以“动态保护”策略构建基于无机介孔纳米粒子的多功能药物载体系统

Compared with the traditional organic/polymeric drug delivery systems, inorganic mesoporous nanoparticles, including mesoporous silica nanoparticles (MSN) and mesoporous ZnO nanoparticles (MZN) based delivery systems have higher drug loading capability and better stability with a "zero premature drug release" property. By introducing appropriate protection strategies scientists can make which targeted drug release more efficiently. In our previous work and works reported by other scientists, it is found that “dynamic protection” strategies can protect the drug carriers effectively, and make which “stealthy” in the physiological environment and "activated" to "anchor" the cancer cells by the acid in tumor tissues. Compared to the neutral pH (∼7.4) in the blood and healthy tissues, weakly acidic conditions could be found in tumor tissues (< 6.8) and intracellular environments (4.5-5.5). Therefore, in this project, we plan to introduce the PEG "dynamic protection" strategy and "charge reversal" strategy respectively to the magnetic MSN (M-MSN) and MZN based systems respectively to fabricate a series of multifunctional dual pH-sensitive anticancer drug delivery systems to achieve the controlled drug release intracellular. By studying the capabilities of the drug carriers “anchoring” and entering cancer cell in different pHs in vitro and in vivo, we plan to elucidate the mechanisms of the two "dynamic protection" strategies and the differences between which. As a result, we can screen the optimal strategy for different drug delivery systems under different conditions. Also, in vitro and in vivo experiments will also be taken to investigate the safety and cancer treatment effect of the different kinds of systems. Furthermore, for M-MSN based systems, we plan to study the application prospects of which in the cancer targeting magnetic resonance imaging (MRI) fields as the cancer theranostics systems. We also plan to study the synergistic therapy capability of MZN based systems. We hope that our work could illuminate the mechanisms and application prospects for the two kinds of “dynamic protection” strategies; and could provide novel ideas for designing multifunctional drug delivery systems with safety and high efficiency.

包括介孔硅（MSN）与介孔氧化锌（MZN）在内的无机介孔纳米粒子药物载体系统相比传统有机/高分子载体载药量高、稳定性好且可实现“零提前释药”。而合适保护机制的引入可使其更加高效的靶向给药。申请人前期工作及相关文献表明“动态保护”策略可有效保护载体，使其在生理环境中“隐身”而经肿瘤“激活”以“锚定”癌细胞。基于体内不同环境pH的差异，本项目拟分别将PEG“动态保护”及“电荷反转”策略引入到磁性MSN（M-MSN）与MZN系统中制备一系列多功能双pH敏感型抗癌药物载体系统，以实现癌细胞内药物控释。通过体内外实验系统研究两种“动态保护”策略对载体“锚定”并进入癌细胞能力的影响，阐明其作用机制并对比差异，以筛选不同条件下最优的保护策略。考察两种策略对载体安全性及肿瘤治疗能力的影响。系统考察M-MSN载体在磁共振成像领域的应用前景及MZN载体的协同治疗能力，为其在癌症诊疗领域的研究和应用奠定基础。

基于无机介孔纳米粒子（IMN）的药物载体系统相比传统有机/高分子载体载药量高、稳定性好且可实现“零提前释药”。而合适保护机制的引入可使其更加高效的靶向给药。申请人前期工作表明“动态保护”策略可有效解决因“隐形”分子的修饰导致载体难以进入癌细胞的难题。为此，本项目将PEG“动态保护”及电荷翻转策略分别引入到IMN中制备了一系列多功能多重敏感型抗癌药物载体系统。我们首先以介孔硅纳米粒子（MSN）为基础，以β-环糊精为“阀门”，引入PEG“动态保护”策略构建了双pH敏感型载体DOX@MSN-B-CD-PEG及DOX@MSN-CD-PEG。PEG可于中性环境下保护载体，而可在肿瘤微酸性环境下脱落，裸露正电荷助载体进入癌细胞，并在更酸的细胞内释放药物。随后我们引入电荷翻转策略制备了双pH敏感的DOX@MSN-ZnO-PLL-PLL(DMA) 及pH/氧化还原双敏感的DOX@HMSN-SS-PLL(cit)。该系统在中性环境下表面电位为负，而可在肿瘤微酸性环境下翻转为正便于细胞吞噬。中空MSN（HMSN）的引入可大幅提高载药量。在此基础上，我们分别引入近红外发射碳点及Fe3O4磁性纳米粒子构建了pH/氧化还原双敏感的DOX@HMSN-SS-C-dots-PLL(cit) 及DOX@MMSN-SS-PEI-cit，分别获得靶向近红外与T2-MR成像能力，实现诊疗一体。最后，针对以上两种策略响应速度过慢的问题，我们构建了一种具备快速电荷翻转能力、pH/氧化还原双敏感的载体DOX@HMSN-SS-PASP-API。体内外实验均表明以上系统可有效降低药物毒副作用、提高利用率，并可有效杀死癌细胞，抑制肿瘤生长。

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