Zinc-Substituted Pheophorbide A Is a Safe and Efficient Antivascular Photodynamic Agent.

Milena J Szafraniec,Monika Toporkiewicz,Andrzej Gamian

doi:10.3390/ph15020235

Abstract

The present study focuses on the photodynamic activity of zinc-substituted pheophorbide a against human endothelial cells. Previously, zinc pheophorbide a has been shown to be a very potent photosensitizer but also a strong albumin binder. Binding to albumin significantly reduces its availability to cancer cells, which may necessitate the use of relatively high doses. Here we show that zinc pheophorbide a is very effective against vascular endothelial cells, even in its albumin-complexed form. Albumin complexation increases the lysosomal accumulation of the drug, thus enhancing its efficiency. Zinc pheophorbide a at nanomolar concentrations induces endothelial cell death via apoptosis, which in many cases is considered a desirable cell death mode because of its anti-inflammatory effect. Additionally, we demonstrate that in comparison to tumor cells, endothelial cells are much more susceptible to photodynamic treatment with the use of the investigated compound. Our findings demonstrate that zinc pheophorbide a is a very promising photosensitizer for use in vascular-targeted photodynamic therapy against solid tumors, acting as a vascular shutdown inducer. It can also possibly find application in the treatment of a range of vascular disorders. Numerous properties of zinc pheophorbide a are comparable or even more favorable than those of the well-known photosensitizer of a similar structure, palladium bacteriopheophorbide (TOOKAD®).

Highlights

Received: 13 January 2022Photodynamic therapy is an evolving modality for the treatment of a range of both neoplastic and non-neoplastic diseases
We observed that at a human serum albumin (HSA) concentration 250 times higher than the concentration of Zn-Pheide, saturation occurs, i.e., Zn-Pheide is completely bound to HSA [14]
We compared the accumulation and the corresponding photodynamic treatment (PDT) effect induced by Zn-Pheide in MCF-7 and human umbilical vein endothelial cells (HUVECs) cells, both in the absence of albumin and at its saturating concentration

Summary

Introduction

Photodynamic therapy is an evolving modality for the treatment of a range of both neoplastic and non-neoplastic diseases It involves either the systemic or local administration of a photosensitive drug (photosensitizer, PS) followed by site-specific irradiation with visible light of a specific wavelength. This induces either the electron transfer processes (type I reaction) or a formation of highly reactive singlet oxygen (type II reaction), which destroy a diseased tissue [1,2]. A particular variant of photodynamic therapy is vascular-targeted photodynamic therapy (VTP), which uses a PS accumulated not in tumor tissue itself, but in the surrounding blood vessels. The advantages of VTP over traditional photodynamic therapy include: (1) the use of hydrophilic PSs, which, due to their short retention time, do not generate adverse photosensitization of a patient; (2) the rapid localization of a PS in endothelium; (3) the availability of molecular oxygen required for a photochemical reaction;

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