Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China; College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
Int J Pharm. 2023 Jul 25;642:123180. doi: 10.1016/j.ijpharm.2023.123180. Epub 2023 Jun 25.
As the main systemic treatment for triple-negative breast cancer (TNBC), the bleak medical prognosis of chemotherapy resulted in impaired life quality by tumor recurrence and metastasis. The feasible cancer starvation therapy could inhibit tumor progression by blocking energy supplements, however, the mono-therapeutic modality showed limited curing efficacy due to heterogeneity and abnormal energy metabolism of TNBC. Thus, the development of a synergistic nano-therapeutic modality involving different anti-tumor mechanisms to simultaneously transport medicines to the organelle where metabolism took place, might remarkably improve curing efficacy, targeting ability, and bio-safety. Herein, the hybrid BLG@TPGS NPs were prepared by doping multi-path energy inhibitors Berberine (BBR) and Lonidamine (LND) as well as the chemotherapeutic agent Gambogic acid (GA). Our research indicated that Nanobomb-BLG@TPGS NPs inherited the mitochondria targeting ability from BBR to accumulate precisely at the "energy factory" mitochondria, and then induce starvation therapy to efficiently eradicated cancer cells by coordinately powered off tumor cells via a "three-prone strategy" to cut off mitochondrial respiration, glycolysis, and glutamine metabolism. The inhibition of tumor proliferation and migration was enlarged by the synergistic combination with chemotherapy. Besides, apoptosis via mitochondria pathway and mitochondria fragmentation supported the hypothesis that NPs eliminated MDA-MB-231 cells by violently attacking MDA-MB-231 cells and especially the mitochondria. In summary, this synergistic chemo-co-starvation nanomedicine proposed an innovative site-specific targeting strategy for improved tumor treatment and decreased toxicity to normal tissues, which provided an option for clinical TNBC-sensitive treatment.
作为三阴性乳腺癌（TNBC）的主要全身治疗方法，化疗的黯淡医学预后导致肿瘤复发和转移导致生活质量受损。可行的癌症饥饿疗法可以通过阻断能量补充来抑制肿瘤进展，然而，由于 TNBC 的异质性和异常能量代谢，单一治疗模式显示出有限的治愈效果。因此，开发涉及不同抗肿瘤机制的协同纳米治疗模式，同时将药物输送到发生代谢的细胞器，可能会显著提高治疗效果、靶向能力和生物安全性。在此，通过掺杂多路径能量抑制剂小檗碱（BBR）和 Lonidamine（LND）以及化疗药物藤黄酸（GA）来制备杂交 BLG@TPGS NPs。我们的研究表明，Nanobomb-BLG@TPGS NPs 从 BBR 继承了线粒体靶向能力，精确地积聚在“能量工厂”线粒体上，然后通过“三易位策略”诱导饥饿疗法，通过切断线粒体呼吸、糖酵解和谷氨酰胺代谢来有效地根除癌细胞。与化疗的协同组合扩大了肿瘤增殖和迁移的抑制作用。此外，通过线粒体途径和线粒体碎片化的凋亡支持了 NPs 通过猛烈攻击 MDA-MB-231 细胞特别是线粒体来消除 MDA-MB-231 细胞的假说。总之，这种协同化疗-饥饿纳米医学为改善肿瘤治疗和降低对正常组织的毒性提供了一种创新的靶向策略，为临床治疗 TNBC 提供了一种选择。
