NMR Insights into Dendrimer-Based HostâGuest Systems - Chemical

Review pubs.acs.org/CR

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 List of Abbreviations References

1. INTRODUCTION The host−guest chemistry was first developed with the discovery of crown ethers by Pederson in the 1960s.1,2 It was found that the cyclic crown ethers are capable of forming stable complexes with many salts of the alkali and alkaline earth metals.2 This observation marked the beginning of Nobel Prize winning research in host−guest or inclusion chemistry. After that, host−guest chemistry has been widely applied in most chemical and biochemical disciplines.3−8 In principle, a host− guest system was formed by molecular recognition of a receptor molecule (host) and a ligand molecule (guest) through noncovalent interactions, such as ionic interactions,9−11 hydrogen-bond interactions,10,12,13 hydrophobic interactions,11,14 chemical coordination,15,16 van der Waals force,17 and π−π stacking force.18 The larger host molecule usually has hydrophobic or hydrophilic cavities in which the guest can be embedded, while organic compounds, their ions, as well as metal ions, and even nanoparticles and biomacromolecules can serve as guests.16,19−22 In macroscopic concept, physical inclusion of guest molecules by a host can also be recognized as a host−guest system. Therefore, host−guest systems can be seen everywhere, such as a cup filled with water, Trojan horse with soldiers in the Greece myth, polymeric capsules with drugs,23 virus envelops loaded with genes,24 liposomes with anticancer agents,25 nanoparticles or nanotubes with chemicals,26 cucurbit[8]uril with naphthol,27 crown ethers with alkali ions,28 porphyrins with metal ions,29 cyclodextrins with adamantine,30 and dendrimers with fullerene (C60) (Scheme 1).31 Guests can benefit from the host−guest system by binding to the host. For example, the soldiers can enter into the city by hiding in the Trojan horse, the drugs can be released at the intestine but not the stomach with decreased side-effects by using polymeric intestinal-targeting capsules, the exogenous gene can be delivered into a cell when encapsulated in virus envelops or liposomes, potassium ions can be separated from other ions by binding to the crown ethers, hydrogen can be stored in carbon nanotubes as a new power source,32 and nonsoluble compounds with poor stability can exist in aqueous

CONTENTS 1. Introduction 2. Theoretical Background of NMR Analysis 2.1. Chemical Shift Titrations 2.2. NOE Measurements 2.3. Diffusion Analysis 2.3.1. PGSE Diffusion Measurements 2.3.2. DOSY 2.4. Relaxation Measurements 2.5. STD 3. Applications of NMR Techniques in the Analysis of Dendrimer-Based Host−Guest Systems 3.1. Interaction Mechanisms in Dendrimer-Based Host−Guest Systems 3.2. Calculation of Binding Parameters in Dendrimer-Based Host−Guest Systems 3.3. Competitive Binding of Guest Molecules on the Surface or in the Interior of Dendrimers 3.4. Localization of the Guests in Dendrimer/ Guest Complexes 3.5. High-Throughput Screening of DendrimerBinding Drugs 3.6. Size Determination of the Nanoparticles Synthesized within Dendrimer 3.7. Supramolecular Structure of Dendrimer/ Surfactant Aggregates 3.8. Dendrimer-Based MRI Contrasts 4. Conclusions Author Information Corresponding Author Notes Biographies Acknowledgments © 2012 American Chemical Society

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Received: August 25, 2011 Published: April 9, 2012 3856

dx.doi.org/10.1021/cr200333h | Chem. Rev. 2012, 112, 3856−3891

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Scheme 1. Common Host−Guest Systems: (a) Crown Ether with Alkali Ions, (b) Porphyrin with Metal Ions, (c) Cyclodextrin with Amantadine. (d) Cucurbit[8]uril with Two Guests, (e) Dendrimer with Fullerene, (f) Carbon Nanotube with Hydrogen Gas, (g) Liposome with Anti-cancer Agents, and (h) Virus Envelop Loaded with Genes

preferred method for commercial production of dendrimers. 50,51 Commercially available dendrimers, both PAMAM and PPI dendrimers, which are mostly used dendrimers in the references, were generated by the divergent method.34,52 Structurally, dendrimers have well-defined number of functional groups on the surface, which can bind guest molecules through ionic interactions or hydrogen-bond interactions.10,53−59 These active terminal groups can be conjugated with different functional moieties for various purposes such as modulating the hydrophobic−hydrophilic balance of dendrimers in water, changing the charge density of the dendrimers, and endowing the dendrimers with new physicochemical properties.60−78 In addition, the nonpolar pockets in dendrimer interior can encapsulate hydrophobic guests by physical encapsulations, van der Waals forces, hydrogen-bond interactions, and hydrophobic interactions.20,71,79−81 On the other hand, if the tertiary amine groups in the interior pockets of dendrimer are quaternized by chemical reactions, the polar and charged pocket can encapsulate guests with opposite charges.82−85 When the dendrimer surface was further functionalized with hydrophobic chains, the resulting dendrimer can be used to transfer an ionic catalyst into a nonpolar solution.86,87 Dendrimers can not only act as containers/carriers for guest molecules, but also significantly improve the chemical or biochemical performance of the entrapped guest molecules. The catalysts like platinum ions or ferrocene molecules can be immobilized on the surface or in the interior of dendrimers with increased catalytic activity due to the polyvalency effect of dendrimer;88−90 Drug molecules like phenobarbital and mycophenolic acid can be

medium for a long period after their inclusion by cyclodextrin molecules. Dendrimers are a new class of artificial macromolecules with a well-defined topological structure like a tree.33−42 Poly(lysine) dendrimers with asymmetrical structures were synthesized by Denkewalter et al.43 in the early 1980s. However, the thoroughly investigated dendrimers that caught our eyes are the Tomalia’s poly(amidoamine) (PAMAM) dendrimers44 and Newkome’s “arborols”45 in 1985. This new class of versatile polymers was further boosted by Fréchet46 who reported the synthesis of aromatic poly(ether) dendrimers in 1990 using a new strategy. Three years later, Meijer et al.47 successfully synthesized kilogram scale of poly(propylene imine) (PPI) dendrimers, which is of great significance to the pioneer work by Vögtle in 1978.48 Dendrimers are constituted of three parts from the interior to the surface: (1) a central core with two or more reactive groups, (2) repeated units covalently attached to the central core and organized in a series of radially homocentric layers called “generations”, and (3) peripheral functional groups on the surface which predominantly determine the physicochemical properties of a dendrimer.34,49,50 Historically, there are two principal ways for a repetitive synthesis of a dendrimer,41,42 the divergent method and the convergent method.44,46 The divergent approach involved topological branch growth of dendrimers from a central core or the root of the resulting “molecular tree”,44 while the convergent one first involved synthesis of the tree branches and followed by anchoring the branches to the core or root of the tree.46 Though the convergent method synthesizes dendrimers with low polydispersity index, the divergent one obtains higher generation dendrimers and remains the 3857


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increase of electron density around the nucleus leads to the decrease of chemical shift (low-frequency shift).118 The variations in chemical shift of both host and guest in NMR spectrum can be used to analyze host−guest interactions. If a guest binds to a host through ionic interaction, electron density around the cation (i.e., protonated amine group) will decrease, as a result, chemical shift for atoms adjacent to the cation should exhibit a high-frequency shift behavior,91 and chemical shift for the atoms near the anion (i.e., carboxylate group) will show a low-frequency shift.119 If a host−guest inclusion is driven by hydrogen-bond or hydrophobic interactions, the chemical shift variations are much more complicated. Formation of hydrogen-bond leads to the decrease of electron density around the hydrogen nucleus, exhibiting a high-frequency shift of hydrogen nucleus.120,121 In the case of hydrophobic interaction, chemical shift variation for a guest encapsulated in the hydrophobic cavity of a host molecule depends on the type of functional groups (i.e., deshielding groups or shielding groups) in the guest and host molecules. If the exchange between free-state and bound-state for a host−guest system is fast on NMR time scale, observed chemical shift is a mole fraction-weighted average of chemical shifts in both states.56,118,122 The observed chemical shift can be described by 1:

attached by dendrimers with enhanced aqueous solubility and molecular stability, reduced release rate and side-effects, and modified pharmacodyamic and pharmacokinetic behaviors;91−95 Imaging agents such as chromophore, fluorescence dye, magnetic resonance imaging (MRI) contrast, and radioactive isotope can be loaded by dendrimers with enhanced imaging sensitivity.96,97 Surfactant molecules can be bound by dendrimers with decreased surface tension and lower critical micelle concentration (usually known as critical aggregation concentration).98−100 Overall, the structural and functional properties of dendrimers make them good candidates as versatile hosts in the host−guest systems.53,101−103 The intermolecular and intramolecular interactions significantly influence the performance of dendrimer-based host− guest systems and the study of physicochemistry of these systems is of exceptional importance to the design and optimization of novel host−guest systems. In the past decade, techniques including ultraviolet−visible and fluorescence spectroscopy,104−109 isothermal titration calorimetry (ITC),92,98 small angle neutron scattering (SANS),110 electron paramagnetic resonance (EPR),111,112 and nuclear magnetic resonance (NMR)56 were used to investigate the physicochemistry of dendrimer-based host−guest systems. The NMR techniques are informative, sensitive, convenient, powerful, and noninvasive tools in the investigation of intermolecular and intramolecular interactions in inclusions, ion-pairs, and aggregates.113,114 It reveals the presence of noncovalent or covalent interactions between host and guest molecules by variations in chemical shift and peak splitting/line-width. Structurally, NMR was widely used to characterize the interaction mechanisms, such as binding sites, molecular orientations, and detailed localizations. Also, NMR can be used to calculate the binding parameters between host and guest such as binding constant and number of binding sites, dynamic behaviors, and the hydrodynamic sizes of the formed aggregates.55,56,114,115 The aim of this critical review is to illustrate how new insights into dendrimer-based host−guest systems can be obtained by NMR studies. The theoretical background of NMR techniques was first introduced, including chemical shift titration, NOE analysis, diffusion NMR, relaxation measurement, and STD. Then the applications of NMR techniques in the analysis of dendrimer-based host− guest systems were discussed, such as qualitative and quantitative analysis of interactions between dendrimers and guest molecules, the localization of guest molecules within dendrimer scaffolds, the physicochemical properties of dendrimer-guest complexes, and methods proposed to screen dendrimer-binding compounds.

