A New Approach to Sensitize Antitumor Monofunctional Platinum(II) Complexes via Short Time Photo-Irradiation

Abstract

Sensitizing the antitumor activity of monofunctional Pt complexes is a reliable approach to developing antitumor agents different from the classic Pt-based drugs. Considering the poor intracellular accumulation of monofunctional Pt complexes, in this study, the photosensitizing monofunctional Pt complex Pt-BA was derived from a weak BODIPY (boron-dipyrromethene)-derived photosensitizer BA, with the purpose to improve its antitumor cytotoxicity via enhancing its intracellular accumulation with a short time photo-irradiation. Photoinduced reactive oxygen species (ROS) determination indicated that the Pt center in Pt-BA is able to improve the photoinduced ROS production ability of BA, which makes Pt-BA a mild photosensitizer. Fluorescence imaging disclosed that dark incubation makes Pt-BA accumulate mainly on the surface of cell membrane, and the later short time photo-irradiation (5 min) promotes distinctly the intracellular accumulation of Pt-BA, which has been confirmed by inductively coupled plasma-mass spectrometry determination. Flow cytometric Annexin V-FITC assay indicated that the short time irradiation of Pt-BA induces in situ the cell membrane damage, which might finally enhance the intracellular accumulation of this monofunctional complex. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay confirmed that the short time photo-irradiation promotes distinctly the antitumor cytotoxicity of Pt-BA against MCF-7, SGC-7901, A549, and HeLa cell lines. The photopromoted antitumor activity of Pt-BA implies that modifying monofunctional Pt complex as a mild photosensitizer to promote its cell accumulation is a useful approach to sensitizing the antitumor activity of monofunctional Pt complex and renders the possibility of monofunctional Pt prodrugs for precise chemotherapy via only short time photoactivation.

Photoactivated Lysosomal Escape of a Monofunctional PtII Complex Pt‐BDPA for Nucleus Access

“…Thep hotoinduced ROS generation of BDPAw as expected to be promoted by the heavy atom effect of the Pt II center in this complex. [9,12] BDPA was synthesized with aKnoevenagel reaction according to our reported procedure (Supporting Information, Scheme S1), [13] and Pt-BDPAwas obtained via reacting BDPAwith K 2 PtCl 4 in methanol with ayield of 23 %. Thecomplex Pt-PDPAwith no photosensitizer was prepared as ac ontrol (Supporting Information, Scheme S1).…”

“…Although Pt-BDPAw as initially constructed with aP t II chelator bis(pyridin-2-ylmethyl)amine (DPA) to improve the photostability of the photosensitizing Pt complex, Pt-BA( Supporting Information, Scheme S1), its lysosome sequestration is quite different from the poor cell uptake of Pt-BA. [9] Because of its photosensitizing nature,this Scheme 1. Chemical structures of Pt-BDPA and Pt-PDPA, and illustration of the photoactivated lysosomale scape of Pt-BDPA.…”

A Platinum(II)‐based Photosensitive Tripod as an Effective Photodynamic Anticancer Agent through DNA Damage

“…On the one hand, the platinum center is able to improve the ROS production ability of PSs due to the heavy atom effect. On the other hand, the photoinduced ROS is able to destroy the cell membranes and promote the cellular uptake of the platinum complexes …”

Tuning the Optical Properties of Phenanthriplatin: Towards New Photoactivatable Analogues

“…The induced electronic transition can involve several processes depending on nature of the populated excited state(s), such as., internal‐ligand, metal‐centered or metal‐to‐ligand charge‐transfer transitions, which eventually determines the action mechanism (for example, photooxidation, ligand photorelease, changes in the metal oxidation state, photosensitization or non‐radiative decay) . In that framework, a recent work by He, Guo and co‐workers demonstrated that it is possible to use photoactivation as a method to promote cell uptake of a monofunctional platinum drug . Although that work is focused on photoinducing reactive oxygen species to damage the cell membrane rather than disrupting the DNA, it clearly highlights the potential of monofunctional drugs in PACT.…”

“…[23] In that framework, ar ecent work by He, Guo and coworkers demonstrated that it is possible to use photoactivation as am ethodt op romote cell uptake of am onofunctional platinum drug. [24] Although that work is focusedo np hotoinducing reactive oxygen speciest od amage the cell membrane rather than disrupting the DNA, it clearly highlights the potential of monofunctional drugs in PACT.…”