Tumor -Targeting Chemotherapeutic Agents

描述（由申请人提供）：癌症是美国第二大死亡原因（85岁及以下人群的第一大死亡原因）。尽管在癌症检测、预防、手术和治疗方面取得了重大进展，但恶性疾病患者仍然没有常见的治愈方法。此外，化疗长期存在的问题是缺乏肿瘤特异性治疗。传统的化疗依赖于一个前提，即快速增殖的癌细胞更有可能被细胞毒素杀死。然而，在现实中，细胞毒性药物很少或没有特异性，这导致全身毒性，引起不希望的严重副作用，如脱发，损害肝，肾和骨髓。因此，在过去的三十年中，各种给药方案和系统已经被探索。通常，肿瘤靶向药物递送系统由肿瘤识别片段和直接连接或通过合适的连接物形成共轭物的细胞毒性战斗部组成。该共轭物可以看作是“分子制导导弹”，应该是全身无毒的。这意味着连接体在血液循环中必须是稳定的。在内化到癌细胞中后，缀合物应该很容易被裂解以再生活性的细胞毒性弹头。快速生长的肿瘤需要多种营养和维生素。因此，肿瘤细胞过度表达许多肿瘤特异性受体，这些受体可以作为将细胞毒性药物递送到肿瘤中的靶点。我们利用单克隆抗体和多不饱和脂肪酸成功地在动物模型中靶向肿瘤异种移植物。在接下来的资助期内，我们计划以维生素（生物素和叶酸）、透明质酸和适配体为导向模块，构建靶向肿瘤化疗的“制导分子导弹”。我们将使用基于机制的连接体，它在血液循环中稳定，但在肿瘤细胞内易于切割。作为承载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（SWNTs）、超短碳纳米管和树状大分子以及具有小分子分裂模块的药物偶联物的高潜力。还将研究具有双靶向模块和/或双弹头的药物偶联物。将通过共聚焦荧光显微镜、MRI和PET等技术研究肿瘤靶向过程和体外和体内药物释放的成像。为此，将合成与包裹钆离子的超短swnt的药物偶联物以及[11C]标记的战斗部。

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.