δobs = Pbδ b + Pf δf = Pbδ b + (1 − Pb)δf

(1)

where Pb and Pf are molar fractions of bound- and free-state, respectively, δb and δf are chemical shifts of bound- and freestate, respectively, δobs is the observed chemical shift of corresponding nucleus. For a 1:1 host−guest binding model, complex formation between host and guest molecules can be expressed by the following equilibrium: Ka

[Host] + [Guest] ⇌ [Complex]

Dendrimers have multiple guest binding sites (n). Assuming that each binding site has identical affinity with the guest, and that each binding site will not affect the binding affinities of other binding sites,55,56,124,125 dendrimer-based host−guest systems can be described as Ka

[Den] + n[Guest] ⇌ [DG]

The binding constant (Ka) of the interaction can be described by 2 Ka =

2. THEORETICAL BACKGROUND OF NMR ANALYSIS

[DG] [Den]f [Guest]f

(2)

where [Den]f, [Guest]f, and [DG] are the molar concentrations of free-state binding sites on dendrimer, free-state guest, and dendrimer/guest complex, respectively. In dendrimer-based host−guest systems, the following relationships should be considered (eq 3):

2.1. Chemical Shift Titrations

NMR spectroscopy is a widely used technique providing information on the structure, dynamics, reaction state, and chemical enviornment of molecules.116,117 An NMR sample in the external magnetic field is disturbed from equilibrium by an applied pulse, and the absorbed energy will be radiated back out at a specific resonance frequency. The response to disturbance is recorded as an NMR spectrum.118 Chemical shift which is independent of the external magnetic field is usually used to describe the chemical environment of specific nuclei. The decrease of electron density around a nucleus causes the increase of chemical shift (high-frequency shift), while the

[Guest]o = [Guest]b + [Guest]f n[Den]o = [Binding site]f + [Guest]b

(3)

[Den]o, [Guest]o, and [Guest]b are the initial concentrations of dendrimer and guest, and the concentration of bound-state guest, respectively. [Binding site]f is the concentration of free binding site in each dendrimer. The molar fraction of boundstate dendrimers can be expressed by eq 4 3858


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[Guest]b n[Den]o

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cross-peaks. The presence of cross-peaks between host and guest in the 2D-NOESY spectrum is an evidence of spatial approach of related nuclei.132 Generally, the intensity (volume) of an NOE cross-peak in NOESY spectrum acquired with a short mixing time is proportional to the inverse-sixth power of the distance between spins, which can be expressed by113

(4)

Taking eqs 3 and 4 into 2, Ka can be described by 5: Ka =

nPb[Den]o ([Guest]o − nPb[Den]o )(1 − Pb)n [Den]o

(5)

VNOE = αNr −6

The combination of eqs 1 and 5 gives the following relationship between chemical shift variations (Δδobs) of dendrimer and binding parameters of the interaction:56 Δδobs =

where VNOE is volume of the cross-peak, r is average spatial distance between two nuclei, and N is the number of related nuclei. By measuring cross-peak intensities in a 2D-NOESY spectrum, information on distances can be extracted. For protons, NOE occurs when nuclei are within 5 Å of each other. The intensity of NOE cross-peak increases with the mixing time in a certain range.133 Long mixing time exceeding that range may generate pseudo-cross-peaks, which is attributed to spin diffusion and magnetization transfer.133 Therefore, to provide precise and clear conclusions on spatial distances, mixing time needs to be chosen carefully in NOE experiments. The cross-peaks in 2D-NOESY are either positive or negative. NOE signals are positive for small molecules with fast motions in low viscosity solvents and negative for large molecules relative to a negative diagonal. Once small guest molecules bind to a macromolecular host through ionic, hydrophobic, hydrogen-bond interactions, etc., they obtain the motion behavior of the host and will have a long correlation time.134,135 As a result, negative NOE cross-peaks for the guest molecules can be observed in corresponding regions in 2DNOESY spectrum. It is worth noticing that the NOE signal might disappear in the 2D-NOESY spectrum for medium size molecules (molecular weight of 5000−10000 Da). In this case, rotating frame nuclear Overhauser effect spectroscopy (ROESY) experiment should be performed.136

⎧ [Guest]o ⎞ Δδmax ⎪⎛ 1 ⎨⎜1 + + ⎟ 2 ⎪⎝ nK a[Den]o n[Den]o ⎠ ⎩ 2 ⎤1/2 ⎫ ⎡⎛ [Guest]o ⎞ 4[Guest]o ⎥ ⎪ 1 ⎢ ⎬ − ⎜1 + + ⎟ − ⎢⎣⎝ nK a[Den]o n[Den]o ⎠ n[Den]o ⎥⎦ ⎪ ⎭

(6)

Similarly, the chemical shift variations of guest molecule can be expressed by 7: ⎧ n[Den]o ⎞ Δδmax ′ ⎪⎛ 1 ⎨⎜1 + Δδobs′ = + ⎟ 2 ⎪⎝ K a[Guest]o [Guest]o ⎠ ⎩ 2 ⎤1/2 ⎫ ⎡⎛ 4n[Den]o ⎥ ⎪ n[Den]o ⎞ 1 ⎬ − ⎢⎜1 + + ⎟ − ⎢⎣⎝ [Guest]o ⎠ [Guest]o ⎥⎦ ⎪ K a[Guest]o ⎭

(7)

Δδmax and Δδmax′ are the maximum chemical shift variations of the host and guest molecules in NMR titration experiments, respectively. The binding parameters Ka and n can be obtained by fitting the titration data with eq 6 or 7 using a nonlinear least-squares method. For hydrogen-bond mediated host−guest systems, the equilibrium between free- and bound-state host or guest can be expressed as126

2.3. Diffusion Analysis

2.3.1. PGSE Diffusion Measurements. PGSE NMR is a powerful tool in proving the presence of interactions and the formation of supramolecular aggregates and inclusion structures.114,137−139 A PGSE experiment consists of a spin−echo sequence and a set of applied pulsed-field gradients.140 The principle of PGSE diffusion experiment has been reviewed by several research groups.113,114,140,141 Only the key points on PGSE will be demonstrated here. PGSE measures the diffusion coefficient of a target subject which mainly depends on its molecular size, shape and charge, as well as on its surrounding environment such as temperature and viscosity.110,113,114,142 Thus, it is possible to study host−guest behaviors on the basis of diffusion coefficients.143 The spin−echo amplitude can be described by the Stejskal and Tanner’s equation144,145

Ka

AH + B ⇌ AHB

Ka of the hydrogen-bond mediated host−guest system can be described by 8: Ka =

[AH···B] [AH]f [B]f

(8)

The relationship between Δδobs and concentration of hydrogen-bond receptor [B]o can be described by 9: 1 1 1 = + Δδobs Δδ[AH···B] K aΔδ[AH···B][B]o

(10)

(9)

Where Δδ[AH···B] is the chemical shift variation of complex. The binding constant can be calculated by fitting the plot of Δδobs−1 versus [B]o−1 using a linear equation.

A(2τ, G) = A(0) exp(− 2τ/T2)exp[−γ 2Dδ2(Δ − δ/3)G2]

2.2. NOE Measurements

(11)

NOE is through-space transfer of nuclear spin polarization from one nuclear spin population to another via dipole−dipole crossrelaxation.113 It is the most effective method to correlate nuclei through space and to determine three-dimensional structures of complexes.127−131 NOE correlations can be mapped by NOESY spectrum. Generally, two-dimensional (2D)-NOESY is more preferred than one-dimensional (1D)-NOESY because 2D-NOESY helps in simplifying spectral interpretation by distributing the crowding 1D NMR spectrum to more than one dimensions. The 2D-NOESY spectrum contains a diagonal and

where A(2τ,G) and A(0) are the intensities of spin−echo signal when the sine-shaped field gradient is present and absent, respectively. γ is the nuclear magnetogyric ratio, Δ is the time interval between gradient pulses, δ is the width of gradient pulses, τ is the rotational correlation time between the π and π/ 2 radiofrequency pulses, T2 is the transverse relaxation time, and G is the strength of applied magnetic field gradient. D is the diffusion coefficient. If the PGSE experiments are acquired with a constant τ and a varying G, the effect of T2 on PGSE 3859


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spectrum with chemical shift on one dimension (horizontal axis) and diffusion coefficient on the other one (vertical axis).150 DOSY is referred to as a noninvasive “chromatography”,151 and has been applied to optimize purification procedures in organic synthesis,150 to predict molecular weights,151 to correlate solid-state crystal structures determined by X-ray diffraction with solution structures.152 It is especially useful in dendrimer-based host−guest systems because different types of aggregate, inclusion, and supramolecular structures were proposed to be present in such systems.153 Further information on the principles of DOSY, its applications in miscellaneous fields, and the advantages of this NMR approach are available in the reviews.113,114,152,154

experiment can be removed, eq 11 can be described by 12 and 13:145 A(G) = A(0) exp[−γ 2Dδ2(Δ − δ/3)G2]

(12)

ln A(G)/A(0) = −γ 2Dδ2(Δ − δ/3)G2

(13)

The diffusion coefficient D can be obtained by plotting lnA(G)/A(0) versus G2.140 After D was obtained, hydrodynamic radius (rH) can be calculated by the Stokes−Einstein equation (eq 14) rH =

KBT 6πηD

(14)

2.4. Relaxation Measurements

where KB is the Boltzmann constant, T is the absolute temperature, and η is the solution viscosity. For dendrimerbased host−guest systems, if a guest binds to a dendrimer, its molecular motion becomes slower. As a result, a decreased diffusion coefficient or an increased hydrodynamic size for the guest is observed. It is worth noting that the Stokes−Einstein equation is based on some assumptions: (1) the analyzed solution is regarded as theoretical hard spherical monomers or aggregates, (2) the species are supposed to be isolated and continuous ones, and (3) the nonideal effects such as crowding and electrostatic attraction are excluded.146 According to eq 14, the calculation of hydrodynamic radius of a molecule requires precise determination of solution viscosity. To avoid the precise measurement of solution viscosity in PGSE studies, internal standard with regular shape, known hydrodynamic size, and inert property such as dioxane and tetramethylsilane were used.113 The ratio of diffusion coefficients of a target molecule and the internal standard is independent of solution viscosity thus allows the calculation of hydrodynamic size by eq 15. D/Dref = rref /rH

Spin relaxation measurement is a convenient approach to the study of host−guest systems undergoing slow-exchange on NMR time scale.155 It is able to provide information on molecular rigidity,156 dynamics,138 and rotational behavior of chemical bond.138,157 The principal relaxation mechanisms include: spin rotation, chemical shift anisotropy, quadrupolar relaxation, scalar relaxation, and dipole−dipole relaxation. For dipole−dipole relaxation, the dipole−dipole coupling constantly varies as a function of vector relationship during the molecule tumbling, creating a fluctuating magnetic field around each nucleus. If the fluctuations occur at the resonance frequency, nuclear relaxation will be caused. The motion of a molecule should be matched to the transition frequency (neither too fast nor too slow) to cause efficient relaxation and a short spin−lattice relaxation time (T1). T1 can be converted to the rotational correlation time τ through eq 19158 1/T1 = 3/2π 2(e 2Qq/h)2 τ

(15)

where e2Qq/h is the quadruple coupling constant. The rotational radius (Rrot) can be described by the Stokes− Einstein−Debye law eq 20157

Besides the information on molecular size, diffusion coefficient can also be used to measure the binding constant of a host− guest system. If a guest molecule is in a fast-exchange of freeand bound-state on NMR time scale, the observed diffusion coefficient is also a time-weighted average of diffusion coefficients of the free- and bound-state guest (eq 16).147 Dobs = XDDG + (1 − X )DG

R rot = (3KB τT /4πη)1/3

DG − Dobs DG − DDG

(16)

(17)

According to dendrimer-based host−guest systems, Ka can be expressed by eq 18: Ka =

