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Cyclic Ruthenium-Peptide Prodrugs Penetrate the Blood-Brain Barrier and Attack Glioblastoma upon Light Activation in
Liyan Zhang1, Gangyin Zhao2, Trevor Dalrymple1
1Leiden Institute of Chemistry, Universiteit Leiden, Einsteinweg 55, 2333 CC Leiden, Netherlands.
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-X1,2 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.
Insights
Ruthenium-peptide conjugates effectively target glioblastoma by crossing the blood-brain barrier. These compounds show promise for photoactivated anticancer therapy, with varying mechanisms for different conjugates.
Area of Science:
- Medicinal Chemistry
- Nanotechnology
- Oncology
Background:
- The blood-brain barrier (BBB) impedes effective glioblastoma treatment.
- Developing targeted therapies that cross the BBB is crucial for treating brain tumors.
Purpose of the Study:
- To investigate ruthenium-peptide conjugates for photoactivated glioblastoma therapy.
- To evaluate their potential to overcome the BBB and target brain tumors.
Main Methods:
- Synthesis and characterization of three cyclic ruthenium-peptide conjugates (Ru-p(HH), Ru-p(MH), Ru-p(MM)).
- In vitro and in vivo studies using glioblastoma 3D spheroids and zebrafish embryo models.
- Assessment of photochemistry, activation mechanisms, BBB penetration, tumor targeting, and antitumor efficacy.
Main Results:
- All conjugates demonstrated effective BBB penetration and glioblastoma targeting in vivo.
- Ru-p(MM) acted as a photoactivated chemotherapy (PACT) agent, while Ru-p(HH) functioned as a photodynamic therapy (PDT) agent.
- The nature of amino acid residues (Histidine or Methionine) influenced the photoactivation mechanism and oxygen dependence.
Conclusions:
- Ruthenium-peptide conjugates represent a promising strategy for photoactivated glioblastoma treatment.
- These agents can successfully cross the BBB, enabling targeted delivery to brain tumors.
- The study highlights the potential of tailored conjugate design for optimizing therapeutic outcomes.
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