Tumor -Targeting Chemotherapeutic Agents

描述(申请人提供)：癌症是美国第二大主要死因(85岁或以下人口的头号死因)。尽管癌症检测、预防、手术和治疗的发展取得了重大进展，但仍没有常见的治疗恶性疾病的方法。此外，化疗的长期问题是缺乏针对肿瘤的特效治疗。传统的化疗依赖于这样的前提，即快速增殖的癌细胞更有可能被细胞毒剂杀死。然而，在现实中，细胞毒剂几乎没有或没有特异性，这会导致全身毒性，导致不良的严重副作用，如脱发、肝、肾和骨髓损害。因此，在过去的三十年里，人们探索了各种给药方案和系统。通常，肿瘤靶向给药系统由肿瘤识别部分和细胞毒性弹头组成，直接或通过合适的连接物连接形成偶联物。这种结合物可以被视为“制导分子导弹”，在系统上应该是无毒的。这意味着连接体在血液循环中必须是稳定的。一旦内化进入癌细胞，结合物应该很容易被切割，以再生活性的细胞毒弹头。快速生长的肿瘤需要各种营养和维生素。因此，肿瘤细胞过度表达许多肿瘤特异性受体，这些受体可以作为靶点将细胞毒剂输送到肿瘤中。通过使用单抗和多不饱和脂肪酸，我们已经成功地在动物模型中靶向了肿瘤异种移植。在下一个资助期，我们计划以维生素(生物素和叶酸)、透明质酸和适体为导向模块，构建肿瘤靶向化疗的“制导分子导弹”。我们将使用基于机制的连接物，这种连接物在血液循环中稳定，但在肿瘤细胞内容易切割。作为携带多个导向模块和弹头的新型肿瘤靶向药物的载体或平台，我们将探索单壁碳纳米管、超短碳纳米管和树枝状大分子的高潜力，以及与小分子分离器模块的药物结合物。还将研究具有双靶向模块和/或双弹头的药物结合物。肿瘤靶向过程和药物释放的成像将通过共聚焦荧光显微镜、核磁共振和正电子发射计算机断层扫描进行研究。为此，将合成与包裹Gd离子的超短单壁碳纳米管以及[11C]标记弹头的药物偶联物。 公共卫生相关性：声明化疗的长期问题之一是缺乏针对肿瘤的治疗方法，即传统化疗依赖于快速增殖的癌细胞更有可能被细胞毒剂杀死的前提。然而，在现实中，细胞毒药物几乎没有或没有特异性，这会导致全身毒性，导致不良的严重副作用。因此，开发新型高效的肿瘤靶向给药系统，并加入有效的抗癌药物，是21世纪化疗的迫切需要，以显著提高化疗的疗效和消除不良反应。这项提案涉及新的肿瘤靶向药物输送系统，以解决这些紧迫的医疗问题。

DESCRIPTION (provided by applicant): Cancer is the second major cause of death (the No. 1 cause of death for age 85 or younger population) in the U.S. Despite the significant progress in the development of cancer detection, prevention, surgery and therapy, there is still no common cure for patients with malignant diseases. In addition, the long-standing problem of chemotherapy is the lack of tumor-specific treatments. Traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects such as hair loss, damages to liver, kidney and bone marrow. Therefore, various drug delivery protocols and systems have been explored in the last three decades. In general, a tumor-targeting drug delivery system consists of a tumor recognition moiety and a cytotoxic warhead connected directly or through a suitable linker to form a conjugate. The conjugate, which can be regarded as "guided molecular missile", should be systemically non-toxic. This means that the linker must be stable in blood circulation. Upon internalization into the cancer cell the conjugate should be readily cleaved to regenerate the active cytotoxic warhead. A rapidly growing tumor requires various nutrients and vitamins. Therefore, tumor cells overexpress many tumor-specific receptors, which can be used as targets to deliver cytotoxic agents into tumors. We have successfully targeted tumor xenografts in animal models by employing monoclonal antibodies and polyunsaturated fatty acids. In the next funding period, we plan to use vitamins (biotin and folic acid), hyaluronic acids and aptamers as the guiding modules to construct "guided molecular missiles" for tumor- targeting chemotherapy. We will use mechanism-based linkers that are stable in blood circulation, but readily cleavable inside tumor cells. As the vehicle or platform for the novel tumor-targeting agents bearing multiple guiding modules as well as warheads, we will explore the high potentials of single-walled carbon nanotubes (SWNTs), ultra-short SWNTs and dendrimers, as well as drug conjugates with small-molecule splitter modules. Drug conjugates with dual targeting modules and/or dual warheads will also be studied. Imaging of the tumor-targeting process and drug release in vitro and in vivo will be investigated by means of confocal fluorescence microscopy, MRI and PET. For that purpose, drug conjugates with ultra-short SWNTs encapsulating gadolinium ions as well as [11C]-labeled warheads will be synthesized. PUBLIC HEALTH RELEVANCE: Statement One of the long-standing problems of chemotherapy is the lack of tumor-specific treatments, i.e., traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects. Therefore, the development of new and efficient tumor-specific drug delivery systems with potent anticancer agents is an urgent need in the 21st century chemotherapy to dramatically enhance the efficacy and eliminate undesirable side effects. This proposal deals with novel tumor-targeting drug delivery systems to address these urgent medical issues.