(20)

where η, KB, and T is the same as described in eq 14. The variation of T1 and Rrot can be used to predict the formation of ionic pairs or inclusions in a host−guest system since these interactions will result in a restricted rotation for the guest molecules thereby affect the T1 and Rrot values. Besides T1, the transverse relaxation time T2 can also be used to give evidence of host−guest interactions.56 In principle, T2 can be obtained by measuring the line width of NMR signals (eq 21)159

The bound-fraction can be defined by eq 17:

X=

(19)

1/T2 = πw1/2

[DG] X = [Den][Guest] (1 − X )([Guest]o − X[Den]o )

(21)

where w1/2 is the peak width at half-height. T2 is correlated to the size of a target object. In this way, guest molecules bound to a macromolecular host can afford the relaxation rate of the macromolecule, thus developing a broader signal in the NMR spectrum.56 Up to now, relaxation measurements have been used to investigate spatial conformation and dynamic mobility of dendrimers and the interactions of dendrimers with various guests.120,121,138,159−163

(18)

Therefore, Ka can be calculated by fitting Dobs versus [Guest]o and [Den]o using a nonlinear least-squares method. 2.3.2. DOSY. The development of DOSY by Johnson Jr. et al. has boosted the applications of diffusion NMR in host− guest systems.148 DOSY allows the determination of diffusion coefficient in mixtures and aggregates, especially in complicated systems containing polydisperse components.149 In a DOSY experiment, polydisperse components with overlapped chemical resonances are separated due to different diffusion coefficients and the NMR data are displayed as a pseudo-2D

2.5. STD

The STD spectroscopy compares the 1H NMR spectra of a sample measured under on-resonance and off-resonace irradiation. It is used to reveal low affinity binding between 3860


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Scheme 2. Dendrimer-Based Host−Guest Systems: (a) Oligoethyleneoxy-functionalized PPI Dendrimer with Rose Bengal; (b) Dendrimer Containing Electron-Acceptor Viologen Units with Eosin; (c) Octacationic Dendrimer with Pd(II) Complex. Panel a was reprinted with permission from reference 169. Copyright 2000 Springer

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Scheme 2. continued

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Scheme 2. continued

and bioavailability for bioactive compounds.94,187−189 The understanding of interaction mechanisms in such systems is of great importance in the design and optimization of novel host−guest systems.190 1 H NMR titration has proved to be an effective tool in our previous studies in the analysis of interaction between dendrimers and guests.20,79,91,100,119,124,191 Take amine-terminated PAMAM dendrimer for example, it has six kinds of protons corresponding to four methylene groups (a−d) in the interior pockets and two methylene groups (b′ and d′) in the outermost layer of dendrimer (Scheme 3a).20,58,91 Peak for protons (d′) usually overlaps with the peak of protons (d) but shifts to high frequency during the formation of ion-pairs on the surface of dendrimer. Similarly, peak for protons (b′) overlaps with the peak of protons (c) and further shifts to high frequency in the presence of negatively charged guest molecules.58 When amine-terminated PAMAM dendrimer was titrated with mycophenolic acid (S1, Chart 1), significant high-frequency shifts of surface protons (b′ and d′) and slight low-frequency shifts of inner protons (a−d) were observed (Figure 1a).91 This result suggests that a combination of surface ionic interaction and interior hydrophobic interaction contributes to the formation of PAMAM/mycophenolic acid complexes. Interestingly, significant high-frequency shifts of the inner protons (a−d) were observed when the dendrimer was titrated with acetic acid, which is an evidence of

small molecule ligands and macromolecular receptor. In an STD experiment, saturation transfer from the receptor to the ligands identifies specific binding of the ligands to the receptor. Since small molecule ligands usually have distinct chemical shifts in high-resolution NMR spectroscopy, STD technique can simultaneously screen several ligands toward a receptor from a mixture thus STD NMR is widely used in high throughput drug screening. The STD signal intensity is proportional to the binding affinity between the ligands and the receptor, allowing quantitative analysis of competitive binding of several compounds with a target.164−166

3. APPLICATIONS OF NMR TECHNIQUES IN THE ANALYSIS OF DENDRIMER-BASED HOST−GUEST SYSTEMS 3.1. Interaction Mechanisms in Dendrimer-Based Host−Guest Systems

Dendrimers have well-defined number of surface functionalities and interior cavities,50 which are responsive for binding and encapsulating a variety of guest molecules.95,167,168 Numerous dendrimer-based host−guest systems have been reported in the past two decades (Scheme 2).31,53,80,95,167,169−182 Interaction of guests with dendrimer through covalent or noncovalent interactions may greatly influence the performance of the guests, e.g., improved catalytic activity,53,183−185 sustained release behaviors,186 and increased aqueous solubility, stability, 3863


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experiments due to relatively low protonation ability of the tertiary amine group and serious steric hindrance of the quaternary ammonium group. Similarly, the host behaviors of benzoate-terminated silane dendrimers toward a series of cationic compounds including acetylcholine (S9), benzyltriethylammonium (BTEA, S10), and dopamine (S11) were investigated by Astruc et al.55,192 Low-frequency shifts of aromatic protons (5,6) of dendrimer (Scheme 4b) were observed upon the addition of guests into dendrimer solutions, reflecting the formation of ionic pairs between the anionic dendrimers and the oppositely charged guests.192 Surprisingly, the guest protons are shielded low-frequency upon the formation of dendrimer/guest complexes, which suggests increased electron density around these protons. This is due to the fact that the hydrophobic part of the guests is backfolded into the interior of dendrimers and localized around the aromatic rings of surface benzoate via hydrophobic or π−π stacking interactions (Scheme 4b−d).55 It has been reported that PAMAM dendrimers have excellent metal ion binding abilities.193−198 The uptake of PtCl42− ions (S12) by G2 and G4 hydroxyl-terminated PAMAM dendrimers with neutral surfaces are studied by 195Pt, 1H, and 13C NMR.199 Significant low-frequency shift of platinum ions was observed after the titration of K2PtCl6 into dendrimer solutions, indicating chemical coordination occurs between the PtCl42− ions and the amine/amide groups in dendrimer. 195Pt NMR results revealed that only the platinum ions bound near dendrimer surface can be detected and nearly 80% of the titrated PtCl42− ions localize deeply in the cavities of G4 PAMAM dendrimer. Platinum ions bound on dendrimer surface is time-dependent and an increased amount of platinum ions bound to three or more nitrogen atoms was detected after 10 days of titration. Paramagnetic cobalt(II) was used as an NMR probe of dendrimer structure and dendrimer/metal ion interaction.200 The presence of sizable pockets within dendrimers and cooperativity among the dendritic arms in Co2+ binding were observed. NMR studies using paramagnetic probes provide a method of dynamic investigation of dendrimers in solutions upon ligand binding and recognition.16,201 Meijer and co-workers investigated the host behaviors of adamantyl/palmityl urea- and thiourea-modified PPI dendrimers (Scheme 5).56,57,106,120,121,202,203 NMR studies revealed that urea-functionalized guest molecules interact with adamantyl thiourea (urea)-functionalized dendrimer host through urea−urea or urea-thiourea hydrogen-bond interactions as well as ionic interactions between the protonated tertiary amines of the dendrimer and the negatively charged terminus (carboxylate, sulfonate, and phosphate) of the guests.56,120,202 The guests employed include urea-functionalized peptides(S13),121 poly(ethylene glycol) (PEG) chains (S14),56,57 aliphatic chains (S15),120 aromatic compounds (S16),202 cyanobiphenyl compounds (S17),203 oligo(p-phenylene vinylene) (OPV, S18).106 High-frequency shifts of urea N−H protons of the guests and methylene protons adjacent to the tertiary amines of adamantyl thiourea (urea)-functionalized PPI dendrimer were observed upon the host−guest complexation in chloroform, indicating the protonation of the tertiary amines in PPI dendrimer and the formation of ionic pairs between dendrimers and the guest. Meanwhile, significant high-frequency shifts were observed for the thiourea (urea) N−H protons of PPI dendrimer, which is an evidence of increased hydrogen-bond interactions between the urea and thiourea groups after

Scheme 3. Repeat Units in the (a) Amine-Terminated Cationic PAMAM Dendrimer; (b) Carboxylate-Terminated Anionic PAMAM Dendrimer; and (c) Hydroxyl-Terminated Neutral PAMAM Dendrimer with Proton Labeling

protonation of the tertiary amine groups and the formation of ionic pairs in the interior of dendrimer. Therefore, PAMAM dendrimers are capable of encapsulating guest molecules via hydrophobic, ionic, and probably hydrogen-bond interactions depending on the hydrophobicity, pKa value, and the functionality of the guests.80,91,119 With the increase in hydrophobicity and size of the guest, PAMAM dendrimer tends to encapsulate guests in its cavities rather than on the surface. For example, when PAMAM dendrimer was titrated with sodium deoxycholate (S2) and a zwitterionic analogue of deoxycholate (S3), neither high-frequency nor low-frequency shifts of the protons (b′ and d′) located on dendrimer surface was observed (Figure 1b), while strong affinities of the guests with the interior cavities of dendrimer were deduced from NOESY studies.20 Hydrogen-bond interaction was proposed to be a predominant force in the formation of PAMAM/pyridine (S4) complexes in which N atom in pyridine ring acts as a hydrogen-bond receptor and the amino/amido N−H groups in dendrimer act as donors.126 PAMAM dendrimer shows a preferential interaction with pyridine along the outermost layer of dendrimer. The external amido groups showed a much more significant high-frequency shift than the internal ones during the titrations of PAMAM with pyridine, which is probably due to the difficulty of pyridine penetration into the interior of PAMAM. In the case of anionic dendrimers, low-frequency shifts of the methylene protons (a′ and c′, Scheme 3b) adjacent to the surface carboxylate functionalities of PAMAM dendrimer were observed due to increasing electron density around these protons during the formation of ionic pairs.119 Primary- and secondary-amine containing drugs (S5, S6) preferentially bind to the anionic PAMAM dendrimers by strong electrostatic interactions, whereas tertiary-amine and quaternary-ammonium containing drugs (S7, S8) show weak binding affinities with carboxylate-terminated dendrimers in 1H NMR titration 3864


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Chart 1. Molecular Structures of the Guests in the Critical Review

complexation.57,106,120,121,202 The variations of chemical shift (Δδ) for the N−H protons decrease with increasing steric hindrance of the guest molecules which weakens hydrogenbond interactions between urea-functionalized dendrimers and guests.106,121 In addition, an increased T1 relaxation time for the polar head of guests (urea site) was observed above a critical guest/dendrimer ratio, while no alteration in T1 was obtained for the hydrophobic tail of guest during this process, suggesting that the polar head of the urea-functionalized guest penetrate into the dendritic shells.120,202 Also, increased T1 for adamantyl thiourea (urea)-functionalized PPI was observed upon increasing guest/dendrimer ratio which agrees well with the decreased flexibility and increased shell packing density of the dendrimer surface as more guests are entrapped. These results confirmed the contributions of ionic and hydrogen-bond interactions in the complexation between adamantyl thiourea (urea)-functionalized PPI dendrimers and guest molecules(Scheme 6).106,120,121 However, in the case of palmityl thiourea

