Biotin–Pt(IV)–Ru(II)–Boron–Dipyrromethene Prodrug as “Platin Bullet” for Targeted Chemo- and Photodynamic Therapy
Arpan Bera, Amrita Nepalia, Aarti Upadhyay, Deepak Kumar Saini, Akhil R. Chakravarty
Abstract
Using the principle of “Magic Bullet”, a cisplatin-derived platinum(IV) prodrug heterobimetallic Pt(IV)–Ru(II) complex, cis,cis,trans -[Pt(NH 3 ) 2 Cl 2 {Ru(tpy–BODIPY)(tpy–COO)}(biotin)]Cl 2 ( Pt–Ru–B, 2 ), having two axial ligands, namely, biotin as water-soluble B-vitamin for enhanced cellular uptake and a BODIPY–ruthenium(II) ( Ru–B, 1 ) photosensitizer having N, N, N -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). Pt–Ru–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. Pt–Ru–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. Pt–Ru–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 Pt–Ru–B revealed inhibition of cancer cell migration, highlighting its potential as an antimetastatic agent.