One ring is not enough to rule them all. Albumin-dependent ABCG2-mediated transport of chlorophyll-derived photosensitizers.

Abstract Breast cancer resistance protein (BCRP, ABCG2) is a member of the ATP-binding-cassette (ABC) superfamily of membrane transporters. It is involved in the efflux of a broad range of xenobiotics of highly diverse structures. BCRP activity greatly influences drug distribution in vivo and is often associated with cancer multidrug resistance, which is observed in the case of both chemotherapy and photodynamic therapy. The set of ABCG2 substrates includes porphyrins and chlorins such as heme, hemin, protoporphyrin IX, chlorin e6, pheophorbide a, and their derivatives. Here we provide an evidence that magnesium- and zinc-substituted derivatives of pheophorbide a, which are very promising photosensitizers for use in photodynamic therapy, are also recognized and transported by ABCG2. Interestingly, despite minor structural differences, they clearly differ in the transport rate, both between each other and compared to pheophorbide a. In addition, their transport rate, like those of other structurally similar compounds, is strictly dependent on the level of serum albumin in the extracellular environment. The results that we present here are crucial for the use of metal-substituted pheophorbides in clinical practice but also provide an important insight into the mechanism of porphyrin transport by ABCG2.