(urea)-functionalized PPI, peak for the urea N−H protons undergoes a negligible high-frequency shift in the 1H NMR spectra after complexation, which is due to strong intramolecular interactions (hydrophobic interactions) between the palmityl chains in the thiourea-functionalized dendrimers.120 In such host/guest pairs, hydrophobic interaction played an important role in the formation of complexes. Tsukube et al. synthesized a series of benzyl ether type dendrimer with a (tetraphenylporphinato)zinc(II) core (Scheme 7) and the dendrimers were titrated with two kinds of guest molecules.182 1H NMR spectrum revealed that pyridine-containing guest (S19) bind to the central core of the dendrimer via coordination interactions, and 90% of the dendrimer core was bound with the guest. This kind of dendrimers can further interact with a second guest molecule with a thymine functional group (S20), and the thymine moiety of the guest forms a three-point hydrogen-bond with the diamidopyridine group in the dendrimer, and 56% of the 3865


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Figure 1. 1H NMR spectra of (a) G5 dendrimer/mycophenolic acid91 and (b) G5 dendrimer/sodium deoxycholate20 complexes at different molar ratios. The concentration of the G5 dendrimer was kept constant at 6.94 × 10−5 M, for dendrimer/mycophenolic acid complex, the molar ratios were set as (1) 4.5, (2) 9, (3) 13.5, (4) 18, (5) 22.5, (6) 27, (7) 31.5, (8) 36; and for dendrimer/sodium deoxycholate complex, the molar ratios were set as (1) 8.7, (2) 17.4, (3) 26, (4) 34.7, (5) 43.4, (6) 52.1, (7) 60.8, (8) 69.4.

of the guest. By plotting the chemical shift variations versus the guest/dendrimer ratio during the titrations, a sinusoidal shape curve can be obtained.55 The curves were further fitted by eq 7 using a nonlinear least-squares method, and the parameters n (41 ± 2) and Ka (400 ± 95 M−1) can be obtained.56 The obtained binding affinity for this host−guest system is in the same order of magnitude as the values calculated from fluorescence measurements.204 For the urea-functionalized PEG chains with a phosphorus acid headgroup (S14b), a slow-exchange between the free- and bound-state guests on NMR time-scale was observed (31P NMR titration). In this case, the molar fraction of bound- and free-state guests can be calculated from related peak areas. We can directly obtain the binding parameters by fitting the fraction of bound-state guest versus guest/dendrimer ratio using eq 22:56

diamidopyridine was bound with the thymine-containing guest (Scheme 7).182 A combination of coordination and hydrogenbond interactions offered a promising strategy of design of bimolecular guest accommodation systems with excellent stability.27 3.2. Calculation of Binding Parameters in Dendrimer-Based Host−Guest Systems

NMR techniques have given useful information on interaction mechanisms during the formation of host−guest systems as discussed in section 3.1. However, specific information about the number of guests bound to dendrimers, the binding affinities between dendrimer and guest, and the exchange kinetics between free- and bound-state remains a question for dendrimer-based host−guest systems.56 In this section, 1H, 13C, and 31P NMR titration combined with the proposed eqs 6 and 7 were used to calculate the binding parameters including number of binding sites (n) and binding affinities (Ka).55,56,122−125 Upon the addition of urea-functionalized PEG chains with a carboxylic acid headgroup (S14a) into admantyl ureafunctionalized PPI dendrimer (Scheme 5), a significant highfrequency shift of the guest carbon atoms was observed in the 13 C NMR spectra, and this indicates ionic interactions between dendrimer and the guests.56 Only one peak was observed for each atom in the guests and the peak shifts in the direction of free-state guest with increasing guest/dendrimer ratio, suggesting that a fast-exchange occurs between free- and bound-state

⎧ n[Den]o ⎞ 1 ⎪⎛ 1 Pb = ⎨⎜1 + + ⎟ 2 ⎪⎝ K a[Guest]o [Guest]o ⎠ ⎩ 2 ⎡⎛ ⎤1/2 ⎫ n[Den]o ⎞ 4n[Den]o ⎥ ⎪ 1 ⎢ ⎬ − ⎜1 + + ⎟ − ⎢⎣⎝ K a[Guest]o [Guest]o ⎠ [Guest]o ⎥⎦ ⎪ ⎭ (22)

The binding number and affinity are calculated to be 61 ± 1 and (4 ± 3) × 104 M−1, respectively. Obviously, urea3866


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Scheme 4. (a) Molecular Structure of the Benzoate-Terminated Silane Dendrimer, and Its Interaction with (b) Dopamine; (c) Acetylcholine; (d) BTEA. Reprinted with Permission from Reference 55. Copyright 2008 John Wiley & Sons

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Scheme 4. continued

dopamine has only one binding constant with the dendrimer.55 Binding affinities of dopamine with the anionic dendrimers are calculated to be 2000−5000 M−1 depending on dendrimer generation. Higher generation dendrimers show stronger binding affinities with the guest than lower generation ones. The binding affinities of acetylcholine and BTEA with dendrimers are 20- to 50-fold weaker in comparison with dopamine (first step, 50−77 and 125−200 M−1; second step, 1.3−12.5 and 3.3 M−1, respectively). The stronger interactions of dopamine with dendrimer is attributed to the fact that dopamine is a primary ammonium compound, while the other two guests are quaternary ammonium ones. Similarly, the binding parameters of PAMAM dendrimer/nucleotide (guanosine monophosphate, GMP, S21) complex were calculated according to the chemical shift plots and eq 6.124 Binding parameters (n and Ka) are calculated to be 107 ± 6 and (1.74 ± 0.72) × 104 M−1, respectively. The order of magnitude of interactions between PAMAM and GMP is comparable and lies in the range observed for other dendrimer/guest interactions.56 In an attempt to determine binding parameters of dendrimer/ sodium dodecyl sulfate (SDS, S22) complexes using eq 6, Ka and n are calculated to be 380 (±357)M−1 and 49 (±43),

functionalized PPI dendrimer shows a much higher binding affinity for phosphorus acid-containing guest than for carboxylic acid-containing guest. In both cases, more than 32 guests were bound to the PPI dendrimer with 32 surface functionalities, suggesting a fraction of the guest molecules are located in the interior pockets of PPI dendrimer. The statistical polydispersity and fraction of bound-state guests are described in Figure 2 to provide a simplified view of multicomponent host−guest systems. It is worth noticing that the binding affinities of guests on dendrimer surface and in its interior is much different from each other due to distinct interaction modes, 1D NMR titration and the equations demonstrated above can only give a semiquantitative determination of the binding parameters.55 To calculate the binding affinities between anionic silane dendrimer and cationic guests, Astruc et al. adopted a similar strategy in which the approximation δb = Δδmax − δf was assumed (δb, Δδmax, and δf are the same as defined in eq 6).55 The plots of Δδ versus guest/dendrimer ratio showed distinct shapes for the guests (Figure 3): a plateau fashion for dopamine (S11), and a sinusoidal shape for acetylcholine (S9) and BTEA (S10), respectively. This is due to the fact that the latter two cationic guests interact with dendrimer in two steps, while 3868


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Scheme 5. Molecular Structures of the (a) Adamantyl/Urea-Modified;56 (b) Adamantyl/Thiourea-Modified;121 and (c) Palmityl/Thiourea-Modified PPI Dendrimers.120 Panel b was Reprinted with Permission from Reference 121. Copyright 2002 John Wiley & Sons

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able to solubilize a larger amount of phenobarbital than higher generation ones at a fixed amine concentration, due to less serious spatial hindrance on the surface. Since surface ionic binding and interior encapsulation of phenobarbital together contributes to enhanced solubility of the drug in the presence of dendrimers, NMR and solubility results can conclude that lower generation dendrimers are easier for ionic attachment of phenobarbital on their surface than higher generation ones. Similar results are also observed for phenylbutazone (S26) and sulfamethoxazole(S27),92,167 and this valuable conclusion can help us with choosing proper dendrimers for design of dendrimer-based drug formulations for various purposes (surface ionic binding versus interior encapsulation). Besides dendrimer generation, their surface functionality and environmental pH condition also influence the interaction behaviors between dendrimers and guests. 1H NMR titration reflected the presence of ionic interactions between cationic dendrimers (amine-terminated PAMAM) and anionic guests (mycophenolic acid, S1, phenylbutazone, S26, Congo red, S28, retinoic acid, S29, and phenobarbital, S25), and between anionic dendrimers (carboxylate-terminated PAMAM) and cationic guests (amantadine, S5, propranolol, S6, venlafaxine, S7, and benzyltrimethyl ammonium, S8).119 Low-frequency shifts of the interior pocket protons of amine-terminated PAMAM dendrimer are observed when the dendrimers are titrated with mycophenolic acid (S1),91 while no shift of the pocket protons of carboxylate-terminated PAMAM dendrimer is found after the addition of the four cationic guests.119 2DNOESY studies further confirmed that cationic PAMAM dendrimers are able to encapsulate a series of anionic guests such as mycophenolic acid (S1) and phenylbutazone (S26), but anionic PAMAM dendrimers mainly bind the cationic guests on their surface without interior encapsulation. The pH-dependent binding/encapsulation of GMP molecules (S21) on the surface or in the interior cavities of amine-terminated PAMAM dendrimer is also investigated.124 GMP starts to bind on the surface of dendrimer as soon as the protonation of surface primary amine begins (pKa ≈ 10.5), but the encapsulation is not observed for dendrimer/GMP complex during this period. The encapsulation occurs at acidic conditions (pH∼5.0) and increases with decreasing pH values. At acidic conditions (pH < 6.5), GMP molecules bound on the surface and in the interior of PAMAM dendrimer through ionic interactions. This process lasts until the pH achieves 1.5, at which phosphate group in GMP protonates and cannot form ionic pairs with dendrimer (Scheme 8). Therefore, binding of guests on dendrimer surface or in its interior are highly affected by the charge property of the dendrimer. To further investigate the binding behaviors of PAMAM dendrimers and the contributions of each interaction force, two groups of hydrophobic drugs (phenobarbital, S25, and primidone, S30) and (sulfamethoxazole, S27, and trimethoprim, S31) with similar molecular structures were used as model guests.167 As shown in 2D-NOESY spectra of dendrimer/drug complexes, NOE cross-peaks are observed for complexes of PAMAM with phenobarbital and sulfamethoxazole, but not observed for that with primidone and trimethoprim. Interestingly, cationic PAMAM dendrimer exhibited excellent solubilize ability toward phenobarbital and sulfamethoxazole but failed to enhance the solubility of primidone and trimethoprim. Primidone has a similar chemical component, molecular size, and hydrophobicity with phenobarbital, thus should show a comparable tendency to localize in

