Anti-Angiogenic Effect of Orally Available Pemetrexed for Metronomic Chemotherapy

• Main Authors: Ruby Maharjan, Rudra Pangeni, Saurav Kumar Jha, Jeong Uk Choi, Kwan-Young Chang, Young Kweon Choi, Jin Woo Park, Youngro Byun
• Format: Article
• Language: English
• Published: MDPI AG 2019-07-01
• Series: Pharmaceutics
• Subjects: metronomic chemotherapy; anti-angiogenesis; oral delivery; low-dose therapy; pemetrexed
• Online Access: https://www.mdpi.com/1999-4923/11/7/332

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 <i>N</i>^&#945;-deoxycholyl-<span style="font-variant: small-caps;">l</span>-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.