Investigating how amine structure influences drug-amine ion-pair formation and uptake via the polyamine transporter in A549 lung cells

Mohamed Sofian, Zarif and Harun, Norsyifa and Mahat, Mohd Muzamir and Nor Hashim, Nikman Adli and Jones, Stuart A. (2021) Investigating how amine structure influences drug-amine ion-pair formation and uptake via the polyamine transporter in A549 lung cells. European Journal of Pharmaceutics and Biopharmaceutics, 168. pp. 53-61. ISSN 0939-6411, DOI

Full text not available from this repository.


Transiently associating amines with therapeutic agents through the formation of ion-pairs has been established both in vitro and in vivo as an effective means to systemically direct drug delivery to the lung via the polyamine transport system (PTS). However, there remains a need to better understand the structural traits required for effective PTS uptake of drug ion-pairs. This study aimed to use a structurally related series of amine counterions to investigate how they influenced the stability of theophylline ion-pairs and their active uptake in A549 cells. Using ethylamine (mono-amine), ethylenediamine (di-amine), spermidine (tri-amine) and spermine (tetraamine) as counterions the ion-pair affinity was shown to increase as the number of protonated amine groups in the counterion structure increased. The mono and diamines generated a single hydrogen bond and the weakest ion-pair affinities (pKFTIR: 1.32 +/- 0.04 and 1.43 +/- 0.02) whereas the polyamines produced two hydrogen bonds and thus the strongest ion-pair affinities (pKFTIR: 1.93 +/- 0.05 and 1.96 +/- 0.04). In A549 cells depleted of endogenous polyamines using alpha-difluoromethylornithine (DFMO), the spermine-theophylline uptake was significantly increased (p < 0.05) compared to non-amine depleted cells and this evidenced the active PTS sequestering of the ion-pair. The mono-amine and di-amine failed to enhance theophylline uptake in these A549 cells, but the tri-amine and tetra-amine both almost doubled the theophylline uptake into the cells when compared to the uptake of free drug. As the data indicated that polyamines with at least 3 amines were required to form ion-pairs that could enhance A549 cell uptake, it suggested that at least two amines were required to physically stabilise the ion-pair and one to interact with the PTS.

Item Type: Article
Funders: Majlis Amanah Rakyat Malaysia (MARA), Geran Penyelidikan Fakulti Farmasi, Universiti Malaya (GPF001E-2020)
Uncontrolled Keywords: Polyamines; Targeted delivery; Ion-pairing; Active uptake; Lung
Subjects: R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Science > Institute of Biological Sciences
Faculty of Pharmacy > Department of Pharmaceutical Technology
Depositing User: Ms Zaharah Ramly
Date Deposited: 20 Jun 2022 07:58
Last Modified: 20 Jun 2022 07:58

Actions (login required)

View Item View Item