Development of peptide drug conjugates for cancer therapy

开发用于癌症治疗的肽药物缀合物

• 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
• 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

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.

摘要 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- 威胁三阴性乳腺癌三阴性乳腺癌（TNBC）是一种高侵袭性乳腺癌。 生存率低的乳腺癌亚型。TNBC患者对目前可用的 临床治疗，包括靶向治疗。化疗通常用于治疗TNBC。我们将 开发用于高效和肿瘤特异性递送化疗药物的新型肽缀合物， 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经被测试用于递送治疗TNBC的抗癌治疗剂。 然而，这些递送系统不能在实体瘤中提供有效的药物递送，这是由于药物递送系统中存在的缺陷。 致密的肿瘤细胞外基质（ECM）的物理屏障。在此之前，我们设计并开发了 靶向ECM的小肽靶向MRI造影剂ZD 2-N3-Gd（HP-DO 3A）（MT 218） 癌蛋白外域B纤连蛋白（EDB-FN）用于准确检测TNBC。MT 218可以 在侵袭性肿瘤（包括TNBC）中以微摩尔浓度输送造影剂， 在使用MRI准确检测小鼠中的三阴性乳腺癌的稳健信号增强中。 目前，MT 218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ZD 2肽靶向药物缀合物用于有效治疗TNBC。具体目标 是：1）合成和表征治疗三阴性乳腺癌的肽药物缀合物; 2） 以确定药物缀合物在小鼠模型中治疗TNBC的体内治疗功效。后 进一步证明了肽药物缀合物在肿瘤模型中的可行性，包括PDX 模型，在第1阶段SBIR项目中，我们将进一步进行全面的临床前评估 其理化性质、药学性质和治疗效果，以进一步临床应用。 发展肽类药物偶联物具有实现高效、肿瘤特异性靶向治疗的巨大潜力， 三阴性乳腺癌的药物递送和有效治疗，并提高 患者的生命和生存。