesis encompasses the proliferation of new blood vessels from existing vasculature and is a highly regulated process. Angiogenesis has a crucial role in normal physiological events such as wound healing, embryonic development and trophoblast implantation. However, it also has a role in aberrant physiological processes such as diabetic retinopathy, rheumatoid arthritis, and the growth of many aggressive solid tumors and metastatic disease. A variety of cellular processes and their respective regulatory molecules work in concert to modulate extracellular matrix remodeling, invasion, migration, and proliferation events. Interfering with aberrant angiogenesis may lessen the symptoms of retinopathy, arthritis and tumorogenesis. We hypothesize that novel nanodevices based on hybrid molecules consisting of biologics, radionuclides and carbon nanotubes will have emergent anti-cancer properties and the amplification of the intrinsic targeting, binding, and therapeutic attributes of this nanodevice should therefore improve potency, specificity, and efficacy relative to conventional anti-angiogenic agents.