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以治疗生命 - 威胁三重阴性乳腺癌。三重阴性乳腺癌（TNBC）是高侵略性的乳腺癌的亚型生存不良。 TNBC患者对当前可用的反应不佳临床疗法，包括靶向疗法。化学疗法通常用于治疗TNBC。我们将开发化学治疗剂的新型肽结合物，以高效和肿瘤特异性递送抗癌药成三重阴性乳腺癌。各种药物输送系统，包括纳米化输送系统已经过测试，用于用于治疗TNBC的抗癌疗法。但是，这些输送系统由于致密肿瘤细胞外基质（ECM）的物理屏障。以前，我们已经设计和开发了小肽靶向MRI对比剂ZD2-N3-GD（HP-DO3A）（MT218）靶向ECM 癌蛋白指体B纤维蛋白（EDB-FN），用于准确检测TNBC。 MT218能够在包括TNBC在内的攻击性肿瘤中以微摩尔浓度以微摩尔浓度输送对比剂，导致在强大的信号增强中，可以准确检测MRI小鼠中三重阴性乳腺癌。目前，MT218处于癌症诊断的II期临床发展中。在这个项目中，我们将设计并开发ZD2肽靶向的药物缀合物，以有效地治疗TNBC。具体目标为：1）合成并表征肽药物结合物以治疗三重阴性乳腺癌； 2）确定药物结合物在小鼠模型中治疗TNBC的体内治疗功效。后进一步证明肽药物结合物在肿瘤模型中的可行性，包括PDX 模型，在此阶段1 SBIR项目中，我们将进一步进行全面的临床前评估其物理化学特性，药物特性和治疗功效，以进一步临床发展。肽药物结合物具有实现高效，肿瘤特异性的巨大潜力药物输送和有效治疗三重阴性乳腺癌，并提高患者的生命和生存。