Photoactive monofunctional Pt(ii)–cyanine complex for nucleus and mitochondria dual-targeted antitumor therapy†

Monofunctional platinum (Pt) complexes, which have single reactive site for 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) of photoactivated Pt–CDPEN is over 16-fold lower than that of cisplatin. Pt–CDPEN exhibited the lysosomal escape property, enabling dual targeting of the cellular nucleus and mitochondria, thus helping to mitigate the chemotherapeutic resistance of Pt drugs. After systemic administration, PEGylated 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.