PEGylated Dimeric BODIPY Photosensitizers as Nanocarriers for Combined Chemotherapy and Cathepsin B-Activated Photodynamic Therapy in 3D Tumor Spheroids.

The development of enzyme-activatable photosensitizers and their combination with conventional chemodrugs for antitumor therapy are of great interest. In this work, we reported a strategy of constructing activatable photosensitizers by interfering with the intramolecular charge transfer (ICT) state of an orthogonal boron dipyrromethene (BODIPY) chromophore. By conjugating a cathepsin B substrate peptide with a photosensitizer, BDP-BDP-NH2, the reactive oxygen species (ROS) generation of the product (ABP) was significantly suppressed due to the blockage of the electron-donating amino group. In vitro experiments proved the recovery of ROS generation under laser irradiation after the peptide linker was cleaved by cathepsin B. The ABP was then PEGylated and modified with a cRGD peptide (RNC) to encapsulate a hydrophobic anticancer drug, 10-hydroxycamptothecin (HCPT). The formed RNC/HCPT nanoparticles had good stability in serum-containing solutions with a hydrodynamic size of around 200 nm. The combination of cathepsin B-activated PDT and chemotherapy exhibited a strong ability to inhibit the growth of 4T1 breast cancer cells while promoting the induction of cell apoptosis. The RNC/HCPT nanoparticles also showed the ability to penetrate the 4T1 three-dimensional (3D) tumor spheroids and effectively shrunk the size of the spheroids. Taken together, our strategy offers a platform for antitumor drug delivery with an activatable PDT effect and combined therapy.