Ruthenium-based agents are promising in cancer chemotherapy but lack specific targeting and controlled release properties. Herein, a new class of bioreducible mer-[Ru(III)Cl₃(dmso)(L)] prodrugs with highly DNA binding affinity were designed and synthesized for nucleus-targeted chemotherapy and selective activation in response to the tumor microenvironment. In this regard, ruthenium(III) prodrugs were reduced into highly active ruthenium(II) drugs in response to high intracellular glutathione levels, resulting in tumor apoptosis through synergistic intercalation that blocked DNA replication and coordination that cleaved nuclear DNA. In light of this, a multifunctional nanodrug (Ru-MSN-PLip) was constructed by integrating RuDPNI prodrug-loaded mesoporous silica nanoparticles (Ru-MSN) with a fusion protein-incorporated liposome (PLip) to achieve multiple targeting and eGFP-based fluorescence imaging of nonsmall cell lung cancer. Due to fusion protein-based cancer cell recognition and Ru(III) prodrug-mediated nuclear DNA targeting, Ru-MSN-PLip achieved sequential delivery and greater antitumor activity. In addition, Ru-MSN-PLip exhibited long-term blood circulation and selective accumulation in tumors, leading to significantly limited tumor growth in vivo without notable toxicity. Our findings indicated the potential applications of these types of bioreducible and traceable nanoprodrugs for efficient and safe nonsmall cell lung cancer therapy.

钌基药物在癌症化学疗法中很有前途，但缺乏特异性的靶向和控释特性。在此，一类新型的生物可还原的mer- [Ru（III）Cl ₃设计并合成了具有高DNA结合亲和力的（dmso）（L）]前药，用于针对核的化学疗法和响应肿瘤微环境的选择性激活。在这方面，响应高细胞内谷胱甘肽水平，钌（III）前药被还原为高活性钌（II）药物，通过协同嵌入阻止了DNA复制和裂解核DNA的配位作用，导致肿瘤凋亡。鉴于此，通过将载有RuDPNI前药的介孔二氧化硅纳米颗粒（Ru-MSN）与融合蛋白结合的脂质体（PLip）整合，以实现多重靶向和基于eGFP的荧光，构建了多功能纳米药物（Ru-MSN-PLip）非小细胞肺癌的影像学检查。由于基于融合蛋白的癌细胞识别和Ru（III）前药介导的核DNA靶向，Ru-MSN-PLip实现了顺序递送和更大的抗肿瘤活性。此外，Ru-MSN-PLip在肿瘤中表现出长期的血液循环和选择性积累，从而导致体内肿瘤的生长受到显着限制，而没有明显的毒性。我们的发现表明，这些类型的可生物还原和可追溯的纳米前药在有效和安全的非小细胞肺癌治疗中的潜在应用。