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Anti-Angiogenic Effect of Orally Available Pemetrexed for Metronomic Chemotherapy

1
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea
2
Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam 58554, Korea
3
Icure B&P, Global R&D center, Seoul 06649, Korea
4
Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul 08826, Korea
*
Authors to whom correspondence should be addressed.
Pharmaceutics 2019, 11(7), 332; https://doi.org/10.3390/pharmaceutics11070332
Received: 25 May 2019 / Revised: 6 July 2019 / Accepted: 11 July 2019 / Published: 13 July 2019
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Abstract

Metronomic chemotherapy (MCT) is defined as the frequent administration of low-dose chemotherapeutics, without long drug-free periods, with the exertion of antitumor activity exclusively through anti-angiogenic mechanisms. In this study, we have developed an orally available formulation of pemetrexed (PMX) for MCT. PMX was first complexed ionically with Nα-deoxycholyl-l-lysyl-methylester (DCK) as the permeation enhancer. This was followed by dispersion with poloxamer 188 and Labrasol to form the solid oral formulation of PMX (PMX/DCK-OP). PMX/DCK-OP exhibited a 10.6-fold increase in permeability across a Caco-2 cell monolayer compared to PMX alone. This resulted in a 70-fold increase in the oral bioavailability of PMX/DCK-OP in mice over oral PMX alone. In the A549 xenograft model, tumor volume was reduced by 51.1% in the PMX/DCK-OP treated group compared to only 32.8% in the maximum tolerated dose (MTD)-treated group. Furthermore, PMX/DCK-OP exhibited a significant anti-angiogenic effect on the A549 xenograft mice when compared to the MTD-treated group, as indicated by microvessel density quantification for CD-31. In addition, PMX/DCK-OP enhanced the release of an endogenous angiogenesis inhibitor, thrombospondin-1 (TSP-1), into both the blood circulation and the tumor microenvironment. Therefore, due to its oral route of administration, PMX/DCK-OP appears to be a better alternative to the conventional treatment of PMX. View Full-Text
Keywords: metronomic chemotherapy; anti-angiogenesis; oral delivery; low-dose therapy; pemetrexed metronomic chemotherapy; anti-angiogenesis; oral delivery; low-dose therapy; pemetrexed
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Maharjan, R.; Pangeni, R.; Jha, S.K.; Choi, J.U.; Chang, K.-Y.; Choi, Y.K.; Park, J.W.; Byun, Y. Anti-Angiogenic Effect of Orally Available Pemetrexed for Metronomic Chemotherapy. Pharmaceutics 2019, 11, 332.

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