Hepsin cleavable nanocapsules for precision medicine in prostate carcinoma (HEPSIN-NANOLYSIS

用于前列腺癌精准医疗的 Hepsin 可裂解纳米胶囊 (HEPSIN-NANOLYSIS

• 批准号: 282144192
• 负责人: Dr. Daniel Crespy
• 金额: --
• 依托单位: Max-Planck-Institut für Polymerforschung
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/282144192?language=en
• 关键词: Hepsin; cleavable; nanocapsules; precision; medicine

The serine protease hepsin is overexpressed in 90% of prostate cancer cases, exhibits pericellular proteolytic activity, and promotes tumor progression and metastasis in mice. Due to these features, hepsin is an attractive target molecule for both diagnosis and therapy of prostate cancer. We intend to use the enzymatic activity of hepsin for the site-specific release of antitumour drugs. A novel, peptide-based nanoscale drug carrier system will be developed and evaluated. The nanocarriers will be designed for selective opening at the surface of prostate cancer cells, thereby enabling specific and efficient therapeutic intervention under considerable reduction of side effects.LY294002, a thoroughly characterized antagonist of PI3-Kinase / AKT-mediated signalling, reveals potent anti-tumor activity in prostate cancer cell lines, either alone or combined with the pro-apoptotic and cancer-specific cytokine TRAIL (tumor necrosis factor related apoptosis-inducing ligand). By encapsulating these drugs in the nanocarrier system to be developed, we aim at a significant improvement of bioavailabilty and efficacy and a minimization of side effects in vivo. The concept will be biologically evaluated using experimental prostate cancer xenografts featuring inducible expression of hepsin in the chicken chorioallantoic membrane (CAM) model.The capsules will be prepared using the inverse miniemulsion method. Co-monomers and synthesis strategies will be optimized. The selection of a hepsin-specific target sequence will be achieved by screening of a bead-based combinatorial peptide library. Aggregation- and adsorption characteristics of peptide-based capsules in biological media will be analysed along with iterative adaptations of surface properties, ultimately leading to nanocarriers which i) are completely biodegradable; ii) efficiently accumulate in tumors, but not in vessels or organs; iii) reveal a surface which is accessible for proteolysis; iv) are specifically degradable by hepsin; and v) rapidly release their cargo upon exposure to enzymatically active hepsin protease. The interdisciplinary project will provide a groundwork for upcoming approaches aiming at the systematic development and evaluation of enzymatically cleavable nanocarriers for cancer therapy. In addition to the establishment of a library-based screening technology and a universal strategy for nanocarrier synthesis and loading, highly standardized in vitro models as well as in vivo analyses in the CAM xenograft model will provide reliable data in preclinical research, which will be achieved under avoidance of animal trials.

丝氨酸蛋白酶 hepsin 在 90% 的前列腺癌病例中过度表达，表现出细胞周蛋白水解活性，并促进小鼠肿瘤进展和转移。由于这些特征，hepsin 成为前列腺癌诊断和治疗的有吸引力的靶分子。我们打算利用hepsin的酶活性来进行抗肿瘤药物的位点特异性释放。将开发和评估一种新型的基于肽的纳米级药物载体系统。纳米载体将被设计用于在前列腺癌细胞表面选择性打开，从而在显着减少副作用的情况下实现特异性和有效的治疗干预。LY294002是一种彻底表征的PI3激酶/AKT介导的信号传导拮抗剂，在前列腺癌细胞系中显示出有效的抗肿瘤活性，无论是单独使用还是与促凋亡和癌症特异性药物联合使用 细胞因子 TRAIL（肿瘤坏死因子相关凋亡诱导配体）。通过将这些药物封装在待开发的纳米载体系统中，我们的目标是显着提高生物利用度和功效，并最大限度地减少体内副作用。该概念将使用实验性前列腺癌异种移植物进行生物学评估，该移植物在鸡绒毛尿囊膜（CAM）模型中可诱导表达hepsin。胶囊将使用反微乳液法制备。共聚单体和合成策略将得到优化。 Hepsin 特异性靶序列的选择将通过筛选基于珠子的组合肽库来实现。将分析生物介质中基于肽的胶囊的聚集和吸附特性以及表面特性的迭代适应，最终产生纳米载体，i) 完全可生物降解； ii) 在肿瘤中有效积聚，但不在血管或器官中积聚； iii) 揭示可进行蛋白水解的表面； iv) 可被hepsin特异性降解； v) 在暴露于具有酶活性的 hepsin 蛋白酶后迅速释放其货物。该跨学科项目将为即将推出的方法奠定基础，旨在系统开发和评估用于癌症治疗的酶可裂解纳米载体。除了建立基于文库的筛选技术和纳米载体合成和装载的通用策略外，高度标准化的体外模型以及CAM异种移植模型的体内分析将为临床前研究提供可靠的数据，这将在避免动物试验的情况下实现。