X RAY GUIDED DRUG DELIVERY SYSTEMS BY APCITIDE

范德比尔特公司开发的X射线引导药物输送系统 大学包括特异性结合的多肽和单链抗体 辐射诱导的血管蛋白。开发这项技术的目标是 是实现部位特异性药物输送到肿瘤微血管系统，这 利用肿瘤抗体规避肿瘤类型特异性的限制 抗原，如CEA或Her2。 目前的临床可行性研究针对的是辐射诱导的激活。 整合素α-2b和β-3。我们发现这些被激活的整合素 照射后积聚在肿瘤血管中。与之结合的配体 α-2b-β3(A2bB3)包括纤维连接蛋白、纤维蛋白原和多肽片段 从这些蛋白质中。一种这样的多肽是RGD，它存在于这些细胞中的每一个上 在受辐射的肿瘤内，配体与A2bB3结合。商业化的 RGD的合成形式，apcitie，(Acutect，Diatide)，与Tc-99m结合以允许 用于对激活的血小板进行成像。在本研究中，我们将利用 APCIPID-TC-99在肿瘤中显示a2bB3整合素活化。 这项研究设计有三个组成部分。第一个是优化 使用APCITE-TC-99和大剂量照射剂给药时间表 立体定向放射治疗转移性疾病。第二，我们将降低局势的升级 应用连续再评估法(CRM)评估放射治疗剂量 使用哪种APCIPTID-TC-99，并评估(成像)反应。 将进行模型拟合，并将减少下一位患者的剂量 估计。最后，我们将根据疾病的部位对剂量降级进行分层 和肿瘤亚型。一次优化，阈值剂量和限制 辐射诱导的多肽结合被确定，我们将设计临床 使用治疗性放射性核素或脂质体的试验。

X-ray guided drug delivery systems developed at Vanderbilt University include peptides and single chain antibodies that bind specifically to radiation-induced vascular proteins. The goal of developing this technology is to achieve site-specific drug delivery to the tumor microvasculature, which circumvents the limitation of tumor-type specificity using antibodies to tumor antigens such as CEA or Her2. The present clinical feasibility study addresses radiation-induced activation of integrins alpha-2b and beta-3. We have found that these activated integrins accumulate in the tumor blood vessels after irradiation. Ligands that bind to alpha-2b-beta3 (a2bB3) include fibronectin and fibrinogen and peptide fragments from those proteins. One such peptide is RGD, which is present on each of these ligands and binds to a2bB3 within irradiated tumors. The commercialized synthetic form of RGD, apcitide, (Acutect, Diatide), conjugates Tc-99m to allow for imaging of activated platelets. In the present study, we will utilize apcitide-Tc-99 to image a2bB3 integrin activation in cancer. The study design has three components. First is the optimization of the schedule of administration of apcitide-Tc-99 and high dose irradiator using stereotactic radiotherapy for metastatic disease. Secondly, we will de-escalate radiation therapy dose by use of the continual reassessment method (CRM) in which apcitide-Tc-99 is administered and the response is assessed (imaged). Model fitting will be performed and reduced dose for the next patient will be estimated. Finally, we will stratify dose de-escalation by the site of disease and tumor subtypes. Once optimization, threshold dose and limitations of radiation-induced peptide binding are determined, we will design clinical trials using therapeutic radionuclides or liposomes.