Scheme 6. Specific Binding Model for the Host−Guest Complex between Adamantyl Thiourea (Urea)Functionalized PPI Dendrimers and Guest Molecules56

respectively.100 It is obvious that these binding parameters are obtained with non-neglected errors. This is because eqs 6 is valid on the basis that fast-exchange occurs between free- and bound-state guests on NMR time scale. However, several types of aggregates were proposed to present in dendrimer/SDS mixtures, and interaction between dendrimer and SDS is not a simple fast- or slow-exchange process. Transitions between fastand slow-exchange were revealed by further NMR studies during the titration of SDS into dendrimer solution.100 As a result, the calculated binding parameters are not accurate, and the order of magnitude for this interaction is considered to be informative rather than the exact value. Fox et al. determined the binding affinities of PAMAM dendrimer with pyridine (S4), quinoline (S23), and quinazoline (S24) by fitting the plot of Δδobs −1 versus pyridine concentration using eq 9.126 Amine-terminated PAMAM dendrimer shows the highest binding affinity of 1.31 M−1 with pyridine, while ester-terminated PAMAM exhibits binding affinities of 1.11 M−1 with pyridine and 0.83/0.69 M−1 with quinoline/quinazoline, respectively. Surprisingly, aliphatic chain-functionalized PAMAM does not interact with quinoline and quinazoline as no change in chemical shift of N−H protons was detected, but this dendrimer shows a relatively high affinity of 1.06 M−1 with pyridine. This result suggests that steric hindrance of quinoline and quinazoline prevents their penetration into the interior of aliphatic chain-terminated dendrimer. The low binding affinities of PAMAM dendrimers with these compounds are due to the following reasons (1) the complexes are formed by hydrogen-bond interactions, and (2) a different equation was adopted to fit the 1H NMR titration data as compared to other studies. Finally, a major disadvantage of eq 9 is that it cannot give the number of binding sites. Therefore, eq 6 are more preferred in the calculation of binding parameters in dendrimer-based host−guest systems. 3.3. Competitive Binding of Guest Molecules on the Surface or in the Interior of Dendrimers

As discussed in section 3.1, there are several types of interactions involved in the formation of dendrimer-based host−guest systems. Cheng et al. systematically investigated the effect of dendrimer generation, surface charge, and guest size and charge property on these interactions.58,64,91−93,119,124,167,191 2D-NOESY analysis revealed that strong NOE cross-peaks are observed for higher generation PAMAM/phenobarbital complexes rather than lower generation-based ones (G6 > G5 > G4 > G3),93 suggesting that higher generation dendrimers are capable of encapsulating more phenobarbital molecules (S25) within their interior cavities than lower generation dendrimers. In addition, aqueous solubility studies showed that lower generation dendrimers are 3870


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Scheme 7. Complexation of the Benzyl Ether Type Dendrimer Containing a (Tetraphenylporphinato)zinc(II) Core with Pyridine-Containing and Thymine-Containing Guests. Reprinted with Permission from Reference 182. Copyright 2007 John Wiley & Sons

indicated that surface ionic interaction not only contributes more to the solubility enhancement of hydrophobic compounds than interior encapsulation, but also plays an important role in the encapsulation process. Most probably, surface ionic binding is the first step of interior encapsulation.134 This speculation is confirmed by 2D-NOESY results that cationic PAMAM dendrimer shows excellent host behavior toward dexamethasone 21-phosphate (S32), but fully acetylated PAMAM with a neutral surface fails to encapsulate the drug.64

the relatively nonpolar interior of PAMAM dendrimer. The only difference in phenobarbital and primidone is that phenobarbital is negatively charged in weak basic condition (pKa ≈ 7.4), while primidone keeps noncharged even in strong alkaline solution (pKa ≈ 13.0) because of the lack of an oxygen atom at C2 in the molecular structure (Scheme 9a). Similar results were found with the sulfamethoxazole and trimethoprim system, where sulfamethoxazole is mildly acidic and trimethoprim is neutral (Scheme 9b). 2D-NOESY and solubility results 3871


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Figure 2. Statistical polydispersity and fraction of bound-state guests in a multicomponent host−guest systems.56

11c).10 Diffusion NMR studies on peptide dendrimers exhibited a decrease of dendrimer hydrodynamic radii after complexation with vitamin B12 (S36), indicating the formation of compact, hydrophobically collapsed inclusions.205,206 1 H−13C heteronuclear single quantum coherence (HSQC) NMR spectrum was used to investigate the structure of liquid crystal dendrimer consisting of PAMAM/PPI dendrimers and long-chain carboxylic acids (C10, C14, and C18, S37−S39).207,208 The guests only localized on PAMAM surface via amide bonds (20%) or ionic interactions. Partial protonation of the tertiary amines of PAMAM dendrimer was observed when the samples were treated by seven heating/cooling cycles, suggesting the formation of ionic pairs between the interior pockets of PAMAM and the carboxylic acids. However, this behavior is not observed for PPI/aliphatic acid complexes, no tertiary amine protonation is observed and only 8% of the aliphatic acids on surface of PPI are mediated by amide bonds (Scheme

When the interactions of cationic PAMAM and PPI dendrimers (Scheme 10) with different vitamins were analyzed by 1H NMR titrations,10 a preferential ionic binding of vitamin C (S33) on the surface rather than in the nonpolar interior of PPI dendrimers was observed. After the saturation of ionic binding on PPI surface, a sharp chemical shift variation was observed for the interior protons of PPI, which indicates an encapsulation of vitamin C in dendrimers (Scheme 11a). However, this selectivity was not observed on PAMAM dendrimers with a relatively polar interior. In the case of vitamin B6 containing three hydroxyl groups (S34), hydrogenbond drives the formation of supramolecular structures and no ionic interaction was observed between dendrimers and vitamin B6 (Scheme 11b). Vitamin B3 with a carboxyl group (S35) is the easiest one to saturate the surface amines on PPI, which is due to increased charge repulsion on dendrimer surface during the formation of dendrimer/vitamin B3 ionic pairs(Scheme 3872


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Scheme 9. Equilibrium of Noncharged and Charged Forms of (a) Phenobarbital and Primidone and (b) Sulfamethoxazole Molecules in Solutions167

Figure 3. Plot of the chemical shift variations versus the guest/host molar ratio. (a) Titration of dendri-27-carboxylate with BTEA. (b) Titration of dendri-27-carboxylate with dopamine. Reprinted with permission from reference 55. Copyright 2008 John Wiley & Sons.

PPI dendrimer occur simultaneously (Scheme 13a), while the encapsulation of glutamic acid (S43) starts after the occurrence of surface binding but before the saturation point (Scheme 13b). Hydrogen-bond interaction drives the encapsulation of arginine (S41), lysine (S42), and cysteine (S44), while ionic and hydrogen-bond interactions together contribute to the inclusion of histidine (S45) and asparagine (S46) (Scheme 13c). Hydrophobic interaction plays important roles in the encapsulations of tryptophan (S40) and phenylalanine (S47) within PPI dendrimer (Scheme 13d). A preferential surface ionic binding rather than interior encapsulations was obtained for other amino acids.209 Competitive binding of several guests by a single dendrimer is essential for us to investigate the relationships of interactions involved in dendrimer-based host−guest systems.58,79,182,210

12). In a separate study, 1H NMR titrations were used to monitor the interactions between amine-terminated PPI dendrimer and the twenty common amino acids. Surface ionic interactions and interior encapsulations were concluded to participate in the host−guest interactions and the binding behavior depends much on the side-chain property of the amino acid including charge and hydrophobicity. The formation of PPI/amino acid complexes is predominantly driven by ionic interactions for all the amino acids (highfrequency shifts of the dendrimer protons upon amino acid titration, Figure 4a) except tryptophan (S40), which is involved in strong hydrophobic interactions with the interior pockets of PPI (significant low-frequency shift, Figure 4b). Surface binding and interior encapsulation of arginine (S41) or lysine (S42) by

Scheme 8. Interaction Models between PAMAM Dendrimer and GMP Molecules at Different pH Conditions

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competitive binding of different guests by the dendrimer. The chemical equilibrium for each guest can be described as

Scheme 10. Molecular Structures of (a) Primary Amine Terminated PAMAM Dendrimer and (b) Primary Amine Terminated PPI Dendrimer

[Dendrimer] + n[Drug] ⇌ [Dendrimer − Drug n]

Assuming a 1:1 binding model with a binding constant of Kc for each binding site Kc

[Binding site] + [Drug] ⇌ [Complex]

The binding constant Kc can be calculated by eq 23 Kc =

[Drug]b [Complex] = [Binding site]f [Drug]f [Binding site]f [Drug]f (23)

Combination of the concentrations of guests and dendrimers determined from 1H NMR analysis and eq 23 gives the value of Kc for each guest molecule. Similarly, the chemical equilibrium of a ternary system containing two guests can be described as [Dendrimer] + m[Drug] + n[Drug′] ⇌ [Dendrimer − Drug m + n]

The ratio of n/m can be defined as the competitive factor α to evaluate the competitive binding of multiple guests by a single dendrimer.58 According to NMR results, the descending order of binding affinity of PAMAM dendrimer with the guests is mycophenolic acid, phenylbutazone, sulfamethoxazole, phenobarbital, and benzoic acid. Factors including hydrophobicity, size, pKa value, charged groups, and spatial hindrance effect of the guests influence the localization of guest molecules on the surface and in the interior pockets. For example, in a ternary host−guest system of dendrimer/mycophenolic acid/phenylbutazone, much more phenylbutazone molecules localized in the interior pockets than mycophenolic acid, while more mycophenolic acid bound on the surface of dendrimer by ionic interactions than phenylbutazone (Scheme 14).58 This is due to the fact that ionic interaction between dendrimer surface and mycophenolic acid (−NH3+/−COO−) is stronger than that between dendrimer and phenylbutazone (−NH3+/−CO−) with higher steric hindrance around the charged groups, and that phenylbutazone with two aromatic rings and an aliphatic chain is much more hydrophobic than mycophenolic acid. In summary, higher generation dendrimers are more suitable for the design of inclusion complexes and lower generation dendrimer is better for ionic pairs.93 Surface ionic interaction contributes more to the solubility enhancement of hydrophobic drugs by dendrimers than interior encapsulation,167 and the encapsulation is even dependent on surface binding.64,134 The relationship between surface ionic binding and interior encapsulation in dendrimer-based host−guest systems depends on the charge, hydrophobicity, pKa value, and size of both dendrimers and guests.20,58,79,91,119,124,191

Also, combination therapy using several drugs delivered by a single carrier is usually required in clinical trails for better therapeutic efficacy.211−213 Cheng et al. investigated the competitive binding of multiple drugs by a single PAMAM dendrimer using 1H NMR and 2D-NOESY analysis.58 Amineterminated PAMAM dendrimer was used as the host, benzoic acid (S48), phenylbutazone (S26), mycophenolic acid (S1), sulfamethoxazole (S27), and phenobarbital (S25) were chosen as model guests, and ethanol was used as the internal standard. Integrations of proton NMR spectra were used to determine the amount of drugs bound by dendrimers and to analyze the

3.4. Localization of the Guests in Dendrimer/Guest Complexes

Fundamentally understanding dendrimer-based host−guest systems at a molecular level lies in the complex structure of dendrimer with guests.214 The structures of dendrimers and their complexes can reveal possible mechanisms for the preparation of dendrimer-based inclusions or aggregates. NOE NMR techniques have continued to contribute to our understanding of this promising field.58,133,134,215 3874


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Scheme 11. Complexation of Cationic PPI Dendrimer with (a) Vitamin C, (b) Vitamin B6, and (c) Vitamin B3. Reprinted with Permission from Reference 10. Copyright 2010 John Wiley & Sons

