两性离子多肽构建的pH敏感仿蛋白质分子纳米靶向药物研究

The targeted nano drug delivery draws great attention due to its good therapeutic results and promising potential applications. However, synthetic polymer based targeted nano drug vehicle is far away from nature protein molecules or other biomacromolecules in terms of biocompatibility, specificity and efficiency. Especially, synthetic polymer could not be digested through metabolization route, which could cause the accumulation of synthetic polymer in cells. Thus, we proposed a mimic way to prepare peptide-based nano drug vehicle (NDV) to solve this problem and also improve the targeting efficiency. The proposed NDV is formed by zwitterionic nonfouling glutamic acid and lysine (EK) polypeptides with hydrophobic oligo peptide brushes. Furthermore, strong acidic groups are introduced near hydrophobic core to promote the pH sensitive affinity switch to target the poly sialic acid (PSA) in tumor tissue. And glutamic acid-arginine (ER) dimers are inserted into EK polypeptides to obtain cleavability by cathepsin B, which is abundant in tumor tissue. Combining all these facts, the accumulation of NDVs could be increase and the internalization of NDVs could be promoted by the deprotection of EK polypeptides layer. Furthermore, the peptide-based hydrophobic core can be digested by other types of cathepsin in lysosomes to increase the release rate of loaded drug molecules. After all, it is expected that this biocompatible smart NDV could have both advantages of protein and synthetic molecules to efficiently inhibit cancer growth and lower toxicity to health tissues at low cost and high stability. This project will also help us understand how to achieve the advanced functions through mimicking protein molecules.

纳米靶向药物因其优良的治疗效果和广泛的应用前景而备受关注。然而，现有纳米靶向药物缺乏在健康组织中的正常代谢能力，易导致合成高分子聚合物在健康组织的细胞内积累，而且缺乏对标靶癌组织的快速识别和响应能力。因此，本课题以蛋白质分子仿生出发，提出了以多肽为基础的纳米药物传递方法。通过两性离子多肽和疏水性多肽片段的接枝和组装，使纳米药物具备蛋白质分子的特征结构，并利用表面两性离子多肽弱酸下的快速质子化达到在癌症组织中的滞留和富集，借助组织蛋白酶B降解两性离子多肽保护层，提高细胞内吞速度，并在溶酶体中降解加速小分子抗癌药物释放，以期得到高效安全的抑瘤效果。这将使仿蛋白质功能载体兼具蛋白质分子的高活性、高生物安全性等特点，合成分子的稳定、无病原体、易于大规模生产的优势，使之能够成为未来可用于临床的纳米靶向药物，这对癌症治疗和仿蛋白质分子设计与合成具有重要的学术价值和实际意义。

本项目针对现有纳米药物难以克服体内免疫网络屏障，缺乏肿瘤靶向能力的问题，在自然科学基金的支持下，顺利完成了基于仿生两性离子多肽的载阿霉素靶向纳米药物研究。主要研究内容包括了该纳米药物的制备、血液相容性、网状内皮系统吞噬逃避、组织内扩散、穿膜行为、胞内药物释放、靶向效果、抑瘤效果、耐受剂量等的系统研究。并获得以下关键结果: 以两性离子多肽为基础的靶向纳米药物在修饰的磺酸根基团调控下能够实现有效肿瘤靶向，在其靶向过程中，健康脏器中化疗药物浓度始终保持低水平，而肿瘤中药物浓度可达正常脏器中10倍以上。由此提高了药物的耐受性，提高到临床一线药物阿霉素脂质体的3倍临床剂量后，小鼠仍然更为健康。因此，该纳米药物获得了出色的抑瘤能力，能够在短时间里彻底在清除肿瘤。另一方面，本研究还发现了该纳米药物载体以GD2表面受体为主的靶向机制。该项目的研究结果有望解决一大类癌症的化疗药物靶向治疗问题，加深了对蛋白质体内靶向机制的理解，对通过仿蛋白质分子设计的化疗药物递送具有重要的学术价值。

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