Jingjing Hu

NMR Insights into Dendrimer-Based Host–Guest Systems

Jingjing Hu,‡ Tongwen Xu,‡ and Yiyun Cheng*,†,§ †Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, 200241, People’s Republic of China ‡CAS Key Laboratory of Soft Matter Chemistry, Department of Chemistry, University of Science and Technology of China, Hefei, Anhui, 230026, People’s Republic of China Shanghai Key Laboratory of Magnetic Resonance, Department of Physics, East China Normal University, Shanghai, 200062, P.R.China

Host−Guest Chemistry and Physicochemical Properties of the Dendrimer−Mycophenolic Acid Complex

The nature of the dendrimer-mycophenolic acid (MPA) complex was investigated by (1)H NMR and 2D NOESY spectroscopy. The (1)H NMR analysis proved that the water-soluble supramolecular structure of the complex was formed based on ionic interactions between dendrimers and MPA molecules on the surface as well as hydrophobic interactions/hydrogen-bond interactions in the interior pockets of dendrimers. The 2D NOESY analysis predicted the localization of MPA molecules in the pockets of dendrimers and gave information on the detailed interactions between dendrimer scaffolds and MPA molecules in the interior. Further solubility and release studies investigated the physicochemical properties of the dendrimer-MPA complexes. These results showed that the host-guest chemistry of dendrimer-MPA complexes proposed by NMR techniques explains the solubilization and release behavior of MPA in the presence of PAMAM dendrimers well. The general host-guest chemistry of the dendrimer-drug complex is promising for the development of new drug delivery systems.

Host-guest chemistry of dendrimer-drug complexes. 2. Effects of molecular properties of guests and surface functionalities of dendrimers.

The host-guest chemistry of dendrimer-drug complexes is investigated by NMR techniques, including (1)H NMR and 2D-NOESY studies. The effects of molecular properties of drug molecules (protonation ability and spatial steric hindrance of charged groups) and surface functionalities of dendrimers (positively charged amine groups and negatively charged carboxylate groups) on the host-guest interactions are discussed. Different interaction mechanisms between dendrimers and drug molecules are proposed on the basis of NMR results. Primary amine- and secondary amine-containing drugs preferentially bind to negatively charged dendrimers by strong electrostatic interactions, whereas tertiary amine and quaternary ammonium-containing drugs have weak binding ability with dendrimers due to relatively low protonation ability of the tertiary amine group and serious steric hindrance of the quaternary ammonium group. Positively charged drugs locate only on the surface of negatively charged dendrimers, whereas negatively charged drugs locate both on the surface and in the interior cavities of positively charged dendrimers. The host-guest chemistry of dendrimer-drug complexes is promising for the development of new drug delivery systems.

Design of interior-functionalized fully acetylated dendrimers for anticancer drug delivery.

In this study, dendrimers was synthesized by introducing functional groups into the interior pockets of fully acetylated dendrimers. NMR techniques including COSY and 2D-NOESY revealed the molecular structures of the synthesized dendrimers and the encapsulation of guest molecule such as methotrexate within their interior pockets. The synthesized polymeric nanocarriers showed much lower cytotoxicity on two cell lines than cationic dendrimers, and exhibited better performance than fully acetylated dendrimers in the sustained release of methotrexate. The results provided a new strategy in the design of non-toxic dendrimers with high performance in the delivery of anti-cancer drugs for clinical applications.

Comparison of generation 3 polyamidoamine dendrimer and generation 4 polypropylenimine dendrimer on drug loading, complex structure, release behavior, and cytotoxicity

Background Polyamidoamine (PAMAM) and polypropylenimine (PPI) dendrimers are the commercially available and most widely used dendrimers in pharmaceutical sciences and biomedical engineering. In the present study, the loading and release behaviors of generation 3 PAMAM and generation 4 PPI dendrimers with the same amount of surface amine groups (32 per dendrimer) were compared using phenylbutazone as a model drug. Methods The dendrimer-phenylbutazone complexes were characterized by 1H nuclear magnetic resonance and nuclear Overhauser effect techniques, and the cytotoxicity of each dendrimer was evaluated. Results Aqueous solubility results suggest that the generation 3 PAMAM dendrimer has a much higher loading ability towards phenylbutazone in comparison with the generation 4 PPI dendrimer at high phenylbutazone-dendrimer feeding ratios. Drug release was much slower from the generation 3 PAMAM matrix than from the generation 4 PPI dendrimer. In addition, the generation 3 PAMAM dendrimer is at least 50-fold less toxic than generation 4 PPI dendrimer on MCF-7 and A549 cell lines. Conclusion Although the nuclear Overhauser effect nuclear magnetic resonance results reveal that the generation 4 PPI dendrimer with a more hydrophobic interior encapsulates more phenylbutazone, the PPI dendrimer-phenylbutazone inclusion is not stable in aqueous solution, which poses a great challenge during drug development.

