多级靶向纳米载药系统在肿瘤影像示踪与癌症诊疗一体化的应用研究

Co-delivery of antitumor gene and imaging agent using nanocarriers can dynamically observe the tumor growth and metastasis and provide effective theranostics. The reduced bioavailability of genes or drugs from the non-targeted nanovehicles may be the result of the nonspecific organization distribution and rapid kidney metabolism. In order to solve the above problems, we will provide a new nano-drug carrier modified with targeted the furin-cleavable peptides. Furin protease is a kind of glycoproteins expressed on the surface of tumor cells. Conventional modification of the furin-cleavable peptides on the nanoparticle surface can lead to poor curative effect on account of the nonspecific interactions with blood proteins or normal tissue cells. To address the problems, the hierarchical targeting and acidity-sensitive surface shielding strategy is utilized for the fabrication of antitumor gene and imaging agent co-delivery nanosystem. In this co-delivery system, the tumor-specific hyaluronic acid coating will protect the furin-targeting peptides and the co-loaded drugs. In the tumor microenvironment, the tumor acidity-sensitive shell will be hydrolysed and the exposed peptides specifically recognized and cleaved by furin will promote the cell uptake and induce the expression of anti-tumor genes effectively. In this project, we will study the drug loading and releasing of the hierarchical targeting nanocarriers, investigate the tumor-targeted fluorescence imaging and synergistic effect of the combined gene and thermal therapy, and expand the application of the novel theranostic nanoplatform for simultaneous tumor targeting diagnosis and therapy in the field of intelligent drug delivery.

共递送造影剂和基因的纳米载药系统可动态追踪肿瘤的生长和侵袭迁移，有效提高癌症的诊断和治疗效果。非靶向纳米载体在体内存在非特异性组织分布和肾代谢较快等缺陷，其所携带基因或药物的生物利用度大大降低。Furin蛋白酶是一种肿瘤细胞表面过表达的糖蛋白，利用携带furin蛋白酶切割位点序列的靶向纳米载体，为解决上述问题提供新的方案。然而，表面修饰靶向furin的短肽分子会与血液蛋白或正常组织细胞之间发生相互作用，降低了药物在肿瘤部位富集。为此，本项目拟设计具有多级靶向和酸响应功能的复合载药系统，通过酸敏感键耦联的负电性透明质酸外壳将靶向furin的短肽遮蔽保护在体系内部，进入肿瘤微环境后，外壳的酸致水解暴露出内部的靶向短肽，介导癌细胞的高效摄取。本项目将设计多级靶向聚合物共载抗癌基因和造影热疗药物，考察其在肿瘤靶向荧光成像和协同治疗上的效果，拓展肿瘤靶向诊疗一体化纳米平台在智能药物传输领域中的应用。

整个项目按照预期研究内容顺利完成，并进行了一些相关的扩展实验。针对肿瘤微环境的特点，本项目开发出多级靶向纳米载药体系，用于靶向联合传输和控制释放多种药物。不同于其他多数研究者着力于开发新颖且复杂纳米药物的研究理念，本研究一直致力于纳米药物更简单、更安全、更有效、更实用的设计和制备过程，并深入探究响应性纳米药物在光热/自噬抑制或化疗/自噬抑制联合治疗作用中的应用。研究主要完成工作包括：(1) 设计逐级靶向纳米载体（HCP）用于物理包载伯氨喹（PQ）和吲哚菁绿（ICG）。在水溶液中，HCP完成核壳结构的自组装，以提高体内的靶向功能与药物的稳定性。通过靶向细胞表面的CD44分子和细胞穿膜肽的增强细胞内吞作用，共载PQ和ICG的HCP纳米颗粒能够被MCF-7细胞选择性识别和内吞，进而在体外和体内均发挥协同的治疗和成像效果。(2) 合成具有氧化还原双响应性的纳米载体malPPM(SS)G（NPs），共载抗细胞自噬药物PQ和化疗试剂阿霉素DOX，研究了其氧化还原环境下药物的释放，初步研究表明，共载药物体系（NPs@PQ/DOX）能够促进B16F10细胞的内吞，对B16F10和MCF-7细胞具有协同的细胞毒性，同时能够逆转MCF-7/ADR耐药细胞的耐药性。通过本课题的研究，希望能够对肿瘤微环境响应性纳米药物载体的研发提供基础性实验依据，同时为基于纳米药物的肿瘤诊疗一体化提供参考和新思路。

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