Improving the limited penetration, accumulation and therapeutic effects of antitumor drugs in the avascular region of the tumor mass is crucial during chemotherapy. P-gp inhibitors have achieved little success despite significant efforts. Excessive P-gp inhibition disturbed the kinetic balance between intracellular accumulation and intercellular penetration, thus resulting in a more inhomogeneous distribution of substrate drugs. Here, we found that ginsenoside Rh2 pretreatment mildly downregulated P-gp expression through reactivating the pentose phosphate pathway and rebalancing redox status. This mild P-gp inhibition not only significantly increased the growth inhibition effect and accumulation profile of adriamycin (ADR) throughout the multicellular tumor spheroid (MCTS) but also had unique advantages in improving drug penetration. Furthermore, we developed a novel individual-cell-based PK-PD integrated model and proved that metabolic reprogramming and redox rebalancing-based P-gp regulation was sufficient to increase the ADR effect in both central and peripheral cells of MCTS. Thus, a “ginsenoside Rh2-ADR” sequential regimen was proposed and exhibited a potent antitumor effect in vivo. This novel P-gp inhibition via metabolic reprogramming and redox rebalancing provided a new idea for achieving better antitumor effects in the tumor avascular region during chemotherapy.

在化疗期间，提高抗肿瘤药物在肿瘤块无血管区域的有限渗透，积累和治疗效果至关重要。尽管付出了巨大的努力，P-gp抑制剂仍未取得成功。对P-gp的过度抑制会干扰细胞内积累与细胞间渗透之间的动力学平衡，从而导致底物药物的分布更加不均匀。在这里，我们发现人参皂苷Rh2预处理通过重新激活磷酸戊糖途径和重新平衡氧化还原状态来轻微下调P-gp表达。这种轻度的P-gp抑制作用不仅显着增加了阿霉素（ADR）在整个多细胞肿瘤球体（MCTS）中的生长抑制作用和积累特性，而且在改善药物渗透性方面具有独特优势。此外，我们开发了一种新颖的基于个人细胞的PK-PD集成模型，并证明了基于代谢重编程和基于氧化还原再平衡的P-gp调节足以增加MCTS中枢和外周细胞的ADR效应。因此，提出了“人参皂苷Rh2-ADR”顺序方案，并在体内表现出有效的抗肿瘤作用。通过代谢重编程和氧化还原再平衡的这种新的P-gp抑制作用为在化疗期间在肿瘤无血管区域实现更好的抗肿瘤作用提供了新思路。提出了“人参皂苷Rh2-ADR”顺序方案，并在体内表现出有效的抗肿瘤作用。通过代谢重编程和氧化还原再平衡的这种新的P-gp抑制作用为在化疗期间在肿瘤无血管区域实现更好的抗肿瘤作用提供了新思路。提出了“人参皂苷Rh2-ADR”顺序方案，并在体内表现出有效的抗肿瘤作用。通过代谢重编程和氧化还原再平衡的这种新颖的P-gp抑制作用为在化疗期间在肿瘤无血管区域实现更好的抗肿瘤作用提供了新思路。