Monofunctional platinum (Pt) complexes, characterized by their single reactive site capable of binding to DNA, exhibit distinct mechanisms of action compared to those of currently approved Pt-based chemotherapeutic drugs. Although monofunctional Pt complexes offer a promising strategy for overcoming chemotherapeutic resistance and reducing systemic toxicity, their antitumor effect is limited. Herein, we developed a photoactive monofunctional Pt(II)-cyanine dye complex (denoted as Pt-CDPEN) for cellular nucleus and mitochondria dual-targeted antitumor therapy. Due to the introduction of heavy atom Pt, Pt-CDPEN showed a 2.1-fold higher singlet oxygen quantum yield than that of cyanine dye. The half-maximal inhibitory concentration (IC50) value of photoactivated Pt-CDPEN is over 16-fold lower than that of cisplatin. Pt-CDPEN exhibited the lysosomal escape property, enabling dual targeting of cellular nucleus and mitochondria, thus helping to mitigate the chemotherapeutic resistance of Pt drugs. After systemic administration, PEGylation Pt-CDPEN (named as LET-9) exhibited high tumor accumulation, efficient antitumor therapy, and good biocompatibility. This Pt(II)-cyanine monofunctional complex provides a new platform for dual-targeted antitumor therapy, through simultaneously improving the efficacy and safety of Pt-based therapies.
