Rationale: Drug combination therapy for cancer treatment exerts a more potent antitumor effect. The targeted delivery and release of multiple drugs in a patient's body thus presents a more effective treatment approach, warranting further research. Methods: Two antitumor drugs (ICG: indocyanine green and THP: pirarubicin) were successfully screened to sequentially trigger self-assembling peptides (P60) to produce bacteria-sized particles (500-1000 nm, P60-ICG-THP). First, after mixing equal amount of P60 and ICG, trace amount of water (the mass ratio between P60 and water: 100:1) was used to trigger their assembly into P60-ICG. Subsequently, the assembly of P60-ICG and THP was further triggered by ultrasound treatment to produce P60-ICG-THP. Results: P60-ICG-THP constituted a cluster of several nanoparticles (50-100 nm) and possessed a negative charge. Owing to its size and charge characteristics, P60-ICG-THP could remain outside the cell membrane, avoiding the phagocytic clearance of blood and normal tissue cells in vivo. However, after localizing in the tumor, the size and charge switches of P60-ICG-THP, rapidly triggered by the low pH of the tumor microenvironment, caused P60-ICG-THP to segregate into two parts: (i) positively charged nanoparticles with a size of approximately 50 nm, and (ii) negatively charged particles of an uneven size. The former, mainly carrying THP (chemotherapeutic agent), could immediately cross the cell membrane and deliver pirarubicin into the nucleus of tumor cells. The latter, carrying ICG (used for photothermal therapy), could also enter the cell via the endocytosis pathway or accumulate in tumor blood vessels to selectively block the supply of nutrients and oxygen (cancer starvation). Both these particles could avoid the rapid excretion of ICG in the liver and were conducive to accumulation in the tumor tissue for photothermal therapy. Conclusion: Our drug delivery system not only achieves the precise subcellular delivery of two anticancer drugs due to their size and charge switches in the tumor site, but also provides a new strategy to combine chemotherapy, photothermal therapy, and cancer starvation therapy for the development of a highly efficient antitumor therapeutic regimen.

中文翻译：

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原位肿瘤触发的亚细胞精确递送多种药物以增强化学-光热-饥饿联合抗肿瘤治疗

理由：用于癌症治疗的药物联合疗法具有更强的抗肿瘤作用。因此，多种药物在患者体内的靶向递送和释放提供了一种更有效的治疗方法，值得进一步研究。方法：成功筛选了两种抗肿瘤药物（ICG：吲哚菁绿和THP：吡柔比星），以依次触发自组装肽（P60）产生细菌大小的颗粒（500-1000 nm，P60-ICG-THP）。首先，将等量的P60和ICG混合后，使用痕量的水（P60和水之间的质量比：100：1）触发将它们组装成P60-ICG。随后，通过超声处理进一步触发P60-ICG-THP的组装，以产生P60-ICG-THP。结果：P60-ICG-THP构成了几个纳米颗粒（50-100 nm）的簇，并具有负电荷。由于其大小和电荷特性，P60-ICG-THP可以保留在细胞膜外部，从而避免体内血液和正常组织细胞的吞噬清除。然而，在肿瘤中定位后，P60-ICG-THP的大小和电荷转换（由肿瘤微环境的低pH值迅速触发）导致P60-ICG-THP分离为两个部分：（i）带正电的纳米颗粒（ii）大小不均匀的带负电粒子。前者主要携带THP（化学治疗剂），可以立即穿过细胞膜，将吡柔比星传递到肿瘤细胞的核中。后者带有ICG（用于光热疗法），也可以通过内吞途径进入细胞或在肿瘤血管中积聚，以选择性地阻断营养和氧气的供应（癌症饥饿）。结论：我们的药物递送系统不仅可以实现两种抗癌药物在肿瘤部位的大小和电荷转换，而且可以实现精确的亚细胞递送，而且还提供了将化学疗法，光热疗法和癌症饥饿疗法相结合的新策略，以开发两种抗癌药。高效的抗肿瘤治疗方案。