Xueke Gao,Minjun Ma,Christian Marcus Pedersen,Rui Liu,Zhenzhou Zhang,Honghong Chang,Yan Qiao,Yingxiong Wang
Despite being used as an anti-leukemic drug, the poor solubility of 6-mercaptopurine (6-MP) limits its use in topical and parenteral applications. Dendrimers are commonly used as drug carriers to improve their solubility in aqueous solution. In this work, the interactions between 6-MP and the amine-terminated poly(amidoamine) dendrimers (PAMAM−NH 2 ) were investigated by various NMR technology. The chemical shift titrations disclosed that the 6-MP interacted with the surface of PAMAM−NH 2 mainly through electrostatics. The determination of diffusion coefficient and relaxation measurements further confirmed the presence of interactions in 6-MP/PAMAM−NH 2 complexes. In addition, the encapsulation of 6-MP within the cavity of PAMAM−NH 2 was revealed through nuclear Overhauser effect spectroscopy and Saturation Transfer Double Difference analysis. Finally, the binding strength (H-8 is 100% and H-2 is 70%) of 6-MP to PAMAM−NH 2 was quantitatively expressed using epitope maps. This study provides a systematic methodology for qualitative and quantitative studies of the interactions between dendrimers and drug molecules in general.
Biotin–dendrimer conjugates (such as biotin-PAMAMs-NH2) are important macromolecules in the field of host–guest chemistry and widely used systems for delivery. The similar chemical structures of the inner and outer layers of PAMAM-NH2 make it difficult to illuminate the interaction and the binding affinity of biotin-PAMAMs-NH2. By utilizing NMR techniques including 1H NMR titration, CSSF-TOCSY, STDD methods, and 2D DOSY analysis, we demonstrate a method to sort out these interactions. The methylene protons of the inner and outer layers of PAMAM-NH2 are successfully identified and accurately positioned so that the carboxylic acid groups of biotins are having ionic interactions with the outermost amine groups of PAMAM-NH2. The inner PAMAM-NH2 is protonated when reaching the isoelectric point of PAMAM-NH2, increasing the hydrodynamic radius. On the basis of the NMR experiments, a model is proposed, where the carboxylic acid groups and heterocyclic skeleton of biotin arched over the outer layers of PAMAM-NH2 like a bridge. Furthermore, using STDD epitope mapping, the binding affinity between biotin and PAMAM-NH2 was quantified. The diffusion behavior of biotin-G5 PAMAM-NH2 complex is more complicated than that of biotin-G3 PAMAM-NH2 complex due to steric hindrance. The results provide a theoretical basis for understanding these complicated drug delivery systems.
Ofloxacin is one of the most potent antibiotics. But its low solubility in water has limited its use in site targeted delivery and topical applications. This study investigates the PAMAM-NH 2 (amine-terminated polyamidoamine dendrimers) delivery of ofloxacin in water based on host-guest chemistry and reveals the interaction mechanism of PAMAM-NH 2 with ofloxacin by utilizing NMR techniques including 1D chemical shift titration, 2D 1 H– 13 C HSQC titration, NOESY technique, STDD method, and 2D DOSY analysis. Ofloxacin interacts with surface amine groups of PAMAM-NH 2 via ionic interactions, and ofloxacin is also encapsulated into the PAMAM interior cave through hydrophobic interactions. An overall mechanism was proposed for the PAMAM-NH 2 adsorption of ofloxacin, and then the binding affinity was determined. The experimental data demonstrate the potential of the PAMAM-NH 2 for the drug molecules delivery.
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