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。已经研究了常规设计的药物，其抑制血管生成或对肿瘤血管内皮细胞具有细胞毒性，但具有有限的效力和特异性，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，其放大常规放射性标记的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混合分子，并应具有紧急抗癌特性。碳纳米管提供了一个平台来扩增这些部分并将其递送到血管内皮细胞。因此，靶向、结合和治疗部分的化学计量扩增应相对于当前治疗剂提高效力、特异性和功效。本项目的目标是靶向并选择性照射肿瘤血管内皮，阻断血管生成，从而有效抑制肿瘤的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，但它们具有低效力和最小特异性、弱结合相互作用、快速清除和每个细胞的靶分子数量有限的缺点。为了克服与低特异性和/或弱结合相关的那些问题，将研究一种策略以合成地放大针对肿瘤新生血管内皮的药物构建体的亲合力和效力。将合成具有多个靶向部分以增加亲合力和多个治疗性α粒子发射放射性核素以增加比活性的构建体。在所提出的模型系统中，将检查针对肿瘤脉管系统整联蛋白表位的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.合成和表征放射性标记的靶向碳纳米管结构; 2.研究构建体在小鼠适当血管模型中的药代动力学和生物分布，并探索特定构建体相对于对照构建体在肿瘤小鼠中的治疗功效。血管生成包括从现有脉管系统增殖新血管，并且是高度调节的过程。血管生成在正常的生理事件中具有关键作用，例如伤口愈合、胚胎发育和滋养层植入。然而，它也在异常的生理过程中发挥作用，如糖尿病视网膜病变、类风湿性关节炎以及许多侵袭性实体瘤和转移性疾病的生长。多种细胞过程和它们各自的调节分子协同工作以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以减轻视网膜病变、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紧急的抗癌特性，并且这种纳米器件的固有靶向、结合和治疗属性的放大因此应相对于常规抗血管生成剂提高效力、特异性和功效。

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.