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

Abstract

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, Ru-p(HH), Ru-p(MH), and Ru-p(MM) ([Ru(Ph₂phen)₂(Ac-X₁RGDX₂-NH₂)]Cl₂ with Ph₂phen = 4,7-diphenyl-1,10-phenanthroline and X₁, X₂ = His or Met), include an integrin-targeted pentapeptide coordinated to a ruthenium warhead via two photoactivated ruthenium–X_1,2 bonds. Their photochemistry, activation mechanism, tumor targeting, and antitumor activity were meticulously addressed. A combined in vitro and in vivo study revealed that the photoactivated cell-killing mechanism and their O₂ dependence were strongly influenced by the nature of X₁ and X₂. Ru-p(MM) was shown to be a photoactivated chemotherapy (PACT) drug, while Ru-p(HH) 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.

We show the excellent blood−brain barrier crossing properties, tumor targeting, and antitumor activity of three cyclic ruthenium-peptide phototherapeutic conjugates for the treatment of glioblastoma.