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

用于癌症基因治疗的靶向纳米粒子的酶触发隐形释放（ETSR）

• 批准号: EP/F003188/2
• 负责人: Maya Thanou
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FF003188%2F2
• 关键词: Enzyme; Triggerable; Stealth; Release; ETSR

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.

靶向肿瘤等疾病组织的药物输送是最终的治疗策略。如果药物可以在肿瘤组织中积累，那么包括细胞毒性在内的不必要的副作用就可以避免，治疗效果可能会得到改善，因为剂量和疗效都可以增加。在这个项目中，我们的主要目标是通过制备自组装、内部携带药物但有药物的合成纳米颗粒和外部的聚合物涂层来利用纳米医学的潜力。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，但包裹的药物在肿瘤靶细胞内或附近的局部释放严重受损。这个问题应该是可以解决的，方法是确保聚合物可以在肿瘤内部所需的时间内释放，使细胞死亡专门针对肿瘤细胞。我们的具体方法是引入具有多肽序列的聚合物，这些聚合物也是肿瘤特异性酶的底物。当这种多肽修饰的纳米颗粒到达肿瘤时，这些存在的酶应该剥离聚合物涂层，揭示出核心纳米颗粒可以很容易地进入细胞并将封装的药物(S)输送到局部肿瘤细胞。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，使其能够很容易地用于肿瘤特异性酶(S)。核酸将作为第一批药物使用，因为这些药物可以非常特异，而且可以说比抗癌细胞毒剂更安全。

项目成果

Improved Synthesis of Linear Poly(ethylenimine) via Low-Temperature Polymerization of 2-Isopropyl-2-oxazoline in Chlorobenzene

• DOI: 10.1021/acs.macromol.5b00437
• 发表时间: 2015-05-26
• 期刊: MACROMOLECULES
• 影响因子: 5.5
• 作者: Monnery, Bryn D.;Shaunak, Sunil;Steinke, Joachim H. G.
• 通讯作者: Steinke, Joachim H. G.

Enzyme-triggered PEGylated siRNA-nanoparticles for controlled release of siRNA

• 发表时间: 2014-01
• 期刊: Journal of RNAi and Gene Silencing : An International Journal of RNA and Gene Targeting Research
• 作者: P. Yingyuad;M. Mével;C. Prata;C. Kontogiorgis;M. Thanou;Andrew D. Miller

Effect of surface charge and ligand organization on the specific cell-uptake of uPAR-targeted nanoparticles.

表面电荷和配体组织对 uPAR 靶向纳米粒子的特定细胞摄取的影响。

• DOI: 10.3109/1061186x.2013.805336
• 发表时间: 2013
• 期刊: Journal of drug targeting
• 影响因子: 4.5
• 作者: Wang M