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会影响肿瘤的生长。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作用，但效力和特异性有限，阻碍了其临床应用。我们假设，纳米级碳纳米管结构可以被设计成放大传统放射性药物结构的内在靶向、结合和治疗属性，从而提高治疗指数。这些新型的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化分子，并应具有紧急抗癌特性。碳纳米管提供了一个平台来放大这些部分，并将其输送到血管内皮细胞。因此，与当前的治疗方法相比，靶向、结合和治疗部分的化学计量放大应该会提高效力、特异性和有效性。该项目的目标是靶向和选择性地照射肿瘤中的血管生成内皮，阻断血管生成，并有效地抑制肿瘤的进一步生长或根除肿瘤。已经研究出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，但它们的效价低、特异性低、结合作用弱、清除快，且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，将研究一种策略，以综合放大针对肿瘤新生血管内皮细胞的药物构建物的亲和力和效力。将合成既具有多个靶向部分以增加亲和力，又具有多个治疗性阿尔法粒子发射放射性核素以提高比活性的构建物。在所提出的模型系统中，将研究针对肿瘤血管整合素表位的RGD多肽靶向分子，并建议将有效的阿尔法发射放射性核素作为治疗方式。其具体目的是：1.合成和表征放射性修饰的、靶向的碳纳米管结构；2.研究碳纳米管结构在小鼠体内的药代动力学和生物分布，并探讨特定结构与对照结构在肿瘤小鼠中的治疗效果。血管生成包括从现有的血管系统中增殖新的血管，这是一个高度调控的过程。血管生成在伤口愈合、胚胎发育和滋养层植入等正常生理过程中起着至关重要的作用。然而，它也在糖尿病视网膜病变、类风湿性关节炎以及许多侵袭性实体肿瘤和转移性疾病的生长等异常生理过程中发挥作用。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。干扰异常的血管生成可能会减轻视网膜病变、关节炎和肿瘤的症状。我们假设，基于由生物制剂、放射性核素和碳纳米管组成的杂化分子的新型纳米设备将具有紧急的抗癌特性，因此，这种纳米设备固有的靶向、结合和治疗属性的放大应该会提高相对于传统抗血管生成剂的效力、特异性和有效性。

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.