Integrin avb3 targeted drug design, delivery, and imaging

描述(由申请人提供)：我们假设小分子拮抗剂和RGD-紫杉醇结合物选择性靶向整合素？V？3将具有适合临床研究的安全性和有效性。本研究的目的是(A)开发我们的高选择性整合素？V？3受体拮抗剂AV38，作为一种单用和联合紫杉醇治疗非小细胞肺癌(NSCLC)的新型抗肿瘤药物；(B)将AV38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来传递？V？3受体阳性的癌细胞；以及(C)通过正电子发射断层扫描(PET)、生物发光成像(BLI)和显微CT等多模式成像技术来监测这些过程。这一建议背后的理论基础来自以下观察：(A)整合素V3在癌细胞和恶性新生血管内皮细胞中过表达；(B)肺癌细胞高度转移，细胞黏附、侵袭转移器官基质，以及随后的肿瘤血管生成，部分是由V3介导的；(C)靶向治疗与常规化疗相结合可在不增加毒性的情况下提高治疗效果；以及(D)几种V3拮抗剂正在进入各种疾病模型的临床和临床前研究，但它们在非小细胞肺癌中的潜力尚未研究。为了更具体地检验我们的主要假设，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-紫杉醇结合物。我们假设整合素靶向递送紫杉醇可以根据整合素的表达水平对肺癌细胞产生优先的细胞毒性。具体目标2：开发一种新型的小分子整合素拮抗剂AV38，作为单药，与紫杉醇联合使用，并作为紫杉醇的结合物。我们假设非肽整合素拮抗剂由于其相对较高的代谢稳定性和易于合成，对于整合素特异性紫杉醇的输送是有效的。具体目的3：评价AIMS 1和AIMS 2中开发的紫杉醇结合物的整合素靶向给药效果和体内药代动力学。我们假设紫杉醇结合物在体内的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性质如分子大小、亲水性、代谢稳定性和分子电荷高度相关。具体目的4：通过肿瘤大小监测、组织病理学和非侵入性分子成像评价紫杉醇结合物的抗肿瘤作用。我们将验证这样的假设，即紫杉醇结合物的肿瘤递送对整合素阳性肺癌最有效。我们开发了一种新的药物结合物系统，可以同时向肿瘤细胞和肿瘤血管传递最大剂量，具有双重抗肿瘤作用。这种新的治疗方案在整合素V3过度表达的肿瘤患者中具有最大的潜力。这些肿瘤通常与非小细胞肺癌(NSCLC)一样具有高度转移性。由于大多数实体肿瘤依赖血管生成并在其细胞表面表达整合素，该项目开发的药物也适用于许多其他类型的肿瘤，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.