Gold Nanoshell-Linear Tetrapyrrole Conjugates for Near Infrared-Activated Dual Photodynamic and Photothermal Therapies

[Image: see text] Photodynamic therapy (PDT) is a treatment in which photoactive compounds delivered to cancerous tissues are excited with light and then transfer the absorbed energy to adjacent tissue oxygen molecules to generate toxic singlet oxygen ((1)O(2)). As (1)O(2) is produced only where light and photosensitizers (PSs) are combined, PDT holds promise as a minimally invasive, highly selective treatment for certain cancers. The practical application of PDT requires easily synthesized, water-soluble PSs that have low dark toxicities, high (1)O(2) quantum yields, and efficient absorption of 650–850 nm near-infrared (NIR) light, which deeply penetrates tissue. We recently developed a linear tetrapyrrole metal complex, Pd[DMBil1]–PEG(750), that meets most of these criteria. This complex is remarkably effective as a PS for PDT against triple-negative breast cancer (TNBC) cells but, critically, it does not absorb NIR light, which is necessary to treat deeper tumors. To enable NIR activation, we synthesized a new derivative, Pd[DMBil1]–PEG(5000)–SH, which bears a thiol functionality that facilitates conjugation to NIR-absorbing gold nanoshells (NSs). Upon excitation with pulsed 800 nm light, NSs emit two-photon-induced photoluminescence spanning 500–700 nm, which can sensitize the attached PSs to initiate PDT. Additionally, NSs produce heat upon 800 nm irradiation, endowing the NS–PS conjugates with an auxiliary photothermal therapeutic (PTT) capability. Here, we demonstrate that NS–PS conjugates are potent mediators of NIR-activated tandem PDT/PTT against TNBC cells in vitro. We show that Pd[DMBil1]–PEG(5000)–SH retains the photophysical properties of the parent Pd[DMBil1] complex, and that NS–PS generate (1)O(2) under pulsed 800 nm irradiation, confirming activation of the PSs by photoluminescence emitted from NSs. TNBC cells readily internalize NS PS conjugates, which generate reactive oxygen species in the cells upon pulsed NIR irradiation to damage DNA and induce apoptosis. Together, these findings demonstrate that exploiting photoluminescent NSs as carriers of efficient Pd[DMBil1] PSs is an effective strategy to enable NIR light-activated tandem PDT/PTT.