Integrin avb3 targeted drug design, delivery, and imaging

描述（由申请人提供）：我们假设选择性靶向整合素？v？通过小分子拮抗剂和RGD-紫杉醇偶联物对3的抑制将具有适合于临床研究的安全性和功效特征。本研究的目的是（A）开发我们的高选择性整合素AV 38？v？3受体拮抗剂作为一种新的抗肿瘤药物，用于非小细胞肺癌（NSCLC）单独和与紫杉醇联合治疗;（B）将AV 38与紫杉醇偶联，并使用这种偶联物以及我们最近描述的RGD-紫杉醇作为选择性递送机制，以？v？3受体阳性癌细胞;和（C）通过多模态成像技术如正电子发射断层扫描（PET）、生物发光成像（BLI）和microCT监测这些过程。这一建议背后的理由来自以下观察：（A）整合素？v？3在癌细胞和恶性新生血管内皮中过表达;（B）肺癌细胞是高度转移性的，并且细胞粘附、侵入转移性器官的基质，以及随后的肿瘤血管生成部分地由？v？3个;（C）靶向治疗与常规化疗的组合增加了治疗的疗效，而没有额外的毒性;和（D）几种拮抗剂？v？3正在各种疾病模型中进行临床和临床前研究，但其在NSCLC中的潜力尚未研究。为了更具体地检验我们的总体假设，我们提出：具体目标1：开发具有最佳受体亲和力和细胞毒性的RGD-紫杉醇缀合物。我们假设，紫杉醇的整合素靶向递送允许根据整合素表达水平对肺癌细胞的优先细胞毒性。具体目标二：开发一种新型小分子整联蛋白拮抗剂AV 38，其可作为单药、与紫杉醇联合使用以及作为紫杉醇偶联物。我们假设，非肽类整联蛋白拮抗剂由于其相对较高的代谢稳定性和易于合成，对于紫杉醇的整联蛋白特异性递送是有效的。具体目标3：评价在目的1和2中开发的紫杉醇缀合物的整合素靶向递送功效和体内药代动力学。我们假设紫杉醇偶联物的体内药代动力学和药效学与体外受体亲和力和细胞毒性以及其他特征如分子大小、亲水性、代谢稳定性和分子电荷高度相关。具体目标4：通过肿瘤大小监测、组织病理学和无创性分子影像学方法评价紫杉醇偶联物的抗肿瘤作用。我们将检验紫杉醇缀合物的肿瘤递送对整联蛋白阳性肺癌最有效的假设。我们开发了一种新型的药物偶联系统，可将最大剂量递送至肿瘤细胞和肿瘤血管，具有双重抗肿瘤作用。这种新的治疗方案在整合素过度表达的肿瘤患者中具有最大的潜力。v？3.这些肿瘤通常是高度转移性的，如非小细胞肺癌（NSCLC）。由于大多数实体瘤是血管生成依赖性的，并在其细胞表面表达整合素，因此该项目中开发的药物也适用于许多其他肿瘤类型，如脑癌、乳腺癌、卵巢癌、前列腺癌和结肠癌。

DESCRIPTION (provided by applicant): We hypothesize that selective targeting of integrin ?v?3 by a small-molecule antagonist and an RGD-paclitaxel conjugate will have safety and efficacy profiles suitable for clinical studies. The purposes of this study are to (A) develop AV38, our highly selective integrin ?v?3 receptor antagonist as a novel anti-neoplastic agent for non-small cell lung cancer (NSCLC) alone and in combination with paclitaxel; (B) conjugate AV38 to paclitaxel and use this conjugate as well as our recently described RGD-paclitaxel as a selective delivery mechanism to ?v?3 receptor-positive cancer cells; and (C) monitor these processes by multimodality imaging techniques such as positron emission tomography (PET), bioluminescence imaging (BLI), and microCT. The rationale behind this proposal comes from the following observations: (A) integrin ?v?3 is overexpressed in cancer cells and in the malignant neovascular endothelium; (B) lung cancer cells are highly metastatic and the adhesion, invasion of cells into the matrix of metastatic organs, and subsequent tumoral angiogenesis is mediated, in part, by ?v?3; (C) combination of targeted therapy with conventional chemotherapy increase the efficacy of therapy without additional toxicity; and (D) several antagonists of ?v?3 are entering into clinical and preclinical studies in a variety of disease models but their potential in NSCLC has yet to be studied. To test our overarching hypothesis more specifically we propose: Specific Aim 1: To develop an RGD-paclitaxel conjugate with optimal receptor affinity and cytotoxicity. We hypothesize that integrin targeted delivery of paclitaxel allows preferential cytotoxicity to lung cancer cells depending on integrin expression levels. Specific Aim 2: To develop AV38, a novel small-molecule integrin antagonist as a single agent, in combination with paclitaxel, and as a paclitaxel-conjugate. We hypothesize that non-peptide integrin antagonists are efficient for integrin specific delivery of paclitaxel due to their relatively high metabolic stability and ease of synthesis. Specific Aim 3: To evaluate the integrin-targeted delivery efficacy and in vivo pharmacokinetics of the paclitaxel conjugates developed in Aims 1 and 2. We hypothesize that in vivo pharmacokinetics and pharmacodynamics of paclitaxel conjugates are highly correlated with in vitro receptor affinity and cytotoxicity as well as other characters such as molecular size, hydrophilicity, metabolic stability, and molecular charge. Specific Aim 4: To evaluate the anti-tumor effect of the paclitaxel conjugates by means of tumor size monitoring, histopathology and non- invasive molecular imaging. We will test the hypothesis that tumor delivery of the paclitaxel conjugate is most effective to integrin positive lung cancer. We have developed a novel drug conjugate system to deliver maximum dose to both tumor cells and tumor vasculature with dual anti-tumor effects. This new treatment regimen has its greatest potential in patients with tumors that overexpress integrin ?v?3. These tumors are usually highly metastatic as in non-small cell lung cancer (NSCLC). Because most solid tumors are angiogenesis dependent and express integrin on their cell surface, drugs developed in this project are also applicable to many other tumor types such as brain, breast, ovarian, prostate, and colon cancer.