Chronopharmacologic Cancer Treatment with an Angiogenic Vessel-Targeted Liposomal Drug

Abstract

Antineovascular therapy (ANET), which eradicates angiogenic endothelial cells by specifically delivered anticancer drugs to tumor cells to obtain complete cutoff of blood supply, is an effective modality for cancer treatment. Since the expression of vascular endothelial growth factor (VEGF) in hypoxic tumor cells is known to fluctuate in a circadian oscillation, we investigated the chronopharmacologic treatment of tumors with ANET. Adriamycin-encapsulated liposomes modified with the Ala-Pro-Arg-Pro-Gly (APRPG) peptide (APRPG-LipADM) were prepared, after the APRPG peptide had been shown to have affinity to angiogenic sites. Colon 26 NL-17 tumor-bearing mice were injected three times with APRPG-LipADM at Zeitgeber time (ZT) 2, 8, 14, and 20 where ZT 0 was the time lights were turned on, and tumor growth was monitored. Tumor growth suppression changed with dosing time and was significantly (p<0.01) more potent at ZT 14 compared with ZT 20. The VEGF concentration in the plasma of the tumor-bearing mice was higher in the light phase compared with that in the dark phase, and this circadian oscillation was related to dosing time dependency with ANET. These results indicate that tumor growth suppression is correlated to some extent with the VEGF concentration in the plasma, and that chronopharmacologic treatment of cancer with ANET may enhance the therapeutic efficacy and reduce the side effects.