College of Pharmaceutical Science, Jilin University , Changchun 130021, China.
CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Excellent Center for Nanoscience, National Center for Nanoscience and Technology , Beijing 100190, China.
ACS Appl Mater Interfaces. 2018 Jan 24;10(3):2347-2353. doi: 10.1021/acsami.7b16685. Epub 2018 Jan 9.
Aerobic glycolysis enables cancer cells to rapidly take up nutrients (e.g., nucleotides, amino acids, and lipids) and incorporate them into the biomass needed to produce a new cell. In contrast to existing chemotherapy/radiotherapy strategies, inhibiting aerobic glycolysis to limit the adenosine 5'-triphosphate (ATP) yield is a highly efficient approach for suppressing tumor cell proliferation. However, most, if not all, current inhibitors of aerobic glycolysis cause significant adverse effects because of their nonspecific delivery and distribution to nondiseased organs, low bioavailability, and a narrow therapeutic window. New strategies to enhance the biosafety and efficacy of these inhibitors are needed for moving them into clinical applications. To address this need, we developed a liposomal nanocarrier functionalized with a well-validated tumor-targeting peptide to specifically deliver the aerobic glycolysis inhibitor 3-bromopyruvate (3-BP) into the tumor tissue. The nanoparticles effectively targeted tumors after systemic administration into tumor-bearing mice and suppressed tumor growth by locally releasing 3-BP to inhibit the ATP production of the tumor cells. No overt side effects were observed in the major organs. This report demonstrates the potential utility of the nanoparticle-enabled delivery of an aerobic glycolysis inhibitor as an anticancer therapeutic agent.
有氧糖酵解使癌细胞能够快速摄取营养物质（例如核苷酸、氨基酸和脂质），并将其纳入生产新细胞所需的生物量中。与现有的化疗/放疗策略相比，抑制有氧糖酵解以限制腺嘌呤 5'-三磷酸（ATP）的产生是抑制肿瘤细胞增殖的一种非常有效的方法。然而，大多数（如果不是全部）现有的有氧糖酵解抑制剂由于其非特异性的传递和分布到非病变器官、低生物利用度和狭窄的治疗窗口而导致显著的不良反应。需要新的策略来提高这些抑制剂的生物安全性和疗效，以便将其推向临床应用。为了解决这一需求，我们开发了一种脂质体纳米载体，该载体通过一种经过充分验证的肿瘤靶向肽进行功能化，以将有氧糖酵解抑制剂 3-溴丙酮酸（3-BP）特异性递送到肿瘤组织中。纳米颗粒在荷瘤小鼠中系统给药后可有效靶向肿瘤，并通过局部释放 3-BP 抑制肿瘤细胞的 ATP 产生来抑制肿瘤生长。在主要器官中未观察到明显的副作用。本报告证明了纳米颗粒介导的有氧糖酵解抑制剂传递作为抗癌治疗剂的潜在用途。
