基因/光动力协同诊疗系统用于循环瘤的靶向治疗

Although great efforts have been made over the past decade to further develop the innovative capabilities of drug/gene carriers, there is still lack of efficient vector to overcome the big challenge of tumor metastasis. A series of "SMART" vectors, with drug/gene controlled release, tumor cell-induced platelet aggregation targeting, and environmental response functions, will be designed and synthesized for the inhibition of tumor metastasis in this project. We focus on their stimulus-response properties and controlled release behaviors, and further.accessed their biomedical properties in vitro and in vivo. System 1: The PpIX-multifuctional peptides will be designed and synthesized using standard Fmoc-based solid phase peptide synthesis (SPPS) protocol. The peptides capping on the surface of silica shell with pH-responsive imine bonds will be cut and released in the acidic lysosomal environment, which allow the photosensitizer presents obvious red fluorescence and excellent PDT efficacy. Biodegradable silica shell will be coated outside the PEI/p53 complex “core”, and would be disrupted by high glutathione levels inside tumor cells, resulting in the escape of the entrapped gene drugs and turning on the gene transfection. System 2: small sized BHQ-doped MSNs will be synthesized for fabricating the silica cages via the host-guest interaction. These cages will complex with therapeutic gene first, and then coated with cracked platelet membranes. Accordingly, they can offer highly specific recognition to the source cell lines in vitro, and in turn the excellent targeting ability to the tumor cell-induced platelet aggregation. Therapeutic genes will be released in the presence of MMP-2, lead to fluorescence recovery of PpIX, and obtained a combined anti-tumor efficiency from gene therapy and PDT. These systems will provide new approaches and useful information to guide the rational design of drug/gene delivery systems, and have great potential as efficient strategies for future cancer therapy.

设计、合成系列智能、靶向循环瘤聚集体的基因/光动力协同诊疗系统。策略1：合成功能多肽，以PEI/p53复合物为核构筑可降解硅球，通过主客体作用将多肽修饰到硅球表面，实现治疗基因和光敏剂共运载。该载体与循环瘤聚集体相遇后会被过度表达的MMP-2酶切断，使PpIX荧光恢复。RGD靶向肽介导载体快速进入癌细胞。内含体酸性环境使腙键断裂，释放出PpIX执行光动力治疗。癌细胞质中存在大量过度表达的谷胱甘肽，可使硅球结构的二硫键断裂，壳层解体，释放内部包载的复合物，实现癌细胞基因转染。策略2：根据循环瘤聚集体富含血小板的特点，合成和制备掺杂有BHQ的小尺寸介孔硅球，通过环糊精与金刚烷的主客体作用，硅球组成介孔硅笼，并复合治疗基因，包覆血小板膜，得到能特异性识别和靶向吸附循环瘤聚集体的治疗系统。该系统与循环瘤聚集体相遇后会被MMP-2酶切断重新分散成小硅球，PpIX荧光恢复，实现光动力学治疗。

由于肿瘤的形成是多因素、多基因参与的复杂过程，因此采用单一的治疗方案往往达不到理想的防治效果。我们通过对生物材料的功能化设计，将多种具有不同治疗机制的治疗策略，融合在同一个治疗体系中，靶向运送到肿瘤等疾病组织靶点，开启其治疗功能，可以互补机制缺陷并实现显著的协同治疗效果。此外，设计对肿瘤组织特殊生理环境具有刺激响应性的生物活性材料，不仅能实现对治疗剂的控制释放，还可有效规避其对正常组织的毒副作用。在本项目中，针对结肠癌、乳腺癌等癌症以及糖尿病等重大疾病，我们构建了一系列“智能”的、可用于肿瘤等重大疾病（靶向）治疗的、具有协同治疗潜力的生物活性材料，它们具有肿瘤微环境刺激响应性，载药量大，长效持久，功能拓展性强，生物安全性高等特点，我们还深入的研究和评价了它们在体外和体内的生物医学性能。作为崭新的肿瘤治疗方案，显示出良好的医学应用前景。通过生物活性材料特定的响应性和其理化、生化性质、生物活性功能等，实现了疾病的精准、长效治疗。