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Updated: Jul 8, 2026
Intravital Microscopy of Tumor-associated Vasculature Using Advanced Dorsal Skinfold Window Chambers on Transgenic Fluorescent Mice
Published on: January 19, 2018
Chronopharmacologic cancer treatment with an angiogenic vessel-targeted liposomal drug
Kosuke Shimizu1, Yasuharu Sawazaki, Toshiki Tanaka
1Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, Suruga-ku, Shizuoka 422-8526, Japan.
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.
Insights
Chronopharmacologic treatment using antineovascular therapy (ANET) with targeted drugs shows improved cancer treatment efficacy. Optimizing drug delivery timing based on circadian rhythms, specifically targeting vascular endothelial growth factor (VEGF) fluctuations, enhances tumor growth suppression.
Area of Science:
- Oncology
- Pharmacology
- Biomedical Engineering
Background:
- Antineovascular therapy (ANET) targets tumor angiogenesis by delivering drugs to endothelial cells, cutting off tumor blood supply.
- Vascular endothelial growth factor (VEGF) expression in tumors exhibits circadian oscillations, influenced by hypoxia.
- Chronopharmacology explores optimizing drug efficacy by aligning treatment schedules with biological rhythms.
Purpose of the Study:
- To investigate the chronopharmacologic potential of ANET for cancer treatment.
- To evaluate the impact of drug administration timing on tumor growth suppression using a targeted ANET drug.
- To correlate plasma VEGF levels with treatment efficacy based on circadian rhythms.
Main Methods:
- Preparation of Adriamycin-encapsulated liposomes modified with an Ala-Pro-Arg-Pro-Gly (APRPG) peptide for targeting angiogenic sites (APRPG-LipADM).
- Administration of APRPG-LipADM to Colon 26 NL-17 tumor-bearing mice at different Zeitgeber times (ZT 2, 8, 14, 20).
- Monitoring tumor growth and measuring plasma VEGF concentrations in relation to dosing times.
Main Results:
- Tumor growth suppression varied significantly with drug administration timing.
- Treatment was significantly more potent when administered at ZT 14 compared to ZT 20 (p<0.01).
- Plasma VEGF concentrations showed higher levels during the light phase (day) than the dark phase (night), correlating with treatment efficacy.
Conclusions:
- Chronopharmacologic administration of ANET enhances therapeutic efficacy in cancer treatment.
- Timing drug delivery based on circadian VEGF oscillations can improve tumor growth suppression.
- This approach holds promise for reducing side effects and increasing the effectiveness of ANET.
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