Targeted Drug Delivery

靶向给药

基本信息

批准号：
8611712
负责人：
Maurizio Pellecchia
金额：
$ 35.76万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8611712
关键词：
Actins Affect Affinity Antibodies Antineoplastic Agents Binding Cell Communication Cell Proliferation Cell Shape Cell Survival Cell physiology Cells Cellular Assay Cellular biology Collaborations Complex Cytoskeleton Cytotoxic agent Development Drug Delivery Systems Drug Design Drug Industry Endocytosis Endothelial Cells Eph Family Receptors EphA2 Receptor EphA4 Receptor Ephrins Goals Human In Vitro Individual Laboratories Ligand Binding Domain Ligands Link Lysosomes Malignant Neoplasms Malignant neoplasm of lung Mediating Modeling Mus Neoplasm Metastasis Normal Cell PC3 cell line Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phosphorylation Play Poison Process Property Proteins Quality of life Receptor Activation Receptor Protein-Tyrosine Kinases Research Role Signal Transduction Structure Subgroup Surface Techniques Therapeutic Tumor Angiogenesis Work base cancer cell cancer therapy cancer type cell motility chemotherapy cytotoxic design drug discovery drug structure in vivo innovation insight kinase inhibitor malignant breast neoplasm novel novel strategies overexpression pre-clinical programs receptor small molecule tumor tumor growth tumor microenvironment tumor progression tumor xenograft

项目摘要

The Eph receptors represent the largest subgroup of the receptor tyrosine kinase (RTK) and they influence cell shape and migration by acting directly on the actin cytoskeleton. In addition, they can affect cell proliferation and survival. In view of their pivotal role in cell-migration and cell-cell interaction, it is not surprising that Eph receptors and ephrins play an important role in tumor growth and cancer cell metastasis. Elevated expression of certain Eph receptors and ephrins has indeed been associated with tumor angiogenesis in many types of cancers. Therefore, there is strong evidence that Eph receptor/ephrin signaling could provide a novel yet unexplored target for the development of effective anti-cancer treatments. Because many Eph receptors are also overexpressed in cancer cells, they could also be used as targets to deliver cytotoxic or anti-cancer agents selectively to the tumors. In fact, following binding of their ephrin ligands, the Eph receptors are actively internalized in the cell where are directed into lysosomes. Hence, our central hypothesis is that Eph receptor targeting ligands covalently linked to a variety of anti-cancer agents could represent novel and effective therapeutics that would selectively deliver cytotoxic agents to cancer cells via the Eph receptors. In particular, we will explore the ability of a selective peptide ligand to deliver toxic substances to cancer cells expressing the EphA2 receptor. Furthermore, we will explore a novel and alternative way to target the EphA4 receptor by direct targeting of its ligand binding domain. To achieve these goals we will combine modern medicinal chemistry with structure-based design, cancer cell biology and in vitro and in vivo pharmacology. Finally, the most promising compounds will be evaluated in cellular assays and ultimately in tumor xenograft studies with breast, lung and prostate cancer cell lines as well as endothelial cells. If proven successful, our studies may result in novel agents that would not only be more efficacious than the current chemotherapeutic compounds, but that would also enhance the quality of life during and after chemotherapy.

EPH受体代表受体酪氨酸激酶（RTK）的最大亚组，它们会影响细胞形状和迁移直接作用于肌动蛋白细胞骨架上。另外，它们会影响细胞增殖和生存。鉴于它们在细胞迁移和细胞 - 细胞相互作用中的关键作用，不是令人惊讶的是，以法受体和埃弗林在肿瘤生长和癌细胞中起着重要作用转移。某些EPH受体和ephrins的表达升高确实与许多类型的癌症中的肿瘤血管生成。因此，有充分的证据表明EPH受体/ephrin 信号传导可以为开发有效抗癌者提供新颖但未开发的目标治疗。由于许多EPH受体在癌细胞中也过表达，因此也可以使用作为将细胞毒性或抗癌剂选择性地转移到肿瘤的靶标。实际上，随后绑定它们的埃弗林配体，EPH受体在细胞中被积极地内部化，该细胞被定向到该细胞中溶酶体。因此，我们的中心假设是靶向配体的EPH受体与A 各种抗癌剂可以代表新颖有效的治疗剂，可以选择性地提供通过EPH受体向癌细胞的细胞毒性剂。特别是，我们将探讨选择性的能力肽配体以将有毒物质传递到表达EPHA2受体的癌细胞。此外，我们将通过直接靶向其配体结合来探索一种新颖的替代方法来靶向EPHA4受体领域。为了实现这些目标，我们将将现代药物化学与基于结构的设计相结合，癌细胞生物学以及体外和体内药理学。最后，最有希望的化合物将是在细胞测定中评估，最终在乳腺癌，肺和前列腺癌研究中进行肿瘤异种移植研究细胞系和内皮细胞。如果被证明成功，我们的研究可能会导致新颖的代理人不仅比当前的化学治疗化合物，但这也将提高在期间和之后的生活质量化学疗法。