Development of peptide drug conjugates for cancer therapy

开发用于癌症治疗的肽药物缀合物

基本信息

批准号：
10760236
负责人：
Ryan Christopher Hall
金额：
$ 26.52万
依托单位：
MOLECULAR THERANOSTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10760236
关键词：
4T1 Affinity Amino Acids Antineoplastic Agents Binding Biological Markers Body Weight decreased Breast Cancer Patient Carcinoma Clinical Contrast Media Detection Development Diagnostic Diffuse Diffusion Dose Doxorubicin Drug Delivery Systems Drug Kinetics Drug Targeting Epidermal Growth Factor Receptor Estrogen Receptors Extracellular Matrix Fibronectins Goals High Pressure Liquid Chromatography Human Imaging technology Immunocompetent In Vitro Injections Invaded Life Magnetic Resonance Imaging Malignant Neoplasms Modeling Molecular Mus Neoplasm Metastasis Normal tissue morphology Oncoproteins Outcome Patients Peptides Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Positron-Emission Tomography Precision therapeutics Progesterone Receptors Property Proteins Quality of life Signal Transduction Small Business Innovation Research Grant Solid Neoplasm System Testing Therapeutic Toxic effect Treatment Efficacy Tumor Angiogenesis anti-cancer therapeutic black women cancer cell cancer clinical trial cancer diagnosis cancer imaging cancer therapy cellular targeting chemotherapy clinical application clinical development clinical practice commercialization cytotoxicity design drug efficacy effective therapy efficacious treatment epithelial to mesenchymal transition hydrophilicity image guided image guided therapy improved in vivo malignant breast neoplasm meter migration molecular imaging mouse model nanosized novel novel therapeutics overexpression patient derived xenograft model peptide drug personalized cancer therapy pre-clinical assessment side effect systemic toxicity targeted treatment theranostics triple-negative invasive breast carcinoma tumor tumor growth tumor specificity uptake young woman

项目摘要

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.

抽象的该项目的最终目标是开发和商业化肽药物缀合物来治疗生命- 威胁三阴性乳腺癌。三阴性乳腺癌（TNBC）是一种高度侵袭性的乳腺癌生存率低的乳腺癌亚型。 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。我们将开发新型化疗药物肽缀合物，用于高效和肿瘤特异性递送抗癌药物转化为三阴性乳腺癌。各种药物输送系统，包括纳米尺寸的递送系统已被测试用于治疗 TNBC 的抗癌疗法。然而，由于以下原因，这些递送系统无法在实体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用于靶向 ECM 的小肽靶向 MRI 造影剂 ZD2-N3-Gd(HP-DO3A) (MT218) 癌蛋白域外 B 纤连蛋白 (EDB-FN) 用于准确检测 TNBC。 MT218能够在侵袭性肿瘤（包括 TNBC）中输送微摩尔浓度的造影剂，从而产生强大的信号增强功能，可通过 MRI 准确检测小鼠中的三阴性乳腺癌。目前，MT218正处于癌症诊断的II期临床开发阶段。在这个项目中，我们将设计并开发ZD2肽靶向药物缀合物以有效治疗TNBC。具体目标是：1）合成和表征用于治疗三阴性乳腺癌的肽药物缀合物； 2）确定药物缀合物在小鼠模型中治疗 TNBC 的体内疗效。后进一步证明了肽药物缀合物在肿瘤模型（包括 PDX）中的可行性模型，在这个第一阶段的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、药学性质及治疗效果进行进一步的临床研究发展。肽药物偶联物具有实现高效、肿瘤特异性的巨大潜力三阴性乳腺癌的药物输送和有效治疗并提高治疗质量患者的生命和生存。