Molecular Toxicology Interdepartmental Degree Program, Fielding School of Public Health, University of California, Los Angeles, CA, 90095, USA; Department of Medicine, Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
Department of Medicine, Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
Semin Cancer Biol. 2021 Aug;73:158-168. doi: 10.1016/j.semcancer.2020.11.002. Epub 2020 Nov 11.
Peptides have many advantages over traditional therapeutics, including small molecules and other biologics, because of their low toxicity and immunogenicity, while still exhibiting efficacy. This review discusses the benefits and mechanism of action of apolipoprotein mimetic peptides in tumor biology and their potential utility in treating various cancers. Among lipoproteins in the circulation, high-density lipoprotein (HDL) and its constituents including apolipoprotein A-I (apoA-I; the predominant protein in HDL), apoJ, and apoE, harbor anti-tumorigenic activities. Peptides that mimic apoA-I function have been developed through molecular mimicry of the amphipathic α-helices of apoA-I. Oral apoA-I mimetic peptides remodel HDL, promote cholesterol efflux, sequester oxidized lipids, and activate anti-inflammatory processes. ApoA-I and apoJ mimetic peptides ameliorate various metrics of cancer progression and have demonstrated efficacy in preclinical models in the inhibition of ovarian, colon, breast, and metastatic lung cancers. Apolipoprotein mimetic peptides are poorly absorbed when administered orally and rapidly degraded when injected into the circulation. The small intestine is the major site of action for apoA-I mimetic peptides and recent studies suggest that modulation of immune cells in the lamina propria of the small intestine is, in part, a potential mechanism of action. Finally, several recent studies underscore the use of reconstituted HDL as target-specific nanoparticles carrying poorly soluble or unstable therapeutics to tumors even across the blood-brain barrier. Preclinical studies suggest that these versatile recombinant lipoprotein based nanoparticles and apolipoprotein mimetics can serve as safe, novel drug delivery, and therapeutic agents for the treatment of a number of cancers.
肽类药物具有许多优于传统治疗药物（如小分子和其他生物制剂）的优势，因为它们的毒性和免疫原性较低，同时仍具有疗效。本综述讨论了载脂蛋白模拟肽在肿瘤生物学中的益处和作用机制，以及它们在治疗各种癌症中的潜在应用。在循环中的脂蛋白中，高密度脂蛋白（HDL）及其成分，包括载脂蛋白 A-I（apoA-I；HDL 中的主要蛋白）、apoJ 和 apoE，具有抗肿瘤作用。通过模拟 apoA-I 的两亲性α-螺旋，开发了模拟 apoA-I 功能的肽。口服 apoA-I 模拟肽重塑 HDL，促进胆固醇外流，隔离氧化脂质，并激活抗炎过程。apoA-I 和 apoJ 模拟肽改善了癌症进展的各种指标，并在卵巢癌、结肠癌、乳腺癌和转移性肺癌的临床前模型中显示出疗效。当口服给予时，载脂蛋白模拟肽的吸收较差，当注入循环中时迅速降解。小肠是 apoA-I 模拟肽的主要作用部位，最近的研究表明，调节小肠固有层中的免疫细胞是其部分作用机制。最后，几项最近的研究强调了使用再构成的 HDL 作为靶向特异性纳米颗粒，携带难溶性或不稳定的治疗药物递送至肿瘤，甚至跨越血脑屏障。临床前研究表明，这些多功能重组脂蛋白基纳米颗粒和载脂蛋白模拟肽可作为安全、新颖的药物递送和治疗剂，用于治疗多种癌症。
