Biotin–Pt(IV)–Ru(II)–Boron–Dipyrromethene Prodrug as “Platin Bullet” for Targeted Chemo- and Photodynamic Therapy

Using the principle of "Magic Bullet", a cisplatin-derived platinum(IV) prodrug heterobimetallic <b>Pt(IV)-Ru(II)</b> complex, <i>cis,cis,trans</i>-[Pt(NH₃)₂Cl₂{Ru(tpy-BODIPY)(tpy-COO)}(biotin)]Cl₂ (<b>Pt-Ru-B</b>, <b>2</b>), having two axial ligands, namely, biotin as water-soluble B-vitamin for enhanced cellular uptake and a BODIPY-ruthenium(II) (<b>Ru-B</b>, <b>1</b>) photosensitizer having <i>N</i>,<i>N</i>,<i>N</i>-donor tpy (4'-phenyl-2,2':6',2″-terpyridine) bonded to boron-dipyrromethene (BODIPY), is developed as a "Platin Bullet" for targeted photodynamic therapy (PDT). <b>Pt-Ru-B</b> exhibited intense absorption near 500 nm and emission near 513 nm (λ_ex = 488 nm) in a 10% dimethyl sulfoxide-Dulbecco's phosphate-buffered saline medium (pH 7.2). The BODIPY complex on light activation generates singlet oxygen as the reactive oxygen species (ROS) giving a quantum yield (Φ_Δ) of ∼0.64 from 1,3-diphenylisobenzofuran experiments. <b>Pt-Ru-B</b> exhibited preferential cellular uptake in cancer cells over noncancerous cells. The dichlorodihydrofluorescein diacetate assay confirmed the generation of cellular ROS. Confocal images revealed its mitochondrial internalization. <b>Pt-Ru-B</b> showed submicromolar photocytotoxicity in visible light (400-700 nm) in A549 and multidrug-resistant MDA-MB-231 cancer cells. It remained nontoxic in the dark and less toxic in nontumorigenic cells. Cellular apoptosis and alteration of the mitochondrial membrane potential were evidenced from the respective Annexin V-FITC/propidium iodide assay and JC-1 dye assay. A wound healing assay using A549 cells and <b>Pt-Ru-B</b> revealed inhibition of cancer cell migration, highlighting its potential as an antimetastatic agent.