Enzyme-Triggerable Stealth Release (ETSR) of targeted nanoparticles for cancer gene therapy

将药物靶向递送到肿瘤等疾病组织是最终的治疗策略。如果药物可以在肿瘤组织中积累，则可以避免包括细胞毒性在内的不希望的副作用，并且由于剂量和功效都可以增加，因此可以改善治疗效果。在这个项目中，我们的主要目标是通过制备自组装，合成纳米颗粒，内部携带药物，但外部有聚合物涂层，来利用纳米医学的潜力。然而，虽然聚合物涂层在帮助改善血液循环时间方面表现出色，但在肿瘤靶细胞中或附近的包封药物的局部释放严重受损。通过确保聚合物可以在肿瘤本身内部的所需时间释放，使细胞死亡仅限于肿瘤细胞，该问题应该是可解决的。我们的具体方法是引入具有肽序列的聚合物，这些肽序列也是肿瘤特异性酶的底物。当这种肽修饰的纳米颗粒到达肿瘤时，那些存在的酶应该剥离聚合物涂层，露出可以容易地进入细胞并将封装的药物递送到局部肿瘤细胞的核心纳米颗粒。我们将通过化学制备所有必要的构建块来构建这些纳米颗粒，并以这样的方式组装这些纳米颗粒，即肽序列将容易用于肿瘤特异性酶。核酸将被用作第一种药物，因为这些药物可能非常特异，并且可以说比抗癌细胞毒性剂更安全。

Targeted drug delivery to disease tissues like tumours is the ultimate therapeutic strategy. If drugs can accumulate in tumour tissue, then unwanted side effects including cellular toxicity can be avoided and therapeutic effects may be improved since both dose and efficacy can increase. In this project our main aim is to harness the potential of nanomedicine by preparing self-assembly, synthetic nanoparticles that carry drugs inside but have and a polymer coating on the outside. However, while the polymer coating is excellent in helping to improve blood-circulation times, local release of encapsulated drugs in or near tumour target cells is heavily impaired. This problem should be soluble by ensuring that the polymer can be released at the required time inside the tumour itself bringing cell death exclusively to tumour cells. Our specific approach is to introduce polymers with peptide sequences that are also substrates for tumour specific enzymes. When such peptide modified nanoparticles reach tumours, those enzymes present should then strip-off the polymer coating revealing core nanoparticles that can easily enter cells and deliver encapsulated drug(s) to local tumour cells. We will construct these nanoparticles by preparing all necessary building blocks chemically and assemble these in such way that peptide sequences will be readily available for the tumour specific enzyme(s). Nucleic acids will used as the first drugs since these can be very specific and are arguably safer than the anticancer cytotoxic agents.