Bioreducible and traceable Ru(III) prodrug-loaded mesoporous silica nanoparticles for sequentially targeted nonsmall cell lung cancer chemotherapy

Abstract 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.