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Evaluating drug delivery to the lung using polyamine ion-pairs

Student thesis: Doctoral ThesisDoctor of Philosophy

Specific ligand targeting has been shown to facilitate drug transport across biological membranes. The aim of this PhD was to investigate whether ion-pairing a drug (theophylline) with a polyamine transporter system (PTS) substrate (polyamine) could actively target drug delivery into the lungs from the pulmonary circulation. To try and achieve this, cyclodextrins were used in a co-solvent to engineer a physically stable cyclodextrin-ion-pair complex. FT-IR and HPLC binding assays showed that theophylline (THE) bound most tightly to spermine (SP) (THE-SP: pKFT-IR = 1.96 ± 0.04, pKHPLC = 2.81 ± 0.06) than to spermidine (SPD) (THE-SPD: pKFT-IR = 1.93 ± 0.05, pKHPLC = 2.79 ± 0.065) followed by ethylenediamine (EDA) (THE-EDA: pKFT-IR = 1.43 ± 0.02, pKHPLC = 2.49 ± 0.05) and the least with ethylamine (EA) (THE-EA: pKFT-IR = 1.32 ± 0.04, pKHPLC = 2.43 ± 0.042). Ion-pairing theophylline with the counter-ions significantly increased the drug’s solubility and reduced its lipophilicity. The formation of 1:1 cyclodextrin/[theophylline-spermine] ion-pair complexes were confirmed by NMR. Reducing the dielectric constant of the vehicle was found to increase the binding affinity of theophylline to spermine (pKTHE-SP in 70 % PG: pKTHE-SP = 2.11 + 0.045 > pKTHE-SP in 10% EtOH: 2.05 + 0.053 > pKTHE-SP in water: 1.96 + 0.06) when assayed with FT-IR. However, it was found that the ion-pair, regardless of the vehicle used or when complexed with cyclodextrins, dissociated rapidly when the pH of the solution was dropped to 7.4. The theophylline-spermine uptake in A549 showed that the PTS was involved in the membrane transport of the drug. In addition, a sustained delivery of theophylline was achieved when cyclodextrin was complexed with the ion-pair, which suggested cyclodextrins could stabilize the ion-pair association. Hence, a cyclodextrin-theophylline-spermine complex described herein represents a potential for lung targeting delivery.
Original languageEnglish
Awarding Institution
Award date2018


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