Development of peptide drug conjugates for cancer therapy

摘要 该项目的最终目标是开发和商业化治疗生命的多肽药物结合物。 威胁要患上三重阴性乳腺癌。三阴性乳腺癌(TNBC)是一种侵袭性很强的肿瘤 存活率低的乳腺癌亚型。TNBC患者对目前可用的药物反应不佳 临床治疗，包括靶向治疗。化疗通常用于治疗TNBC。我们会 开发新型化疗多肽结合物，用于高效和肿瘤特异性递送 将抗癌药物转化为三阴性乳腺癌。各种药物输送系统，包括 纳米级的输送系统，已经被测试用于输送治疗TNBC的抗癌疗法。 然而，这些递送系统无法在实体肿瘤中提供有效的药物递送 致密肿瘤细胞外基质(ECM)的物理屏障。此前，我们已经设计和开发了 靶向ECM的小肽MRI造影剂ZD2-N3-Gd(HP-DO3A)(MT218) 癌蛋白B区外纤维连接蛋白(EDB-FN)用于准确检测TNBC。MT218能够 在包括TNBC在内的侵袭性肿瘤中以微摩尔浓度输送造影剂，结果 在稳健的信号增强方面，通过MRI准确检测三阴性的小鼠乳腺癌。 目前，MT218正处于癌症诊断的第二阶段临床开发。在这个项目中，我们将设计 开发ZD2多肽靶向药物结合物，有效治疗TNBC。具体目标 1)合成和表征一种治疗三阴性乳腺癌的多肽药物结合物；2) 确定该药物结合物对小鼠肿瘤模型的体内治疗效果。之后 进一步证明多肽药物结合物在肿瘤模型中的可行性，包括PDX 模型，在此第一阶段SBIR项目中，我们将进一步进行全面的临床前评估 对其理化性质、药理性质和治疗效果进行进一步临床研究 发展。多肽药物结合物具有实现高效、肿瘤特异性的巨大潜力 三阴性乳腺癌的药物传递和有效治疗，提高治疗质量 患者的生命和生存。

Abstract The ultimate goal of this project is to develop and commercialize peptide drug conjugates to treat life- threatening triple negative breast cancer. Triple negative breast cancer (TNBC) is a high aggressive subtype of breast cancer with poor survival. TNBC patients do not respond well to currently available clinical therapies, including targeted therapy. Chemotherapy is commonly used to treat TNBC. We will develop novel peptide conjugates of chemotherapeutics for highly efficient and tumor-specific delivery of the anticancer drugs into triple negative breast cancer. Various drug delivery systems, including nanosized delivery systems, have been tested for delivery of anticancer therapeutics for treating TNBC. However, these delivery systems are unable to provide efficient drug delivery in solid tumors due to the physical barrier of dense tumor extracellular matrix (ECM). Previously, we have designed and developed a small peptide targeted MRI contrast agent ZD2-N3-Gd(HP-DO3A) (MT218) to target an ECM oncoprotein extradomain B fibronectin (EDB-FN) for accurate detection of TNBC. MT218 is able to deliver the contrast agent at micromolar concentrations in aggressive tumors, including TNBC, resulting in robust signal enhancement for accurate detection of triple negative breast cancer in mice with MRI. Currently, MT218 is in phase II clinical development for cancer diagnosis. In this project, we will design and develop ZD2 peptide targeted drug conjugates for efficacious treatment of TNBC. The specific aims are: 1) to synthesize and characterize a peptide drug conjugate to treat triple negative breast cancer; 2) to determine in vivo therapeutic efficacy of the drug conjugate to treat TNBC in mouse models. After further demonstrating the feasibility of the peptide drug conjugate in tumor models, including a PDX model, in this phase 1 SBIR project, we will then further perform comprehensive preclinical assessment of its physicochemical properties, pharmaceutical properties, and therapeutic efficacy for further clinical development. The peptide drug conjugate has a great potential to achieve highly efficient, tumor-specific drug delivery and efficacious treatment of triple negative breast cancer and to improve the quality of the life and survival of the patients.