甲胎蛋白携带药物靶向治疗肿瘤

Alpha Fetoprotein Delivered Drugs Targeting Therapy of Cancer

甲胎蛋白(alpha fetoprotein, AFP)是一种在胎儿发育时期高表达的蛋白质,它又是一种穿梭蛋白质,能够将营养物质输送给胚胎细胞。相似的是,在肝癌等恶性肿瘤发展时期,肿瘤细胞也高表达AFP及其受体,它们通过AFP受体摄取AFP及其运载的物质。因此,可以将AFP与抗癌药物结合,选择性攻击肿瘤细胞。AFP与药物的结合方式有多种,它可以和药物非共价结合,药物被包裹在AFP的疏水袋中;也可以通过共价键与药物结合,或者利用AFP与纳米颗粒和脂质体连接来提高输送药物的效果,肿瘤细胞的酸性环境能促使结合的药物有效释放。为了避免AFP致癌的风险,还可以通过改造AFP或利用AFP片段来输送药物。由于AFP介导的肿瘤靶向治疗主要是攻击具有AFP受体的癌细胞,因此对正常细胞影响并不大。AFP携带药物不仅能促进肿瘤细胞对药物的吸收、提高药物的抗肿瘤活性,还能克服多重耐药(multidrug resistance, MDR)问题。另外,AFP携带药物还具有免疫治疗的效果。AFP携带药物不仅能激活T细胞受体,消除免疫耐受,抑制肿瘤的生长,还能利用改造好的AFP靶向抑制髓源性抑制细胞(myeloid-derived suppressor cells, MDSCs),激活NK细胞和T细胞,从而破坏癌细胞以及阻止癌干细胞的转移。因此,AFP携带药物治疗是免疫治疗与靶向化疗相结合的新疗法,它将成为治疗癌症的一种策略。

Alpha fetoprotein(AFP) is a highly expressed protein during fetal development. It’s a shuttle protein that transports nutrients to embryonic cells. Similarly, during the development of malignant tumors such as liver cancer, tumor cells also express high levels of AFP and its receptors. They uptake AFP and its delivered substances through AFP receptors. Therefore, AFP can be combined with anticancer drugs to attack tumor cells selectively. There are several ways of AFP to deliver drugs, which can be noncovalently bound with drugs, and the drugs are wrapped in the hydrophobic pocket of AFP;they can also combine with drugs through covalent bonds, or use AFP to connect with nanoparticles and liposomes to improve the effect of drug delivery. AFP delivered drugs can be effectively released in the low pH environment of cancer cells. In order to avoid the risk of AFP carcinogenesis, drugs can be delivered by modifying AFP or using AFP fragments. Because AFP delivered drugs targeting therapy mainly attacks cancer cells that expressed AFP receptor, it has little effect on normal cells. AFP delivred drugs can not only promote the absorption of drugs by tumor cells, enhance the anti-cancer activity of drugs, but also overcome the problem of multidrug resistance(MDR). In addition, studies have found that AFP delivered drugs also have the effect of immunotherapy. AFP delivered drugs can not only activate T cell receptors, eliminate immune tolerance and inhibit tumor growth, but also inhibit myeloid derived suppressor cells(MDSCs), activate NK cells and T cells, thus destroying cancer cells and preventing cancer stem cell metastasis. Therefore, AFP delivery of drug is a new therapy combining immunotherapy and targeted chemotherapy, and it may become a strategy for cancer treatment in the future.