A self-assembled Ru–Pt metallacage as a lysosome-targeting photosensitizer for 2-photon photodynamic therapy

Zhixuan Zhou; Jiangping Liu; Juanjuan Huang; Thomas W. Rees; Yiliang Wang; Heng Wang; Xiaopeng Li; Hui Chao; Peter J. Stang

doi:10.1073/pnas.1912549116

New Research In

Contributed by Peter J. Stang, August 26, 2019 (sent for review July 22, 2019; reviewed by Kendall N. Houk and Timothy M. Swager)

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Significance

Photodynamic therapy (PDT) is an emerging treatment method for various types of diseases. In PDT, photosensitizers absorb light of appropriate energy and then convert oxygen into highly reactive oxygen species that destroy malignant cells. Photosensitizers with 2-photon absorption bring benefits such as increased penetration depth with near-infrared light excitation and reduced photodamage to healthy tissues. Herein, we describe the use of molecular self-assembly for a metallacage with strong 2-photon absorption by combining multiple Ru(II) complexes with Pt(II) building blocks via coordination. The metallacages were encapsulated in a polymer to form nanoparticles which, upon internalization into cells, accumulate in the lysosomes leading to high photocytoxicity. In vivo studies demonstrated the outstanding therapeutic performance of the nanoparticles in 2-photon PDT.

Abstract

Photodynamic therapy (PDT) is a treatment procedure that relies on cytotoxic reactive oxygen species (ROS) generated by the light activation of a photosensitizer. The photophysical and biological properties of photosensitizers are vital for the therapeutic outcome of PDT. In this work a 2D rhomboidal metallacycle and a 3D octahedral metallacage were designed and synthesized via the coordination-driven self-assembly of a Ru(II)-based photosensitizer and complementary Pt(II)-based building blocks. The metallacage showed deep-red luminescence, a large 2-photon absorption cross-section, and highly efficient ROS generation. The metallacage was encapsulated into an amphiphilic block copolymer to form nanoparticles to encourage cell uptake and localization. Upon internalization into cells, the nanoparticles selectively accumulate in the lysosomes, a favorable location for PDT. The nanoparticles are almost nontoxic in the dark, and can efficiently destroy tumor cells via the generation of ROS in the lysosomes under 2-photon near-infrared light irradiation. The superb PDT efficacy of the metallacage-containing nanoparticles was further validated by studies on 3D multicellular spheroids (MCS) and in vivo studies on A549 tumor-bearing mice.

Footnotes

↵¹Z.Z. and J.L. contributed equally to this work.
↵²To whom correspondence may be addressed. Email: ceschh{at}mail.sysu.edu.cn or stang{at}chem.utah.edu.

Author contributions: Z.Z., J.L., H.C., and P.J.S. designed research; Z.Z. and J.L. performed research; H.W. and X.L. contributed new reagents/analytic tools; Z.Z., J.L., J.H., T.W.R., Y.W., H.C., and P.J.S. analyzed data; and Z.Z., J.L., J.H., T.W.R., H.C., and P.J.S. wrote the paper.
Reviewers: K.N.H., University of California, Los Angeles; and T.M.S., Massachusetts Institute of Technology.
The authors declare no competing interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1912549116/-/DCSupplemental.

Published under the PNAS license.

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