NOE NMR techniques were used to characterize the spatial conformation of dendrimer by Chai et al.216 2D-NOESY and 3D-NOESY-HSQC NMR techniques clearly solved the solution structure of PPI and silane dendrimer.214−216 These pioneer studies allow further investigations using 2D-NOESY spectra in the analysis of structures of dendrimers and dendrimer/guest complexes.215,217,218 In the 2D-NOESY spectra of G6 PAMAM/phenylbutazone complexes, strong NOE cross-peaks between the aromatic protons (1−3) and

methyl protons (8) of phenylbutazone (S26) and the methylene protons (a−d) of G6 PAMAM dendrimer were observed in Figure 5.92 It is known that NOE interaction is distance-dependent and the NOE cross-peak is detected between nuclei within 5 Å,113,131,180 the cross-peaks in Figure 5 should not be created by the phenylbutazone molecules attached on the surface of dendrimer via ionic interactions. Therefore, we can conclude that at least partial phenylbutazone molecules are encapsulated into the cavities of G6 PAMAM 3875


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Scheme 12. Structure of Liquid Crystal Dendrimer Consisting of (a) PAMAM Dendrimer and Long-Chain Carboxylic Acids and (b) PPI Dendrimer and Long-Chain Carboxylic Acids207

cross-peaks between these protons are clearly observed, suggesting intermolecular NOE interactions between phenylbutazone within the dendrimer/drug complex. The intensity order of the NOE cross-peaks between protons (1−3) and protons (6−8) of phenylbutazone (8 > 7 > 6) indicates the orientation of phenylbutazone molecules on dendrimer surface (Scheme 15). In the 2D-NOESY spectrum of dendrimer/SDS (S22) complexes, cross-peak between distant proton pairs (1/ 4) located in the polar head and hydrophobic tail of SDS molecules is clearly shown, suggesting the formation of SDS bilayer structures on dendrimer surface.99 In most cases, methyl and aromatic groups of the guests are close to the scaffolds protons of dendrimers, indicating that the formation of inclusion is driven by hydrophobic interactions.20,64,79,91,99,100,167,219,220 In the 1H−1H NOESY spectrum of G5 PAMAM/sodium deoxycholate complex (Figure 6),20 strong NOE cross-peaks between the methyl groups (18, 19, and 21) of deoxycholate (S2) and cavity protons (a−d) of G5 PAMAM, and medium cross-peaks between the methine/methylene groups (3α, 12α, 2, 4, and 5) bonded or next to the two hydroxyl groups and the cavity protons of dendrimer were observed. As no ionic attachment of deoxycholate molecules on dendrimer surface were revealed by 1H NMR titrations, the NOE cross-peaks observed in Figure 6 should be created by the inclusions of deoxycholate molecules in G5 PAMAM. NOE studies suggested that deoxycholate localized in the dendrimer pockets is hydroxyl group-centered and methyl group-assisted, and the inclusion is driven by hydrogen-bond and hydrophobic interactions (Scheme 16). The important role of hydroxyl and methyl groups in the encapsulation process is also observed in the 2D-NOESY spectrum of PAMAM/dexamethasone 21phosphate (S32) complexes.64 Interestingly, when a zwitterionic analogue of deoxycholate with a molecular weight of 614 Da (S3) was used as a guest model, no NOE cross-peak was observed between dendrimer and the guest probably due to the size limit of dendrimer pockets and the increased polarity of the analogue in comparison with sodium deoxycholate (392 Da).

dendrimer, and these molecules localize near protons (a, c) rather than protons (b, d) of the dendrimer (Scheme 15). Although the spatial distance between aromatic protons (1−3) and methyl protons (8) of phenylbutazone is larger than 5 Å,

Figure 4. Chemical shift variations of PPI protons in 1H NMR spectra during the titrations of the dendrimer by amino acids, (a) glycine, and (b) tryptophan.209. 3876


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Scheme 13. Interaction Models of PPI Dendrimer with Amino Acids: (a) Arginine or Lysine; (b) Glutamic Acid; (c) Histidine and Asparagine; (d) Tryptophan and Phenylalanine Molecules209

characterized by the presence of anisotropic interactions,222,223 is also used to reveal the spatial relationships in dendrimerbased host−guest systems.224,225 1H radio frequency driven dipolar recoupling (RFDR) and magic angle spinning (MAS) NOESY were used to obtain a molecular level image of the complex of G5 PAMAM dendrimer with phospholipid bilayer.224 Dendrimers showed thermodynamic stability within the lipid bilayer and their localization in the hydrophobic region of the phospholipid bilayer restricted the motion of phospholipid tails. NOE measurements showed the encapsulation of phospholipid chains into the interior cavities of PAMAM dendrimer, which is a potential mechanism of membrane disruption by dendrimers (Scheme 18).

In a separate study, high frequency 2D-NMR (750 MHz) was used to characterize the supramolecular complexes between adamantyl urea-modified PPI dendrimers (Scheme 5) and glycine-urea containing guests (S13−S18).203 Clear cross-peaks were observed between the urea groups (11A and 11B) on PPI surface and the glycine protons (H11′) in 2D-NOESY spectrum of the complex, suggesting that the glycine head of the guest molecule localizes among the adamantyl groups on PPI surface. In addition, methylene protons (10 and 9) located adjacent to the surface tertiary amine groups are also correlated with the glycine protons (11′) of guest in the 2D-NOESY spectrum, suggesting ionic interactions between carboxylate groups of glycine and protonated tertiary amine groups on dendrimer. The NOE analysis supports a specific binding model (Scheme 6) for the formation of stable host−guest complexes. Similarly, the localizations and orientations of various guest molecules within adamantyl urea/thiourea-modified PPI dendrimers were revealed by 2D-NOESY experiments.56,57,120,121,202 In addition, heteronuclear NOE spectroscopy (HOESY) was also able to reveal the precise spatial relationships between dendritic host and guests. 1H,19F-HOESY spectrum of the complexes of organoruthenium dendrimers (RuPF6−PPI n = 2, 4, 8, 16, Scheme 17) with PF6− (S49) showed NOE cross-peaks between the fluorine atoms and dendrimer surface protons (1, 4, 5, 7, 8, 9, 10).221 However, no signal is observed between PF6− ions and the interior protons of organoruthenium dendrimers. These results clearly demonstrated that PF6− ions bound on dendrimer surface formed stable ionic pairs with Ru2+ ions rather than the formation of inclusion structures.141 Besides, solid-state NMR spectroscopy, which is

3.5. High-Throughput Screening of Dendrimer-Binding Drugs

Dendrimer-based drug delivery systems have attracted increasing attentions during these years.35,59,102,168,174,178,226−229 There are numerous drugs that may benefit from dendrimer technology via the formation of dendrimer-drug ionic pairs, inclusions, or conjugates.172,173,226,230−235 There is a potential for significant fragmentation of the literature if the host behavior of dendrimer toward a specific drug is investigated in a “one drug at a time” fashion. The increasing amount of drugs in the libraries has made it difficult for a pharmaceutist to design a high performance dendrimer/drug formulation in a relatively short time.134 Therefore, it is an urgent need to develop a convenient approach for the high-throughput screening dendrimer-binding drugs. 3877


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Scheme 14. Interaction Models in a Ternary Host−Guest System Consisting of Dendrimer/Mycophenolic Acid/ Phenylbutazone58

lower than 1000 Da should show positive NOE signals (green) with a slow buildup rate, while dendrimers and dendrimer-drug complexes should exhibit negative NOE signals (red) with a fast buildup rate. Thus, the red NOE signals for phenylbutazone, sulfamethoxazole, and mycophenolic acid in Figure 7 suggest that these compounds are dendrimer-binding drugs, while the green signals for trimethoprim and primidone reflect that these guests are not bound to dendrimers. Second, the NOE cross-peak intensities can be used to order the inclusion affinities between dendrimer and the compounds (phenylbutazone > sulfamethoxazole > mycophenolic acid). Third, the cross-peaks provide structure information on the dendrimerdrug complexes such as the localizations and orientations of the drugs within the complexes. Though the 2D-NOESY analysis is powerful in the screening of dendrimer-binding drugs, the experiment needs a relatively long period (a whole day for the dendrimer-drug complex). To reduce the experimental time in 2D NOE experiment, the authors used a Hadamard-encoded cross-relaxation spectroscopy to speed up the screening process.236−238 Hadamard-encoded NOE experiments provide the same information as 2D NOE experiment with reduced experimental time from whole days to several minutes, and the screening results are verified by conducting NOE experiments for each drug in the screening pool. For soluble compounds, NOE experiment cannot be used to screening dendrimer-binding compounds as the cross-peaks between dendrimer and these soluble drugs are extremely weak.134 STD NMR strategy, which was proven to be a sensitive and powerful tool to study complexes and inclusions, was used to analyze the competitive binding of soluble drugs by dendrimers.134,239−241 For a screening pool containing eight

Figure 5. 1H−1H NOESY spectra of G6 PAMAM/phenylbutazone complex at a mixing time of 300 ms. The intramoleculear NOE crosspeaks between dendrimer protons are indicated by rectangle and the other NOE cross-peaks are labeled by arrows. Reprinted with permission from reference 92. Copyright 2009 John Wiley & Sons.

Cheng et al. proposed a method to screen dendrimer-binding drugs by a combination of NOE and saturation transfer difference (STD) NMR techniques(Scheme 19).134 Cationic dendrimers were capable of solubilizing a large family of insoluble drugs. In this case, a mixture of insoluble drugs was used as the screening pool and dendrimer solutions were added into the pool to extract dendrimer-binding drugs. The extracted solutions were analyzed by 2D-NOESY spectrum. For an insoluble drug mixture containing phenylbutazone (S26), mycophenolic acid (S1), trimethoprim (S31), sulfamethoxazole (S27), and primidone (S30), the 2D-NOESY spectrum in Figure 7 provides lots of information on the dendrimer-drug complexes. First, free drug molecules with a molecular weight 3878


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Scheme 15. Localization Details of Phenylbutazone in the Cavities and on the Surface of Cationic PAMAM Dendrimer92

Figure 6. 1H−1H NOESY spectrum of G5 PAMAM/sodium deoxycholate complex at a mixing time of 300 ms. The intermolecular NOE crosspeaks between dendrimer and sodium deoxycholate protons are labeled by arrows.20.

compounds, strong STD signals for n-butanoic acid (S50) and N,N-dimethylformamide (S51), and medium signals for sodium salicylate (S52), L-alanine (S53), and D,L-2-aminobutyric acid (S54) were observed, suggesting that these compounds are dendrimer-binding agents. In other words, the absence of STD signals for pyridine (S4), ethyl triphenyl phosphonium bromide (S55), and nicotinamide (S56) indicates weak binding affinities of these chemicals with dendrimer. This STD NMR assisted screening experiment can be finished within half an hour.134 The combination of Hadamard-encoded NOE and STD NMR provide a convenient and convincing strategy in the high

throughput screening dendrimer-binding drugs. In a recent experiment, Cheng et al. employed PGSE and DOSY NMR to screening dendrimer-binding compounds. A solution mixture of the twenty common amino acids was used as the screening pool, and correlation spectroscopy (COSY) experiment was used to help with the chemical shift assignment of the amino acids in the screening pool. The diffusion NMR techniques also proved to be promising tools in the high-throughput screening of dendrimer-binding drugs and allowed a fast discovery of amino acids with high binding affinities toward dendrimers 3879


