Recombinant human
erythropoietin (rhuEpo) is currently under debate for the treatment of
chemotherapy-induced
anemia due to clinical trials showing adverse effects in Epo-treated patients and the discovery of the
erythropoietin-receptor (EpoR) in
tumor and endothelial cells. Here, using Epo-Cy5.5 as
theranostic near-infrared
fluorescent probe we analyzed the effects of rhuEpo as co-medication to
carboplatin in
non-small-cell-lung-cancer (NSCLC)-xenografts with different
tumor cell EpoR-expression (H838 ~8-fold higher than A549). Nude mice bearing subcutaneous A549 and H838 NSCLC-xenografts received either only
carboplatin or
carboplatin and co-medication of rhuEpo in two different doses.
Tumor sizes and relative blood volumes (rBV) were longitudinally measured by 3D-contrast-enhanced ultrasound (3D-US). Tumoral EpoR-levels were determined by combined fluorescence molecular tomography (FMT)/ micro computed tomography (µCT) hybrid imaging. We found that rhuEpo predominantly acted on the
tumor endothelium. In both xenografts, rhuEpo co-medication significantly increased vessel densities, diameters and the amount of perfused vessels. Accordingly, rhuEpo induced EpoR-phoshorylation and stimulated proliferation of endothelial cells. However, compared with solely
carboplatin-treated
tumors,
tumor growth was significantly slower in the groups co-medicated with rhuEpo. This is explained by the Epo-mediated
vascular remodeling leading to improved
drug delivery as obvious by a more than 2-fold higher
carboplatin accumulation and significantly enhanced
tumor apoptosis. In addition, co-medication of rhuEpo reduced tumor hypoxia and diminished intratumoral EpoR-levels which continuously increased during
carboplatin (Cp) -treatment. These findings suggest that co-medication of rhuEpo in well balanced doses can be used to improve the accumulation of anticancer drugs. Doses and indications may be personalized and refined using
theranostic EpoR-probes.