Cyclic Ruthenium-Peptide Prodrugs Penetrate the Blood-Brain Barrier and Attack Glioblastoma upon Light Activation in Orthotopic Zebrafish Tumor Models.

The blood-brain barrier (BBB) presents one of the main obstacles to delivering anticancer drugs in glioblastoma. Herein, we investigated the potential of a series of cyclic ruthenium-peptide conjugates as photoactivated therapy candidates for the treatment of this aggressive tumor. The three compounds studied, , , and ([Ru(Phphen) Ac-XRGDX-NH)]Cl with Phphen = 4,7-diphenyl-1,10-phenanthroline and X, X = His or Met), include an integrin-targeted pentapeptide coordinated to a ruthenium warhead via two photoactivated ruthenium-X bonds. Their photochemistry, activation mechanism, tumor targeting, and antitumor activity were meticulously addressed. A combined and study revealed that the photoactivated cell-killing mechanism and their O dependence were strongly influenced by the nature of X and X. was shown to be a photoactivated chemotherapy (PACT) drug, while behaved as a photodynamic therapy (PDT) drug. All conjugates, however, showed comparable antitumor targeting and efficacy toward human glioblastoma 3D spheroids and orthotopic glioblastoma tumor models in zebrafish embryos. Most importantly, in this model, all three compounds could effectively cross the BBB, resulting in excellent targeting of the tumors in the brain.