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

靶向药物输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，那么就可以避免包括细胞毒性在内的不必要的副作用，并且可以改善治疗效果，因为剂量和功效都可以增加。在这个项目中，我们的主要目标是利用纳米医学的潜力，通过制备自组装的合成纳米粒子，这些纳米粒子内部携带药物，但外面有一层聚合物涂层。然而，尽管聚合物涂层在帮助改善血液循环时间方面非常出色，但被封装的药物在肿瘤靶细胞内或附近的局部释放受到严重损害。这个问题应该是可以解决的，通过确保聚合物可以在肿瘤内部所需的时间释放，使肿瘤细胞完全死亡。我们的具体方法是引入聚合物与肽序列，也是底物的肿瘤特异性酶。当这种肽修饰的纳米颗粒到达肿瘤时，存在的酶会剥去聚合物涂层，露出核心纳米颗粒，这些纳米颗粒可以很容易地进入细胞并将封装的药物递送到局部肿瘤细胞。我们将通过化学方法准备所有必要的构建块来构建这些纳米颗粒，并以这种方式组装这些纳米颗粒，从而使肿瘤特异性酶可以很容易地获得肽序列。核酸将被用作第一批药物，因为它们可以非常具体，并且可以说比抗癌细胞毒素更安全。

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.