Bioresponsive theranostics for activity on demand delivery of Vascular Endothelial Growth Factor (VEGF)

生物反应性VEGF165的特点是这种潜在的治疗方法在未来的应用，如心肌梗死。VEGF165的递送是通过病变组织和健康组织内的过氧化物和/或蛋白酶梯度触发的。为此，我们提出了连接器结构，以响应VEGF165从共轭物中卸载的一个或两个梯度。由聚乙二醇(PEG) -连接子- VEGF165组成的缀合物尤其受益于本提案的两个重点，(i)连接子开发和（ii）通过扩展的遗传密码对VEGF165进行位点定向偶联。通过位点定向的VEGF165偶联，链接器- peg战略性地定位在VEGF165低亲和力受体结合位点附近，从而在循环过程中阻断VEGF165的活性。然而，在靶组织内，连接物- peg被生物反应性地从VEGF165中去除，从而在靶位点开启生长因子。我们期望减少副作用，并且-由于分配量减少-减少药效所需的剂量，从而通过“按需活动”改善药物特性。此外，对过氧化氢响应结构部署了过氧化氢连接剂的诊断特征。本项目是无机化学与药学学科合作的成果。

Bioresponsive VEGF165 delivery features this potential therapeutic for future application following e.g. myocardial infarction. VEGF165 delivery is triggered through peroxide and / or protease gradients within the diseased vs. healthy tissue. To this end, we are proposing linker structures, responding to one or both gradients with VEGF165 unload from the conjugate. The conjugates - consisting of polyethyleneglycol (PEG) - Linker - VEGF165 - particularly benefit from two foci of this proposal, (i) linker development and (ii) site directed conjugation to VEGF165, engineered by means of an expanded genetic code. Through site directed VEGF165 conjugation, the linker-PEG is strategically located close to VEGF165's low affinity receptor binding sites, thereby blocking VEGF165 activity during circulation. Within the target tissue, however, the linker-PEG is bioresponsively removed from VEGF165, thereby switching the growth factor on at target sites. We expect a reduction of side effects and - as of a reduced volume of distribution - reduced doses required for efficacy, leading into improved pharmaceutical properties through 'activity on demand'. Furthermore, diagnostic features of the peroxide linker are deployed for the peroxide-responding structures. This interdisciplinary project is the cooperative outcome of Inorganic Chemistry and Pharmaceutical Sciences.