Targeted Nanocarriers for Treatment of Lung Cancer

描述（由申请人提供）：肺癌是美国男性和女性癌症死亡的主要原因。传统治疗方法的肺癌患者的生存率仍远不能令人满意。最近，已经产生了用选择性抑制肿瘤血液供应从而控制癌细胞存活、增殖和/或转移的新型药物与常规抗癌或抗血管生成药物组合治疗肺癌的新方法， 临床兴趣。我们的初步研究表明，DIM-C-pPhC_6H_5（DIM-P），一个C取代的 二吲哚基甲烷显示出抗血管生成活性。本提案的目的是制备靶向聚乙二醇化CREKA肽包衣的DIM-P纳米载体（PCNCs-D），并研究其用于治疗肺癌的抗肿瘤活性和抗血管生成潜力。我们初步的管形成试验，蛋白质印迹和免疫组织化学研究强烈表明，DIM-P和PCNCs-D具有抗血管生成活性。我们的假设是：DIM-P的靶向聚乙二醇化纳米载体将靶向肿瘤血管系统并增加血浆半衰期，从而通过对肺肿瘤发挥抗血管生成活性来抑制肿瘤生长。该提案的新方面是研究使用PCNCs-D的新型靶向纳米载体药物递送治疗方法的抗血管生成功效，并了解体内肿瘤模型中参与抗血管生成作用的分子途径。本研究的假设和目标应遵循以下具体目标：（1）配制DIM-P靶向纳米载体;（2）评价DIM-P靶向纳米载体的抗血管生成和体内疗效;（3）阐明消退肿瘤中PCNCs-D活性的机制途径。这些研究的结果将证明， 新型PCNCs-D作为抗血管生成药物有效靶向递送的用途 用于肺癌治疗。拟议的研究有很大的潜力证明， 这是一种未经测试的高度创新的肺癌治疗方法。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death in both men and women in the United States. Survival rate of lung cancer patients treated by conventional modalities remains far from satisfactory. Recently, new approaches in the treatment of lung cancer with novel drugs that selectively inhibit tumor blood supply thus controlling cancer cell survival, proliferation and/or metastasis in combination with conventional anticancer or antiangiogenic drugs have generated clinical interest. Our preliminary studies demonstrated that DIM-C-pPhC6H5 (DIM-P), a c substituted diindolylmethanes exhibits antiangiogenic activity. The objective of this proposal is to formulate targeted pegylated CREKA peptide coated nanocarriers of DIM-P (PCNCs-D) and investigate its antitumor activity and antiangiogenic potential for treatment of lung cancer. Our preliminary tube formation assay, western blot and immunohistochemistry studies strongly suggest that DIM-P and PCNCs-D exhibits antiangiogenic activity. Our hypothesis is: targeted pegylated nanocarriers of DIM-P will target tumor blood vasculature and increase plasma half life thereby inhibiting tumor growth by exerting antiangiogenic activity against lung tumors. The novel aspects of this proposal are to study the antiangiogenic efficacy of a novel targeted nanocarrier drug delivery therapy approach using PCNCs-D and to understand the molecular pathways involved in the antiangiogenic effect in an in vivo tumor model. The hypotheses and objectives of the proposed research shall be pursued with the following specific aims: (1) To formulate targeted nanocarriers of DIM-P; (2) To evaluate antiangiogenic and in vivo efficacy of targeted nanocarriers of DIM-P; and (3) To elucidate mechanism pathways involved in PCNCs-D activity in regressed tumors. The results emanating from these studies will demonstrate the usefulness of novel PCNCs-D as an effective targeted delivery of antiangiogenic drug for lung cancer treatment. The proposed studies have strong potential to demonstrate an untested and highly innovative approach for lung cancer treatment.