Back to Journals » International Journal of Nanomedicine » Volume 13

Enhanced oral absorption of pemetrexed by ion-pairing complex formation with deoxycholic acid derivative and multiple nanoemulsion formulations: preparation, characterization, and in vivo oral bioavailability and anticancer effect

Authors Pangeni R, Choi JU, Panthi VK, Byun Y, Park JW

Received 12 March 2018

Accepted for publication 15 April 2018

Published 6 June 2018 Volume 2018:13 Pages 3329—3351

DOI https://doi.org/10.2147/IJN.S167958

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Cristina Weinberg

Peer reviewer comments 2

Editor who approved publication: Dr Thomas Webster


Rudra Pangeni,1,* Jeong Uk Choi,2,* Vijay Kumar Panthi,1 Youngro Byun,3 Jin Woo Park1

1College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam, Republic of Korea; 2College of Pharmacy, Seoul National University, Seoul, Republic of Korea; 3Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul, Republic of Korea

*These authors contributed equally to this work

Objective: The current study sought to design an oral delivery system of pemetrexed (PMX), a multitargeted antifolate antimetabolite, by enhancing its intestinal membrane permeability.
Materials and methods: PMX was ionically complexed with a permeation enhancer such as -deoxycholyl-l-lysyl-methylester (DCK) and prepared as an amorphous solid dispersion by mixing with dispersants such as 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and poloxamer 188 (P188), forming an HP-beta-CD/PMX/DCK/P188; the complex was incorporated into multiple water-in-oil-in-water nanoemulsions in a supersaturated state (HP-beta-CD/PMX/DCK/P188-NE).
Results: After complex formation, the partition coefficient and in vitro membrane permeability of PMX were markedly increased, but it showed similar cytotoxic and inhibitory effects on cancer cell proliferation/migration. Furthermore, the intestinal membrane permeability and epithelial cell uptake of PMX were synergistically improved after HP-beta-CD/PMX/DCK/P188 was incorporated into a nanoemulsion with a size of 14.5±0.45 nm. The in vitro permeability of HP-beta-CD/PMX/DCK/P188-NE across a Caco-2 cell monolayer was 9.82-fold greater than that of free PMX, which might be attributable to the partitioning of PMX to the epithelial cells being facilitated via specific interaction of DCK with bile acid transporters, as well as the enhanced lipophilicity accompanied by surfactant-induced changes in the intestinal membrane structure and fluidity. Therefore, the oral bioavailability of HP-beta-CD/PMX/DCK/P188-NE in rats was evaluated as 26.8%±2.98% which was 223% higher than that of oral PMX. Moreover, oral HP-beta-CD/PMX/DCK/P188-NE significantly suppressed tumor growth in Lewis lung carcinoma cell-bearing mice, and the tumor volume was maximally inhibited by 61% compared with that in the control group.
Conclusion: These results imply that HP-beta-CD/PMX/DCK/P188-NE is an effective and promising delivery system for enhancing the oral absorption of PMX. Thus, there is the potential for new medical applications, including applications in metronomic cancer treatment.

Keywords: pemetrexed, deoxycholic acid derivative, multiple nanoemulsions, permeability, oral absorption, oral anticancer therapy

Creative Commons License This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

Download Article [PDF]  View Full Text [HTML][Machine readable]