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have been widely used as catalysts,245,246,252 therapeutics,71 labeling probes,253 and X-ray computed tomography (CT) contrasts.72,249 Hydroxyl group-terminated G4 PAMAM dendrimer with 55atom palladium nanoparticle (G4-OH(Pd55)) was synthesized by Crooks et al. and the product G4-OH(Pd55) was characterized by 1H NMR and DOSY.16 DOSY results show that G4-OH(Pd55) and G4-OH have a similar hydrodynamic size in aqueous solution, providing convincing evidence that the palladium nanoparticle is encapsulated within the interior cavities of PAMAM dendrimer. The interior scaffold protons of dendrimer associated with palladium nanoparticle shows weaker 1H NMR signal intensities as compared to free G4OH, while the surface dendrimer protons exhibited the same 1 H NMR signal intensities in both G4-OH and G4-OH(Pd55) (Scheme 3c). In the dendrimer-encapsulated nanoparticles, different electronic environment seen by each magnetic nucleus produces a distribution of Knight shifts of the NMR frequencies that is observed as a broadened line shape. Resonances of the protons closest to the nanoparticle interface might be broadened into the baseline.16 The removal of the palladium nanoparticles loaded within dendrimer by 2-mercaptoethanol (S57) leads to an increased 1H NMR intensities of the related protons (Scheme 21). The close proximity of metal nanoparticles toward dendrimer protons causes a partial loss of 1H NMR signals. This principle was used to determine the size of the nanoparticles synthesized within dendrimer.21 Hydroxyl group-terminated G6 PAMAM dendrimer (G6-OH) was used as template and four dendrimerencapsulated palladium nanoparticles G6-OH(Pd55), G6-OH(Pd147), G6-OH(Pd200), and G6-OH(Pd250) were synthesized.

Scheme 16. Interaction Model of Deoxycholate in the Pocket of PAMAM Dendrimer, Which Is Hydroxyl GroupCentered and Methyl Group-Assisted20

among 20 candidates (unpublished data, the project has already been finished and will be published in a near future). 3.6. Size Determination of the Nanoparticles Synthesized within Dendrimer

Dendrimers were used as templates for the synthesis of monometallic, alloy, core/shell, bimetallic nanoparticles by several research groups (Scheme 20a).16,70,71,242−247 Metal ions are complexed to the interior tertiary amines of dendrimer and the bound metal ions are chemically reduced, resulting in the formation of dendrimer-encapsulated nanoparticles (Scheme 20b).197,198,248 These nanoparticles usually contain up to a few hundred atoms. Up to now, gold,65−67,74,244,249 palladium,16,250 and platinum particles246,251 were synthesized using dendrimer as a template, and these dendrimer-encapsulated nanoparticles

Scheme 17. Molecular Structure of Organoruthenium Dendrimer. Reprinted with Permission from Reference 221. Copyright 2009 John Wiley & Sons

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Scheme 18. Proposed Interaction Models of PAMAM Dendrimers and DMPC Lipid: (a) Dendrimer-Filled Lipid Vesicle Model of Lipid Bilayer Disruption; (b) Membrane Disruption by the Formation of Dendrimer-Filled Micelles224

Scheme 19. Dendrimer-Binding Drugs Screened by a Combination of NOE and Saturation Transfer Difference (STD) NMR Techniques134

Figure 7. 1H−1H NOESY spectrum of dendrimer/insoluble drug complexes at a mixing time of 300 ms. (A, phenylbutazone; B, mycophenolic acid; C, trimethoprim; D, sulfamethoxazole; E, primidone; EA, ethanol).134

can be used as a calibration curve to determine the size of palladium nanoparticles encapsulated within dendrimer by 1H NMR spectroscopy.21 This convenient method can sensitively probe slight changes in the size, shape, and environment of the nanoparticles within dendrimers, and provide as high accurate size information as TEM and scanning tunneling microscopy (STM) measurements.254 3.7. Supramolecular Structure of Dendrimer/Surfactant Aggregates

Dendrimers are monomolecular micelles with amphiphilic properties.255−257 Their hydrophobic interior and hydrophilic surface are able to bind ionic surfactant molecules via hydrophobic and ionic interactions.98 In other words, ionic surfactants make ideal guests for dendrimers due to their long hydrophobic tail and polar head in their structures.99,219 Dendrimer/surfactant complexes create a template-assisted supramolecular assembly consisting of dendrimer at the core and amphiphilic surfactants bound on the surface through ionic interactions.219 The interactions between dendrimer and surfactants cause a dramatical change in the aggregation behavior of the surfactant as well as the physicochemical properties of both components.98,258,259 Generally, surfactants start to form micelles at a critical micelle concentration (CMC). However, this critical concentration decreases to a much lower value (critical aggregation concentration, CAC) in the presence of dendrimers.98 Also, the rheological and bioadhesive behaviors of dendrimers will be improved after their complex-

Since the signal intensity of interior dendrimer protons (Id) decrease in the presence of palladium nanoparticles, and the intensities of dendrimer surface protons (ID) are scarcely influenced by the nanoparticle, ID can be used as internal standard in this system and ID/Id can reveal the effect of palladium nanoparticle on dendrimer interior signals (Scheme 3c). As shown in Figure 8, ID/Id increases linearly with the average number of palladium atoms within G6-OH. This curve 3881


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Scheme 20. (a) Models for Alloy, Core/Shell, Bimetallic Nanoparticles Based on Dendrimers197 and (b) DendrimerEncapsulated Nanoparticles242

Figure 8. Plot of ID/Id from 1H NMR spectrum versus the average number of atoms in each palladium nanoparticle encapsulated within PAMAM dendrimers.21

dendrimer surface, but also localize in its interior pockets,99 suggesting the coexistence of ionic pairs and inclusions in the complexes. This encapsulation behavior is dendrimer generation dependent (G3 < G4 < G5 > G6) and surfactant concentration dependent (more SDS monomers are encapsulated at higher SDS concentrations). When G4 PAMAM dendrimer was titrated with SDS (Figure 9a), supramolecular structure of dendrimer/SDS complexes varies with SDS/ dendrimer ratio.100 At a SDS/dendrimer ratio below 16, no shift of protons (b′ and d′) on the outermost layer of dendrimer was observed, suggesting the absence of ionic bindings of SDS on dendrimer surface. However, slight decrease in dendrimer size and significant increase in SDS hydrodynamic radii were revealed by PGSE diffusion NMR studies in this range, confirming that inclusion of SDS monomers in the cavities of G4 dendrimer is predominant during this period (Scheme 22a).205 The decreased dendrimer size is attributed to hydrophobic interactions between SDS and dendrimer scaffolds, leading to a slight shrinkage of the dendrimer structure. At a SDS/dendrimer ratio of 16−64, significant highfrequency shifts of protons (b′ and d′) were observed. SDS molecules start to bind on the surface of dendrimer via ionic/ ion-dipole interactions (Scheme 22b). Only one peak for each SDS and dendrimer proton observed in the 1H NMR spectrum suggests a fast-exchange of free- and bound-state SDS molecules. The increased SDS diffusion coefficient with increasing SDS concentration confirms this fast-exchange model on dendrimer surface (Figure 9b). This situation changed when the SDS/dendrimer ratio reaches 128. New peaks represented for protons (b′) and protons (d′) appeared in Figure 9a. The newly appeared peaks with higher chemical shifts correspond to a stable dendrimer/SDS complex in which SDS are bound on dendrimer surface in a bilayer fashion and

ation with surfactants.219 Up to now, different types of dendrimer/surfactant complexes or aggregates were reported by techniques including fluorescence spectroscopy,260−265 solution turbidity measurement,266 ITC,98,267 EPR,111,112,268,269 Krafft temperature,270−273 viscosity,273,274 surface tension,261−264,273 SDS specific electrode,267 atom force microscopy (AFM),272,275,276 transmission electron m i c ro s co p y ( T E M) , 2 7 5 d y n a m i c l i g h t s c a t t e r i n g (DLS), 261−264,273 SANS, 110 and electrical conductivity.261,262,266,272,273 Here, the use of NMR analysis in the study of supramolecular structure of dendrimer/surfactant aggregates will be demonstrated. 2D-NOESY spectrum of dendrimer/SDS (S22) complexes clearly proved that the anionic surfactants not only bind on

Scheme 21. Palladium Nanoparticles Synthesized within Dendrimer and Removed out of Dendrimer by Thiol Compounds16

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Figure 9. (a) 1H NMR spectra for G4 dendrimer/SDS/D2O solution, the SDS/G4 dendrimer ratios were set as (1) 0, (2) 4, (3) 8, (4) 16, (5) 32, (6) 64, (7) 128, (8) 256, (9) 512, (10) 1024. (b) Diffusion coefficient of SDS in the presence of G4 PAMAM dendrimer as a function of the SDS/ G4 dendrimer molar ratio. The G4 PAMAM dendrimer concentration being constant of 1.41 × 10−4 M.100.

Scheme 22. Supramolecular Structures of Dendrimer/SDS Complexes at Different SDS/Dendrimer Molar Ratios Which Increase from a to e100

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Scheme 23. Supramolecular Structures for Dendrimer with Two Surfactants at Different Molar Ratios of Two Surfactants/ Dendrimer Which Increase from a to f79

In addition to the applications of diffusion NMR in the analysis of dendrimer/surfactant supramolecular aggregates, it also helps us in analyzing dendrimer conformation. Majoral et al. found nanoscopic changes in phosphorus dendrimer caused by the addition of tetrahydrofuran (THF).277 DOSY results showed a dramatic “swelling” behavior of phosphorus dendrimer (60 Å in D2O, while 82 Å in D2O/THF-d8). To better understand the nanosponge assumed internal structure of phosphorus dendrimer, tetramethysilane (TMS) was used as a NMR probe. TMS molecules encapsulated within dendrimer pocket (slowest), adsorbed on dendrimer surface (moderate), and dispersed in the solvent (fastest) showed different diffusion coefficients in the DOSY spectrum. The diffusion coefficients for both TMS species that interacted with phosphorus dendrimer increase after the addition of THF, suggesting increased porosity of the nanofrontier between the interior and the exterior of PAMAM dendrimer.277

the exchange between free- and bound- SDS is slow. Obviously, fast- and slow-exchange is coexistent in the complex structure at SDS/dendrimer ratio of 128 (Scheme 22c). At a higher SDS/ dendrimer ratio of 256, the peaks corresponding to fastexchange disappear and most of the SDS molecules are bound on dendrimer surface via the bilayer structures (Scheme 22d). Finally, the peaks for protons (b′ and d′) exhibited a lowfrequency shift at SDS/dendrimer ratios above 256. In this case, the SDS molecules form micelles in the solution and interact with dendrimer surface via micellar forms (Scheme 22e). Sustainable growth in dendrimer size reveals that more and more SDS molecules are bound on dendrimer surface during the titration experiment. The formation of SDS micelles and larger supramolecular structures is further confirmed by PGSE diffusion studies. The combination of 1H NMR titration and PGSE NMR was also used to study a ternary system containing PAMAM dendrimer, SDS (S22), and sodium deoxycholate (S2).79 A simultaneous encapsulation of SDS and sodium deoxycholate within dendrimer pockets was found at low surfactant concentrations. The inclusion structure is confirmed by 2DNOESY spectrum of the dendrimer/SDS/sodium deoxycholate complex. SDS molecules showed a similar behavior as compared to that observed in dendrimer/SDS binary systems, and sodium deoxycholate tend to localize either in the interior of dendrimer pockets or in the SDS micelles. Miscellaneous mixed micelles, supramolecular structures, and competitive binding of the two surfactants by dendrimer were proposed based on the NMR studies (Scheme 23). It is worth noticing that the CAC of SDS in the presence of G4 PAMAM was reported to be 0.7 mM by SDS selective electrode studies.267 However, PGSE NMR studies showed that interaction between dendrimer and SDS starts at a much lower concentration (∼0.1 mM),79 suggesting the superiority of NMR methods over other techniques in the determination of intermolecular interactions.

