持续定位输送模式下的多元协同促进纳米粒肿瘤内药物递送功效

Nanocarriers bring the hope of tumor-targeted drug delivery. However, the drug delivery of nanocarriers encounters a series of obstacles to enter tumor cells,such as clearance by renal filtration and the reticuloendothelial system, extravasation through the enlarged endothelial gaps in tumors,tumor dense extracellular matrix, cell membrane barrier and drug-resistence. Tumor penetration enhancer(TPE) and tumor-penetrating peptide(TPP) can assist nanocarriers to overcome the obstacles from tumor microenvironment and tumor cells. To take full advantage of this approach, drug-loaded nanoparticles(NPs) modified by tumor-penetrating peptide and penetration enhancers should be effectively and sustainedly delivered to tumor site. Then, it is necessary to fully understand the cooperation relationship of TPE,NPs and TPP,and the regulatory mechanism in the drug transport process in tumor. It is difficult to achieve sustained delivery of NPs and enhancers to tumor site for systematic administration because of the complicated effectors of the blood circulation system.Our project aims to establish a delivery system by assembling functional NPs, which can anchor a large amount of functional NPs and tumor penetration enhancers at tumor site to realize a sustained and local release model. We will focus on the studies of the cooperation relationship and mechanism of the penetration enhancers, NPs and peptide, to disclose the structure-activity relationship and the dependence on the administration dose, actuation duration and site. The influence of the cooperation of the enhancers, NPs and peptide on histophysiology of tumor will also be investigated. It is expected to explore a reasonable strtagy to improve intratumor drug delivery efficiency, and provide valuable guide to the exploitation of nano-delivery systems and clinical therapy of cancer.

纳米载体为抗肿瘤药物靶向递送带来了希望，但其在体内的药物递送受到来自于血液循环系统、肿瘤组织和肿瘤细胞的多重阻碍。促进肿瘤渗透性的促渗剂和肿瘤穿透肽可协助纳米载体克服肿瘤组织和肿瘤细胞障碍，提高肿瘤内的药物递送功效，但它们的高效利用，还受到如何向肿瘤部位高效、持续输送问题的限制。此外，促渗剂、穿透肽、纳米粒在肿瘤内的协同作用和调控机制还须深入揭示。鉴于系统给药受血液循环系统复杂因素的影响，难以持续稳定向肿瘤部位输送纳米粒，本项目拟通过温敏自凝胶性多功能纳米粒的组装，构建多元持续定位递送系统，把高剂量的纳米粒和促渗剂锚固在肿瘤部位并持续释放；在持续定位输送模式下，研究促渗剂、穿透肽协同纳米粒肿瘤内渗透和肿瘤细胞摄取的作用机理、构效关系和"量-时-空"依赖性，及其对肿瘤组织生物学特征的影响；探索促进纳米粒肿瘤内药物递送功效的有效途径；为具有临床应用前景的纳米载体设计和临床治疗提供指导和依据。

本项目以肿瘤靶向药物递送纳米载体的结构设计为基础，通过可注射纳米粒自温敏凝胶的肿瘤局部给药和纳米粒的静脉注射两种途径，研究促进纳米粒的肿瘤内富集、肿瘤渗透和细胞胞吞及胞内药物释放的构效关系，探索促进纳米粒肿瘤内药物递送功效的有效途径。主要成果有：1.肿瘤局部纳米药物递送：以自主开发的纳米粒自温敏凝胶体系为局部给药平台，把放射性碘131标记的透明质酸、金纳米棒分别组合到纳米凝胶体系中，实现了多种治疗剂的局部联合给药，多元协同作用获得了较好的抗肿瘤效果，并降低了毒副作用；同时，建立了3种新型的纳米粒原位凝胶体系，拓展了纳米粒原位凝胶给药系统的功能性和适用性。2. 促进纳米粒肿瘤渗透性新途径：揭示了纳米粒内核的软硬度对纳米粒肿瘤内渗透行为的影响，发现软质内核有利于深部渗透；设计制备的膜融合脂质体内包载键接药物的碳点，能够响应肿瘤微环境发生尺寸由大变小和电荷由负变正的双重转变，以此程序性逐一克服静脉注射纳米药物递送过程的各个屏障；还以自产生活性氧协同小粒径纳米载体的设计，克服了肿瘤低氧导致的渗透性差和耐药问题。3.促进胞内药物递送：设计了寡聚精氨酸修饰的膜融合脂质体纳米载体，通过穿膜和与细胞膜快速融合的协同作用使纳米粒直接进入细胞内，避免内涵体对药物的影响，实现药物的高效胞内递送；并采用该纳米载体体内联合递送anti-S100A4抗体和阿霉素，协同治疗有效抑制了肿瘤生长和转移。4. 药物的稳定输送与胞内快速释放：针对纳米载体血液循环稳定性和肿瘤细胞内去稳定性而快速释药的需求，设计制备了多个肿瘤微环境响应性的纳米载体，合理协调了药物输运和靶点有效释放功能。.发表SCI收录论文23篇，申报及获得专利5项，培养10多名博士研究生和10多名硕士研究生。投稿待审和待投稿论文3篇。参加10场国内外相关学术会议，共22人次。

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