Development of peptide-drug conjugates with a caged enzymatic cleavage site for improved drug delivery

开发具有笼状酶裂解位点的肽-药物缀合物，以改善药物输送

• 批准号: 326370480
• 负责人: Dr. Mareen Pagel
• 金额: --
• 依托单位: Institute for Research in Biomedicine (IRB)
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 无数据
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/326370480?language=en
• 关键词: Development; peptide; drug; conjugates; caged

Brain tumors such as glioblastoma are one of the most deadly cancer types. The treatment of this highly invasive cancer is limited due to the bad blood brain barrier permeability of many chemotherapeutics. To overcome this issue and the generation of side-effects as a result of low cancer cell selectivity, peptide-drug conjugates are often used. It has been shown that specific peptide sequences, derived from nature, can cross the blood brain barrier. Furthermore, certain peptides bind with high affinity and selectivity to receptors that are overexpressed in the membrane of cancer cells. These promising features will be utilized in a conjugate, consisting of a blood brain barrier shuttle, a peptidic receptor ligand and a chemotherapeutic agent. The resulting Trojan horse is envisioned to carry the drug across the blood brain barrier and to selectively treat cancer by shuttling the drug inside tumor cells. To further increase the selectivity, an enzymatically cleavable peptide linker will be introduced to the conjugate. Specific enzymes are involved in tumor growth, which means that they are secreted in high levels at the malignant site. If the peptide linker is cleaved by such a specific enzyme, the drug will be released to act mostly at a location where the tumor is growing and migrating. To stabilize this linker in the blood, the enzymatic cleavage site shall be temporally caged (protected) by a novel mechanism that relies on the Diels-Alder reaction with inverse electron demand. The synthesis and in vitro testing of these multifunctional constructs will help to improve permeability and selectivity of drug-conjugates. Furthermore, it is planned to establish and optimize the application of caging an enzymatic cleavage site, which can contribute to the development of a novel prodrug-method.

脑肿瘤如胶质母细胞瘤是最致命的癌症类型之一。由于许多化疗药物的血脑屏障渗透性较差，这种高度侵袭性癌症的治疗受到限制。为了克服这个问题和由于低癌细胞选择性而产生的副作用，经常使用肽-药物缀合物。已经表明，来自自然界的特定肽序列可以穿过血脑屏障。此外，某些肽以高亲和力和选择性结合癌细胞膜中过表达的受体。这些有前途的功能将被用于缀合物，由血脑屏障穿梭，肽受体配体和化疗剂。由此产生的特洛伊木马被设想为携带药物穿过血脑屏障，并通过在肿瘤细胞内穿梭药物来选择性地治疗癌症。为了进一步增加选择性，将酶促可裂解的肽接头引入缀合物。特定的酶参与肿瘤生长，这意味着它们在恶性部位以高水平分泌。如果肽接头被这种特异性酶切割，药物将被释放，主要作用于肿瘤生长和迁移的位置。为了稳定血液中的这种接头，酶裂解位点应通过依赖于具有逆电子需求的狄尔斯-阿尔德反应的新机制暂时笼住（保护）。这些多功能结构的合成和体外测试将有助于提高药物缀合物的渗透性和选择性。此外，计划建立和优化笼化酶切位点的应用，这可以有助于开发新的前药方法。