摘要
饥饿治疗是一种新兴的肿瘤治疗手段,其靶向肿瘤细胞异常活跃的营养物质吸收和代谢途径,抑制和杀伤肿瘤。除了葡萄糖以外,饥饿治疗的靶点也包括肿瘤细胞内的其他营养物质。然而,靶向效率较差以及药物耐受等问题可能会影响其临床转化。近年来,纳米材料辅助的饥饿治疗快速发展,可以部分解决上述问题。本文介绍了一系列具有饥饿治疗作用以及将饥饿治疗与其他疗法相结合的纳米药物,其靶向葡萄糖代谢以外的营养物质,包括乳酸、氨基酸和脂质,为进一步开发具有饥饿治疗作用的纳米药物提供参考。
饥饿治疗(starvation therapy, ST)是一种剥夺肿瘤需要的关键营养物质并干预其代谢的治疗方式,近年来引起了广泛关注。肿瘤细胞通过提高摄取、转运和利用营养物质的效率以促进其生长、增殖和转

Figure 1 Metabolic pathways and drugs targeting metabolism involved in this review
MCT: Monocarboxylate transporter; ASCT2: Alanine-serine-cysteine transporter 2; LAT1: L-type/large neutral amino acid transporter-1; TCA cycle: Tricarboxylic acid cycle; FASN: Fatty acid synthase; MGLL: Monoacylglycerol lipase; SR-B1: Scavenger receptor type B1
虽然ST有独特优势,但仍有一些问题阻碍其进一步应用。首先,抑制肿瘤细胞与正常细胞共有的代谢途径会损伤正常组织,也可能影响免疫细胞分
本综述系统回顾了消耗非葡萄糖的营养物质或干预其摄取及合成的纳米药物,详尽阐述了它们的设计理念和抗肿瘤机制(

Figure 2 Schematic diagram of nanomaterial assisted starvation therapy (ST) involved in this paper
siRNA: Small interfering ribonucleic acid; Ce-BTC: Ce-benzenetricarboxylic acid; Ce6: Chlorene6; AQ4N: Banoxantrone dihydrochloride; DOX: Doxorubicin; IO: Iiron oxide; CDT: Chemodynamic therapy; PDT: Photodynamic therapy; MTT: Magnetothermal therapy; PTT: Photothermal therapy
无论是否处于缺氧环境,大部分肿瘤细胞都生成大量乳
肿瘤细胞对氨基酸的需求比正常细胞更高。除了必需氨基酸外,肿瘤细胞也需要外源性补充一些非必需氨基酸如丝氨酸和谷氨酰胺,以支持其高代谢活
除了合成蛋白质以外,氨基酸也可以作为中间代谢物和信号转导分子发挥重要作用。如丝氨酸是核苷酸合成和脱氧核糖核酸(deoxyribonucleic acid,DNA)甲基化的原料;亮氨酸、谷氨酰胺和精氨酸可以激活哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)通
目前,一些靶向氨基酸代谢的药物正在进行临床试验或已被批准进入临床应用,如抑制谷氨酰胺酶的CB-839和将精氨酸转化为瓜氨酸的聚乙二醇化精氨酸脱亚氨酶正进行临床试
从肿瘤微环境(tumor microenvironment,TME)中摄取的脂肪酸是肿瘤代谢的重要底物,其具有缓解肿瘤代谢应激的功能。由于脂肪酸产生的ATP比葡萄糖多,许多肿瘤细胞过表达脂肪酸氧化(fatty acid oxidation,FAO)所需酶以满足高水平的能量需
靶向脂质代谢中重要的酶可能是针对肿瘤脂质代谢的一个可行方案。因此,靶向乙酰辅酶A羧化酶和胆碱激酶的药物正在进行临床研
基于MCT1在细胞和TME间转运乳酸的功能,Yu
化学动力治疗(chemodynamic therapy,CDT)是指通过F
光敏剂在光照下能产生活性氧(reactive oxygen species,ROS),以杀伤肿瘤,该治疗方式被称为光动力治疗(photodynamic therapy,PDT)。然而,PDT的疗效高度依赖于肿瘤区域的氧浓度,改善乏氧的TME能提高PDT的杀瘤能
作为一种传统疗法,化疗的非选择性毒性是一个亟待解决的问
除了激活前药,靶向乳酸代谢也可以促进药物的精准释放。细菌Shewanella oneidensis MR-1(SO)可在无氧环境下将电子从乳酸转移到含M
Jiang
类似于LOD,L-氨基酸氧化酶(L-amino acid oxidase, AAO)能特异性氧化L-氨基酸为α-酮酸、H2O2和氨。AAO能通过H2O2与CDT联合。Chu
除了直接消耗氨基酸,阻断肿瘤细胞中上调的氨基酸转运蛋白是干预氨基酸代谢的另一种方式。参与亮氨酸转运的氨基酸转运蛋白B(0+)[(amino acid transporter B(0+),AT
脂肪酸合酶(fatty acid synthase,FASN)是催化脂肪酸合成的重要生物酶,并在许多肿瘤中过表达,因此被认为是潜在治疗靶
升高肿瘤区域温度可以使细胞膜解体、细胞骨架损伤和DNA合成受抑制,导致肿瘤细胞发生凋
纳米材料辅助的ST通过增强药物靶向性和释放的精准性,提高给药效率且避免了对正常组织的不良反应。这一特性可以更好地发挥ST的优势,部分解决了传统的全身给药会损伤正常组织的缺点。因此,许多营养物质,包括乳酸、氨基酸和脂质的代谢已成为纳米药物的干预靶点,并取得了很好的代谢干预效果。除此以外,由于纳米药物可以将多种药物整合为一个有机整体,并由此介导多重疗法。因此,PDT、CDT和化疗等均可与ST相结合,多种疗法可产生交互作用并增强疗效,起到“1 + 1 > 2”的效果。本文涉及的相关纳米药物见
MIL-101:A metal-organic framework containing F
尽管如此,在纳米材料辅助的ST进入临床应用之前,仍有一些问题有待解决。首先,纳米药物应用的主要障碍是这些纳米材料组分的长期生物安全性问题,特别是不可降解的无机纳米材料在给药后可在体内长时间停留引起毒性。除此以外,机体也可能无法耐受长期的代谢干预。尽管许多研究都列出了短期生物安全数据及纳米药物在体内的生物分布,但大多只观察了较短时间,而且不同实验动物和人类之间的差异也很
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