Synthesis and biological evaluation of a Platinum(II)-c(RGDyK) conjugate for integrin-targeted photodynamic therapy

T Chatzisideri; S Thysiadis; S Katsamakas; P Dalezis; I Sigala; T Lazarides; E Nikolakaki; D Trafalis; O A Gederaas; M Lindgren; V Sarli

doi:10.1016/j.ejmech.2017.09.058

Synthesis and biological evaluation of a Platinum(II)-c(RGDyK) conjugate for integrin-targeted photodynamic therapy

Eur J Med Chem. 2017 Dec 1:141:221-231. doi: 10.1016/j.ejmech.2017.09.058. Epub 2017 Sep 28.

Authors

T Chatzisideri¹, S Thysiadis¹, S Katsamakas², P Dalezis³, I Sigala¹, T Lazarides¹, E Nikolakaki¹, D Trafalis⁴, O A Gederaas⁵, M Lindgren⁶, V Sarli⁷

Affiliations

¹ Department of Chemistry, Aristotle University of Thessaloniki, University Campus, 54124, Thessaloniki, Greece.
² Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, University Campus, 54124, Thessaloniki, Greece.
³ Laboratory of Pharmacology, Medical School National and Kapodistrian University of Athens 75 Mikras Asias Street, Athens, 11527, Greece.
⁴ Laboratory of Pharmacology, Medical School National and Kapodistrian University of Athens 75 Mikras Asias Street, Athens, 11527, Greece. Electronic address: dtrafal@med.uoa.gr.
⁵ Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NTNU, N-7491 Trondheim, Norway. Electronic address: odrun.gederaas@ntnu.no.
⁶ Department of Physics, Norwegian University of Science and Technology, NTNU, N-7491 Trondheim, Norway. Electronic address: mikael.lindgren@ntnu.no.
⁷ Department of Chemistry, Aristotle University of Thessaloniki, University Campus, 54124, Thessaloniki, Greece. Electronic address: sarli@chem.auth.gr.

PMID: 29031069
DOI: 10.1016/j.ejmech.2017.09.058

Abstract

A cancer-targeting conjugate 4 of a cyclometalated [N,C,N-Pt(II)] complex bearing a NˆCˆN 1,3-di(2-pyridyl)-benzene with c(RGDyK) peptide as guiding molecule was designed and synthesized for real-time drug delivery monitoring in cancer cells and photodynamic therapy (PDT). This conjugate demonstrates a mild cytostatic effect to six cancer cell lines expressing integrins at different extent, while possessing promising features for PDT. Conjugate 4 demonstrated rapid cell uptake by receptor-mediated endocytosis and efficient generation of ¹O₂ upon irradiation. Incubation of rat bladder cancer cells AY27 with conjugate 4 (50 μΜ) prior to blue light exposure (5 min) resulted in significant reduction (50%) of cell survival compared to control cells as measured by MTT assay post 24 h after treatment.

Keywords: Angiogenesis; Integrin avβ3; Photodynamic therapy; Pt(II)-RGD conjugate; RGD peptide; Targeted drug delivery; Theranostic agent; Tumor therapy.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Integrins / antagonists & inhibitors*
Integrins / metabolism
Molecular Structure
Oligopeptides / chemistry
Oligopeptides / pharmacology*
Organoplatinum Compounds / chemical synthesis
Organoplatinum Compounds / chemistry
Organoplatinum Compounds / pharmacology*
Photochemotherapy*
Platinum / chemistry
Platinum / pharmacology*
Rats
Structure-Activity Relationship

Substances

Antineoplastic Agents
Integrins
Oligopeptides
Organoplatinum Compounds
Platinum
arginyl-glycyl-aspartic acid