3.8. Dendrimer-Based MRI Contrasts

MRI has already been proved to be a powerful technique in clinical diagnosis. Many pulse sequences are used to generate MRI signals, but conventional longitudinal relaxation time T1 and transverse relaxation time T2 weighted imaging remain the most used ones.278 During the development of MRI, contrast agents have been used to increase the sensitivity of MRI signals. Nowadays, dendrimers have been widely used as scaffolds for these contrast agents such as gadolinium(III) (Gd3+)-based chelates due to the large number of surface functionalities, the multivalency effect, and the nanoscale and easily tunable size. The contrast agents bound to dendrimers showed much increased relaxivity and prolonged intravascular retention and blood circulation time.279−281 Since this topic does not belong to dendrimer-based host−guest systems and several reviews have already demonstrated the applications of dendrimers in the MRI contrasts,279−282 only a few references will be 3884


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Table 1. Representative Examples of Dendrimer-Based MRI Contrast Agents agent DTPA G2-(1B4M-Gd-DTPA)16 G3-(1B4M-Gd-DTPA)32 G4-(1B4M-Gd-DTPA)64 G5-(1B4M-Gd-DTPA)96 G6A-(1B4M-Gd-DTPA)192 G6E-(1B4M-Gd-DTPA)256 G7-(1B4M-Gd-DTPA)512 G8-(1B4M-Gd-DTPA)1024 G9-(1B4M-Gd-DTPA)2048 G10-(1B4M-Gd-DTPA)4096 G2-(1B4M-Gd-DTPA)16 G3-(1B4M-Gd-DTPA)32 G4-(1B4M-Gd-DTPA)63 G4-PEG2K-(Gd-DTPA) G4-PEG5K-(Gd-DTPA) G5-PEG2K-(Gd-DTPA) G4 Ac-PAMAM-(Gd-DTPA) Ig-G2 Ig-G4 Bt5-G6-(1B4M-Gd)251 G6-(1B4M-Gd)254 G2SS-Gd-1B4M-DTPA G4SS-(Gd-DOTA)30 G5SS-(Gd-DOTA)58 Ab-(G4S15)4 Ab-(G5S29)4 G6-(GD-DO3A) G6SS-(GD-DO3A) Gd-TREN-bis(1-Me-3,2-HOPO)-TAM-ethylamine Gd-TREN-bis(1,2-HOPO)-TAM-ethylamine

dendrimer scaffold

maximun MW

EDA PAMAM EDA PAMAM EDA PAMAM ammonia core PAMAM ammonia core PAMAM EDA PAMAM EDA PAMAM EDA PAMAM EDA PAMAM EDA PAMAM DAB PPI DAB PPI DAB PPI G4 PAMAM-PEG2K G4 PAMAM-PEG5K G5 PAMAM-PEG2K G4 Ac-PAMAM G2-EDA PAMAM G4-EDA PAMAM G6 EDA PAMAM-biotin G6 EDA PAMAM-avidin biotinylated-G2SS PAMAM-avidin-RhodG G4 cystamine PAMAM G5 cystamine PAMAM antibody-G4S PAMAM antibody-G5S PAMAM G6 PAMAM G6-cystamine PAMAM poly-L-lysine-based dendrimer esteramide-based dendrimer

0.8 kDa 15 kDa 29 kDa 59 kDa 88 kDa 175 kDa 238 kDa 470 kDa 954 kDa 1910 kDa 3820 kDa 12 kDa 25 kDa 51 kDa 66 kDa 122 kDa 100 kDa 36 kDa ∼170 kDa ∼200 kDa 238 kDa ∼300 kDa NA 37631 71759 155262 223581 NA NA ∼40 kDa ∼40 kDa

R1 (mM−1 S−1) 5.5 20 25 29 NA NA 33 NA 35 NA NA 12 17 29 26 23 24 25

33 NA 12.4 16.5 27.3 6.7 9.1 11.6 11.1 21.0 38.1

ref 283

285

286

± ± ± ±

1.2 1.4 1.1 1.3

287 288 289 290

291 ± 0.6

292

which is about 10-fold higher than those of commercially available MRI contrast agents (3−5 mM−1S−1). Poly(ester amide) dendrimer based conjugates exhibited much higher relaxivities than poly(lysine) based ones.292

discussed here and we summarized the representative examples in Table 1.283−292 PAMAM dendrimers of G2 to G10 were conjugated to acyclic diethylenetriamine pentaacetic acid (DTPA) derivatives and bound with Gd3+ ions by Kobayashi et al. The R1 relaxivity of the contrast agents has been improved from 5.5 mM−1 S−1 for Gd3+-DTPA to 35 mM−1 S−1 for Gd3+-G8 PAMAM-DTPA conjugate.283,284 The effects of dendrimer core and generation on the relaxivities of dendrimer conjugates were investigated by using PAMAM and PPI dendrimers of different generations. The R1 values of the conjugates are 20, 25, and 28 mM−1 S−1 for G2, G3, and G4 PAMAM conjugates, respectively, while the values are 12, 17, and 29 mM−1 S−1 for G3, G4, and G5 PPI dendrimer conjugates, respectively. Surprisingly, it was observed that the in vivo retention time of Gd3+-labeled PPI dendrimers decreases with dendrimer generation, while PAMAM dendrimer-based Gd3+ chelates showed an opposite tendency.285 The same group also investigated the effect of PEGylation on the in vitro relaxivities and in vivo biodistribution behaviors of dendrimer-DTPA-Gd3+ chelates. Short PEG chains with a molecular weight around 2000 Da slightly affected the relaxivity of the conjugates, but longer PEG chains with a molecular weight above 5000 Da significantly influenced the relaxivity values.286 Raymond et al. reported the use of poly(lysine) and poly(ester amide) dendrimers to improve the relaxivities of Gd3+ chelates. The R1 relaxivities of the conjugates have been improved up to 38.14 ± 0.02 mM−1 S−1 per Gd3+ gadolinium and 228 mM−1S−1 per dendrimer,

4. CONCLUSIONS In this critical review, applications of various NMR techniques to investigate the host behaviors of different dendrimers were reviewed. Chemical shift titration experiments give information on the types of interactions between dendrimer and guests, and can be used to calculate the binding parameters of the host− guest systems including number of binding sites and binding affinities. NOE analysis provides precise spatial conformations such as the localizations and orientations of the guests within the dendrimer/guest complexes. Diffusion NMR reveals the size of the dendrimer/guest complexes and can be used to predict the supramolecular structure of the dendrimer/ surfactant aggregates. Relaxation measurement reflects the mobility and rigidity of the guest molecules bound with dendrimers. Besides, the combination of NOE, diffusion, and STD NMR experiments is successfully used for highthroughput screening dendrimer-binding drugs. NMR techniques also provide precise size information of palladium nanoparticles loaded within dendrimers. In conclusion, NMR techniques can help us in better understanding dendrimerbased host−guest systems, such as interaction mechanisms, dynamics, complex structures, drugs localization and orientation, complex and aggregate size, and so on. These studies 3885


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suggest that NMR is a powerful technique in the analysis of dendrimer-based host−guest systems.

Distinguished Young Scholars in 2010. His current researches are focused on the synthesis and applications of functional polymers.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies

Yiyun Cheng is a Full Professor of Biomedical Engineering at School of Life Sciences, East China Normal University. He received his PhD from University of Science and Technology of China under the mentorship of Professor Yunyu Shi and was a postdoctoral fellow at Washington University in St. Louis with Professor Younan Xia. Yiyun won the CAS President’s Excellent Award, the Excellent PhD Thesis Award of Chinese Academy of Science, the Shanghai Dawn Scholar, and the New Century Excellent Talents in the Universities of Ministry of Education, China. He was the Regional Editor of Current Drug Discovery Technologies and the Editorial Board Members of five international journals, and was invited as reviewers for more than 40 international journals and has published more than 40 peer-reviewed manuscripts including Nature Materials, Chemical Society Reviews, and Journal of the American Chemical Society with a total citation more than 800 by other research groups. His research interests are focused on the biomedical applications of dendrimers and other dendritic polymers.

Jingjing Hu obtained her bachelor in material engineering from Jilin University in 2007. She is a PhD candidate in the Department of Chemistry, University of Science and Technology of China, cosupervised by Professor Yiyun Cheng and Professor Tongwen Xu. Her Research is focused on the design of dendrimer-based host−guest systems.

ACKNOWLEDGMENTS We thank financial supports from the grant from the Science and Technology of Shanghai Municipality (11DZ2260300), the Talent Program of East China Normal University (No.77202201), the Innovation Program of Shanghai Municipal Education Commission (No.12ZZ044), and the “Dawn” Program of Shanghai Education Commission (No.10SG27) on this project. LIST OF CAC CMC DOSY EPR GMP HOESY HSQC ITC MRI NMR NOE NOESY PAMAM PPI PGSE ROESY

Tongwen Xu is a Full Professor of Chemistry at the University of Science and Technology of China. He received PhD in Chemical Engineering from Tianjin University in 1995. Tongwen was a postdoctoral research fellow at Nankai University during 1995− 1997. He has published over 200 peer-reviewed publications with Hindex 28, 19 invited book chapters, 20 issued Chinese patents and have given more than 20 invited lectures in academia and industry around the world. Tongwen act as editor in chief of 3 international books and executive guest editors or editorial board members for 7 international journals. Tongwen was issued by the first class Technical Advance Awards of Chinese Membrane Society in 2006 and 2009, the first class Technical Advance Awards of Chinese Petroleum and Chemical Engineering Society in 2008 and 2009, Awards for Excellent Chemical Engineer of China in 2008, and National Science Foundation for

SDS 3886

ABBREVIATIONS critical aggregation concentration critical micelle concentration diffusion-ordered NMR spectroscopy electron paramagnetic resonance guanosine monophosphate heteronuclear nuclear overhauser effect spectroscopy heteronuclear single quantum coherence isothermal titration calorimetry magnetic resonance imaging nuclear magnetic resonance nuclear Overhauser effect nuclear Overhauser effect spectroscopy poly(amidoamine) poly(propylene imine) pulsed gradient spin−echo rotating frame nuclear Overhauser effect spectroscopy sodium dodecyl sulfate dx.doi.org/10.1021/cr200333h | Chem. Rev. 2012, 112, 3856−3891

Chemical Reviews SANS STD

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small angle neutron scattering saturation transfer difference

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