Self‐Assembled Fluorodendrimers Combine the Features of Lipid and Polymeric Vectors in Gene Delivery

An ideal vector in gene therapy should exhibit high serum stability, excellent biocompatibility, a desired transfection efficacy and permeability into targeted tissues. Here, we describe a class of low-molecular-weight fluorodendrimers for efficient gene delivery. These materials self-assemble into uniform nanospheres and allow for efficient transfection at low charge ratios and very low DNA doses with minimal cytotoxicity. Our results demonstrate that these vectors combine the features of synthetic gene vectors such as liposomes and cationic polymers and present promising potential for clinical gene therapy.

Host−Guest Chemistry of Dendrimer−Drug Complexes. 3. Competitive Binding of Multiple Drugs by a Single Dendrimer for Combination Therapy

The host-guest chemistry of dendrimer-drug complexes is of great significance to the design and optimization of dendrimer-based drug delivery systems. The competitive binding of multiple drugs by a single dendrimer in aqueous solutions was investigated by (1)H NMR and 2D-NOESY studies. These rapid, noninvasive, and accurate NMR techniques allow us to monitor the signals of various drugs as well as carriers in a complicated host-guest system. Ethanol was used as an internal standard to simultaneously quantify dendrimers and drugs and to estimate the binding ability of dendrimers toward different drug molecules. The results suggested that supramolecular structure of dendrimer-multiple drug complexes is formed based on electrostatic interactions and hydrophobic/hydrogen-bond interactions. Factors including hydrophobic properties, sizes, pK(a) values, charged groups, and spatial hindrance effects of the drugs influenced the localization of drug molecules on the surface and in the interior pockets. In a ternary host-guest system of dendrimer/mycophenolic acid/phenylbutazone, many more phenylbutazone molecules localized in the inner pockets than mycophenolic acid, while more mycophenolic acid bound on the surface by ion-pairs than phenylbutazone. These results provide new insight into host-guest chemistry of dendrimer-drug complexes and the design/optimization of dendrimer-based drug delivery systems.

New insights into the interactions between dendrimers and surfactants: 2. Design of new drug formulations based on dendrimer-surfactant aggregates.

The interactions between dendrimers and surfactants led to the formation of aggregates dispersed in aqueous solutions. The potential of the resulting dendrimer-surfactant aggregates as new drug formulations was evaluated. The size, morphology, and stability of the aggregates and the localization of drugs in them were determined by dynamic laser light scattering, atomic force microscopy, agarose gel electrophoresis, and nuclear magnetic resonance studies. The drug-loaded aggregates have a spherical shape and an average size of 40 nm. The drug-loading efficiency of dendrimers is significantly influenced in the presence of surfactants. The release rate of the drugs from the dendrimer-surfactant aggregates can be modulated by varying the amount of surfactant in the aggregates. The dendrimer-surfactant aggregates are promising carriers for hydrophobic drugs in transdermal administration routes.

Insights into the Interactions between Dendrimers and Bioactive Surfactants: 3. Size-Dependent and Hydrophobic Property-Dependent Encapsulation of Bile Salts

The supramolecular structures of dendrimer-bile salt complexes have been investigated by multidimensional and multinuclear NMR techniques, such as (1)H NMR, COSY, TOCSY, NOESY, and DOSY. 2D-NOESY analysis indicated the localization of bile salt in the interior pockets of dendrimers. The orientation of the guest in the pockets was predicted by the NOE cross-peaks based on NOESY spectrum. (1)H NMR experiments suggested that no electrostatic interactions between the amine groups of dendrimers and the negatively charged group of bile salts occur in the complexes. DOSY studies further confirmed the inclusion structures based on the diffusion coefficient information. The supramolecular structures of dendrimer-bile salt complexes were mainly formed by hydrophobic interactions/hydrogen-bond interactions in the interior pockets of dendrimers. In addition, size- and hydrophobic property-dependent encapsulation of bile salts and bile derivates in the cavities was observed. These results suggest a new interaction model of dendrimer-surfactant aggregates and provide new insight into the interactions between dendrimers and bioactive surfactants.

New Insights into Interactions between Dendrimers and Surfactants. 4. Fast-Exchange/Slow-Exchange Transitions in the Structure of Dendrimer−Surfactant Aggregates

The interactions between poly(amidoamine) (PAMAM) dendrimer and surfactant (sodium dodecyl sulfate, SDS) in aqueous solutions were investigated by a combination of (1)H NMR, diffusion measurements (PFG NMR), and NOE techniques. The diffusion studies suggested that different types of dendrimer-surfactant aggregates are formed by varying surfactant concentrations in the dendrimer solution. The (1)H NMR analysis proved that the presence of fast-exchange/slow-exchange transitions in the dendrimer-surfactant aggregates. The supramolecular structure of the aggregate was based on the hydrophobic interactions between the dendrimer scaffold and the surfactant aliphatic chain, as well as electrostatic/hydrogen-bond interactions between dendrimers and SDS monomers, bilayers, or globular micelles. In comparison with previous investigations, the present study provides a new insight into interactions between dendrimers and surfactants, which may be helpful for the design of dendrimer-based microreactors or nanovehicles.