A uPAR targeted nanoplatform with an NIR laser-responsive drug release property for tri-modal imaging and synergistic photothermal-chemotherapy of triple-negative breast cancer

In the present work, an iridium (Ir) complex loaded theranostic nanoplatform was designed for high-efficiency triple-negative breast cancer (TNBC) therapy. For this purpose, the Ir complex was firstly loaded on a photothermal agent of gold nanostars (GNS) by simply mixing followed by functionalization using a urokinase-type plasminogen activator receptor (uPAR) targeted polyetherimide-AE105 peptide conjugate (P-AE105) with the formation of GNS@Ir@P-AE105. It was demonstrated that the resultant GNS@Ir@P-AE105 was a multifunctional nanoplatform with advantages of (1) NIR laser controlled release of the Ir complex; (2) precise delivery of the Ir complex to TNBC cells; (3) excellent photothermal (PT)/photoacoustic (PA)/X-ray computed tomography (CT) tri-modal imaging ability; and (4) a synergistic photothermal-chemotherapeutic effect. An in-depth investigation of the mechanism revealed that binding forces of the Ir complex-GNS and P-AE105-GNS were significantly diminished upon NIR laser irradiation, which conferred an NIR laser-responsive Ir complex release property to the nanoplatform. Moreover, the nanoplatform exerted high efficiency anti-TNBC effects via a ROS-induced p53 apoptotic pathway. Specifically, combinational photothermal-chemotherapeutic treatments stimulated intracellular ROS generation, which significantly up-regulated apoptotic-relative p53 gene expression either by causing severe DNA damage or inducing an arrest effect on the sub-G1 phase of the cell cycle. Taken together, our work provides a novel theranostic nanoplatform for efficient and simultaneous diagnosis and therapy of TNBC.