双亲性金属铱阳离子肽与白蛋白的新型纳米组装及抗癌机理研究

一类通过破坏磷脂膜系统而实现癌细胞杀伤的双亲性多肽因其作用机制难以导致抗药性，始终是抗癌药物研发的诱人方向。但因双亲性多肽的体内动力学、肿瘤靶向性、毒副作用方面的问题，药物开发和转化仍然困难。以血清白蛋白作为载体可有效改善药物的体内动力学和利用率，而与白蛋白形成纳米剂型更可提高化疗药物的肿瘤靶向性并降低毒副作用。近期我们发现具有疏水配位金属端与阳离子多肽端的铱-多肽复合物可通过疏水和静电的双重相互作用与白蛋白快速组装成稳定的纳米粒。本项目首先将对这种新颖的纳米组装方式的疏水结合位点、分子比例、电荷依赖性、组装形态等进行物理化学机制的系统研究。进而利用该复合物纳米粒可诱导肿瘤细胞肿胀破裂释放内容物的胀亡机制，深入探究胀亡致死模式通过诱发体内特异性免疫反应而清除肿瘤的潜力。因此，本项目将拓展白蛋白作为药物载体的构建方法和应用基础，并开拓双亲性多肽复合物和细胞胀亡在肿瘤治疗中的应用。

Membrane disruption-based cytotoxic mechanism of a class of amphipathic peptides is well-known for its low probability of developing drug-resistance in target cells, and thus remains an attractive direction for drug discovery research. However, problems derived from in vivo kinetics, specificity and side-effects of amphipathic peptides have hindered the progress of pharmaceutical development and translation. Serum albumin as a carrier protein can significantly improve the pharmacokinetics and usage rate of the drug it binds; moreover, an albumin-drug nanoparticle formulation can improve tumor-targeting efficiency and reduce side-toxicity of cancer chemotherapeutics. We have recently discovered that iridium(III)-peptide complexes harboring a hydrophobic end and a cationic charged end can rapidly assemble with albumin into stable nanoparticles depending on both hydrophobic and electrostatic interactions. In this proposal, we will systematically investigate the physicochemical principles underlying this novel nano-assembly process, including hydrophobic binding pockets, cationic charge dependence, molar ratio, morphology and stability etc. Next we will take advantage of the nano-assembly-induced oncotic mode of cell death featuring an eruptive release of cellular contents, and investigate how oncosis can further evoke in vivo immune responses to eradicate tumors in mouse models. Together, this project will expand the platform of using albumin as a drug nano-carrier by providing methodology and examples of application, and will further explore the potential of cationic amphipathic peptide complexes in cancer therapy.