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岁或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普遍的治愈方法。此外，化疗的长期问题是缺乏肿瘤特异性治疗。传统的化疗依赖于这样一个前提，即快速增殖的癌细胞更有可能被细胞毒性剂杀死。然而，实际上，细胞毒性剂具有非常少的特异性或没有特异性，这导致全身毒性，引起不期望的严重副作用，如脱发，肝、肾和骨髓损伤。因此，在过去的三十年中，已经探索了各种药物递送方案和系统。通常，肿瘤靶向药物递送系统由肿瘤识别部分和细胞毒性弹头直接连接或通过合适的接头连接以形成缀合物组成。该偶联物可被视为“制导分子导弹”，应该是全身无毒的。这意味着接头必须在血液循环中稳定。在内化到癌细胞中后，缀合物应容易被切割以再生活性细胞毒性弹头。快速生长的肿瘤需要各种营养素和维生素。因此，肿瘤细胞过表达许多肿瘤特异性受体，其可用作将细胞毒性剂递送到肿瘤中的靶标。我们已经成功地通过采用单克隆抗体和多不饱和脂肪酸在动物模型中靶向肿瘤异种移植物。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“导向分子导弹”。我们将使用在血液循环中稳定，但在肿瘤细胞内容易裂解的基于机制的接头。作为承载多个导向模块以及弹头的新型肿瘤靶向剂的载体或平台，我们将探索单壁碳纳米管（SWNTs）、超短SWNTs和树枝状聚合物以及具有小分子分裂模块的药物缀合物的高潜力。还将研究具有双靶向模块和/或双弹头的药物缀合物。将通过共聚焦荧光显微镜、MRI和PET研究肿瘤靶向过程和体外和体内药物释放的成像。为此，将合成具有封装钆离子的超短单壁碳纳米管以及[11 C]标记弹头的药物缀合物。

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.