胶原酶修饰的兼具肿瘤靶向和pH响应的多功能纳米药物输送体系的构建

For the past few years, pH-responsive nano-drug delivery systems were investigated thoroughly and widely used in antitumor area. However, it is crucial for these acid-sensitive carriers to penetrate into tumor parenchyma and uptake by cancer cells after leak out from the tumor blood vessels to realize pH-responsive drug release. It shows significant low pH values (<6.8) only at the area of 200 μm far from vascular in tumor tissues, which is due to the abnormal tumor microenvironment. Extracellular matrix (ECM) is composed of a dense collagen network, which is one of the major obstacles that can significantly impede the penetration of nanoparticles into tumors. In this study, we aim to synthesize a series of drug-loaded polymer nanogels by the interaction between soybean peptide from hydrolysis of soy protein and pH-responsive orthoester monomers. After then, tumor homing peptide iRGD will be decorated on the surface of nanogels to improve its tumor-targeting ability. In order to enhance the penetration capacity in ECM, these nanogels will be modified with collagenase to select degrade ECM. From this research, the development of collagenase modified tumor-targeting and pH-responsive multi-functional nano-drug delivery systems with excellent permeability in tumor area and control drug release is expected to be able to realize.

酸敏感纳米药物输送体系从肿瘤血管中渗透到肿瘤实质且被癌细胞摄取是顺利实现pH响应给药的关键。由于肿瘤生理的异常，只有在距离血管超过200μm的地方，才表现出较低的pH值（<6.8），而致密的细胞外基质（ECM）是纳米药物载体在肿瘤中渗透的主要阻碍之一。本项目拟选用大豆肽和酸敏感原酸酯单体制备pH响应纳米凝胶，进一步将胶原酶和肿瘤靶向多肽iRGD共价修饰在其表面制备多功能载药纳米凝胶：胶原酶可以有效降解ECM的主要成分胶原蛋白，为载体的渗透打开“通道”；iRGD能够特异性识别癌细胞表面受体，赋予了载体主动靶向功能；酸性条件下原酸酯键断裂造成载体解聚，从而实现选择性控制释放药物的目的。通过本项目的研究，有望制备能够有效渗透肿瘤间质，且兼具主动靶向及pH响应的多功能载药纳米凝胶，达到有效抑制肿瘤的目的，为抗肿瘤纳米药物输送体系的研究提供新的思路和方法。

主动靶向富集能力、良好的肿瘤组织渗透能力和肿瘤内pH响应释放药物是提高纳米载体药物输送能力，顺利实现疗效的关键。然而，致密的细胞外基质（ECM）是纳米药物载体在肿瘤中渗透的主要阻碍之一。本项目首先合成酸敏感原酸酯单体作为交联剂，在水溶液中与双键修饰的海藻酸大分子反应，得到pH响应的纳米凝胶，并进一步将胶原酶修饰在纳米凝胶表面，得到复合纳米凝胶。胶原酶可以有效降解ECM，提高修饰后纳米凝胶的肿瘤内渗透能力。对制备的纳米凝胶的生理稳定性及pH响应降解和药物释放能力进行了详细研究。通过多种癌细胞株及对应的多细胞球体详细研究了该药物载体的细胞摄取及毒性，并利用小鼠肝癌模型研究了该药物输送体系在体内的药物分布、肿瘤富集和渗透以及抗肿瘤能力。胶原酶修饰后降解了ECM，显著增强了纳米凝胶的肿瘤内渗透和扩散能力，得到更高的药物富集和更好的抗肿瘤效应。为了提高药物输送体系的肿瘤靶向能力，本项目设计制备了乳糖酸和菠萝蛋白酶修饰的壳聚糖纳米药物载体用于阿霉素的输送。乳糖酸可以提高纳米粒子的肿瘤靶向能力，而菠萝蛋白酶可以降解ECM提高纳米粒子的渗透能力。对制备的纳米粒子的化学结构、粒径大小、稳定性、药物负载及降解能力进行了详细表征。利用多种癌细胞株研究了纳米粒子被癌细胞摄取能力和细胞毒性，利用荷瘤小鼠研究了该体系的肿瘤靶向、药物分布、肿瘤渗透、扩散能力和抗肿瘤效应。通过本项目的研究，有望制备能够有效渗透肿瘤间质，且兼具主动靶向及pH响应的多功能载药纳米凝胶，达到有效抑制肿瘤的目的，为抗肿瘤纳米药物输送体系的研究提供新的思路和方法。

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