Bioorthogonal Photoactivation of 2‐Nitrobenzyl Caged Doxorubicin Anticancer Prodrugs on Gold Nanostars

Bioorthogonal chemistry that can be controlled through near-infrared (NIR) light is a promising route to therapeutics. This study proposes a method to intracellularly photoactivate prodrugs using plasmonic gold nanostars (AuNSt) and NIR irradiation. Two strategies are followed. On one hand, doxorubicin (Dox) masked with a 2-nitrobenzyl carbamate (proDox₁) is used as a photoactivatable prodrug. In the second strategy, a photolabile Dox prodrug (proDox₂) obtained by modification of Dox with 2-nitrobenzyl diol bearing a disulfide is attached to the AuNSt surface. Under NIR irradiation AuNSt induce local electromagnetic field enhancement, leading to photocleavage of the 2-nitrobenzyl moiety in both proDox₁ and proDox₂, and subsequent Dox release. Near field enhancement by excitation of surface plasmons in AuNSt is sufficient to record the surface-enhanced Raman scattering (SERS) spectra of proDox₁ and proDox₂. The therapeutic potential of this bioorthogonal photoactivation strategy is confirmed in vitro and in vivo using a mouse model of human melanoma. NIR-activated AuNSt induce in vivo the intracellular release of Dox and subsequent cancer cell death, thus reducing tumor growth at low irradiation power density to avoid undesired photothermal effects. These results demonstrate that AuNSt are suitable platforms for NIR light-triggered drug delivery in cancer therapy.