“肿瘤引发靶向”复合药物载体的制备及其在肿瘤诊疗领域的应用研究

Due to the “zero premature release” behavior of mesoporous silica nanoparticle (MSN) drug delivery systems, they are considered as the excellent choices to avoid premature release of drugs during the delivery processes to decrease the toxicity and increase the effective drug accumulation. But in most cases, lacking of suitable protection mechanisms makes MSNs difficult to targeting delivery efficiently. In our previous work, we found that PEG dynamic protection strategy can protect the micelle drug carriers effectively, makes which “stealth” in the normal physiological environment and "activated" by the acid in tumor tissues. Considering the above factors, we plan to fabricate a novel kind of “tumor-triggered targeting” PEG/chitosan (CHI)/MSN complex drug delivery system in which PEG is used to protect the targeting peptide GRGDS through dynamic protection strategy. Furthermore, we plan to introduce magnetic Fe3O4 nanoparticles into this system. As a result, the carriers can also be used for cancer targeting magnetic resonance imaging (MRI). The mechanism of PEG dynamic protection strategy will be elucidated by systematic study of the PEG leaving efficiencies and the abilities of the carriers penetrating into the cancer cells in different pHs. The effect of peptide and CHI in targeting and entering the cancer cells will be discussed. In vitro drug release experiments are planned to take to confirm the “zero premature release” ability of the carriers. Also, in vitro and in vivo experiments will be taken to investigate the safety and cancer treatment effect of the carriers. We hope that our work could provide a theoretical basis for PEG dynamic protection strategy in the application of MSN drug delivery systems, and lay the foundation for the researches and applications of this kind of systems in cancer diagnosis and treatment fields. We also hope that our work could provide new ideas for designing novel multifunctional drug delivery systems with safety, high efficiency and economy.

介孔硅纳米粒子（MSN）载体因其非刺激环境下零释放的能力可有效解决药物在传递中提前释放的问题，但缺乏保护机制使其难以高效的靶向给药。申请人前期工作表明PEG动态保护策略可有效保护胶束，使其在正常生理环境中“隐身”而经肿瘤“激活”靶向能力。为此本项目拟构建“肿瘤引发靶向”的PEG/壳聚糖（CHI）/MSN复合载体系统，以PEG动态保护靶向多肽，并将可用于MRI的Fe3O4纳米粒子引入系统以实现诊疗一体。通过考察不同pH下PEG的脱落效率及癌细胞对载体的吞噬能力阐明PEG动态保护的作用机制；研究多肽及CHI对载体靶向并进入癌细胞能力的影响；考察载体“零提前释药”的能力；通过体外细胞实验及动物实验系统考察此策略对载体安全性及癌症诊疗能力的影响，为PEG动态保护策略在MSN载体系统的应用研究提供理论依据，并为其在癌症诊疗领域的研究和应用奠定基础，为设计高效、安全、经济的多功能药物载体提供新思路。

介孔硅纳米粒子（MSN）载体因其非刺激环境下零释放的能力可有效解决药物传递中提前释药的问题，但缺乏保护机制使其难以高效的靶向给药。基于PEG的动态保护策略以及壳聚糖（CHI）的辅助跨膜能力，本项目制备了“肿瘤引发靶向”的PEG/CHI/MSN复合载体系统，考察了其在正常生理环境中“隐身”而经肿瘤“激活”靶向能力、癌症治疗能力，并为进一步阐明本系统中逐层动态释放机制提供理论依据，为设计高效、安全、经济的多功能药物载体提供新思路。本研究得到了以下结果：.1. 以MSN为基础构建了一种pH敏感型改性糊精接枝的药物载体DOX@MSN-DDA-CL，该载体显著提高了药物在小鼠体内的滞留效应，可以被动靶向肿瘤，并可在肿瘤的微酸性环境下释放药物并杀死癌细胞。.2. 以MSN及氧化葡聚糖（PAD）为基础构建了一系列pH敏感型药物载体系统，其载药量、包封率以及药物释放速率可由PAD的氧化度调控。.3. 以MSN为纳米贮存器构建了一种“肿瘤引发靶向”的“隐形”CHI/MSN复合药物载体，其在中性条件下因mPEG的保护而“隐形”而在肿瘤微酸性条件下被“激活”而更易于细胞吞噬，而载体可因细胞内高GSH浓度而释放DOX以杀死癌细胞。

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