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Encapsulation of a Ruthenium(II) Complex in Polylactide Nanoparticles: A Route to Remarkable Cellular Uptake for Photodynamic Therapy of Cancer

preprint
submitted on 15.10.2019 and posted on 21.10.2019 by Nancy Soliman, Luke K. McKenzie, Johannes Karges, Emilie Bertrand, Mickaël Tharaud, Marta Jakubaszek, Vincent Guérineau, Bruno Goud, Marcel Hollenstein, Gilles Gasser, Christophe M. Thomas
Ruthenium complexes, and especially ruthenium(II) polypyridyl complexes, have attracted a lot of attention as potential photosensitizers for photodynamic therapy. However, some are unsuitable due to their low cellular uptake, potentially due to their relatively low degree of lipophilicity, which prevents them from penetrating tumor cells. Here, we report the conjugation of a non-cell-penetrating ruthenium polypyridyl complex, [Ru(bipy)2-dppz-7-hydroxymethyl][PF6]2 (bipy = 2,2’-bipyridine, dppz = dipyrido[3,2-a:2;2’,3’-c]phenazine) (RuOH), to a highly hydrophobic biodegradable and biocompatible polylactide to enhance its cellular uptake. The ruthenium-polylactide conjugates were prepared by drug-initiated ring-opening polymerization of lactide through the formation of a zinc alkoxide initiator and formulated into nanoparticles by nanoprecipitation. They were characterized by means of nuclear magnetic resonance spectroscopy (NMR), matrix-assisted laser desorption/ionization – time of flight mass spectrometry (MALDI-TOF MS) and dynamic light scattering (DLS). Finally, their photo-therapeutic activity (λexc = 480 nm, 3.21 J cm-2) in cancerous human cervical carcinoma (HeLa) and non-cancerous retinal pigment epithelium (RPE-1) cells was tested alongside that of RuOH and their cellular uptake in HeLa cells was assessed by confocal microscopy and inductively coupled plasma - mass spectrometry (ICP-MS). All nanoparticles showed improved photophysical properties including luminescence and singlet oxygen generation, enhanced cellular uptake and, capitalizing on this, an improved photo-toxicity.

History

Email Address of Submitting Author

christophe.thomas@chimie-paristech.fr

Institution

Chimie ParisTech, PSL University, CNRS, Institut de Recherche de Chimie Paris

Country

France

ORCID For Submitting Author

0000-0001-8014-4255

Declaration of Conflict of Interest

The authors declare no conflict of interest.

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