Aqueous Poly(amidoamine) Dendrimer G3 and G4 Generations with

Mar 3, 2014 - ... G3 and G4 Generations with Several Interior Cores at pHs 5 and 7: A ... G3 is more open-shaped and has higher structural asymmetry t...
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Aqueous Poly(amidoamine) Dendrimer G3 and G4 Generations with Several Interior Cores at pHs 5 and 7: A Molecular Dynamics Simulation Study Sajjad Kavyani,† Sepideh Amjad-Iranagh,‡ and Hamid Modarress*,† †

Department of Chemical Engineering and ‡Department of Chemistry, Amirkabir University of Technology, 424 Hafez, Tehran, Iran 15875-4413 ABSTRACT: Poly(amidoamine) (PAMAM) dendrimers play an important role in drug delivery systems, because the dendrimers are susceptible to gain unique features with modification of their structure such as changing their terminals or improving their interior core. To investigate the core improvement and the effect of core nature on PAMAM dendrimers, we studied two generations G3 and G4 PAMAM dendrimers with the interior cores of commonly used ethylendiamine (EDA), 1,5-diaminohexane (DAH), and bis(3-aminopropyl) ether (BAPE) solvated in water, as an aqueous dendrimer system, by using molecular dynamics simulation and applying a coarsegrained (CG) dendrimer force field. To consider the electrostatic interactions, the simulations were performed at two protonation states, pHs 5 and 7. The results indicated that the core improvement of PAMAM dendrimers with DAH produces the largest size for G3 and G4 dendrimers at both pHs 5 and 7. The increase in the size was also observed for BAPE core but it was not so significant as that for DAH core. By considering the internal structure of dendrimers, it was found that PAMAM dendrimer shell with DAH core had more cavities than with BAPE core at both pHs 5 and 7. Also the moment of inertia calculations showed that the generation G3 is more open-shaped and has higher structural asymmetry than the generation G4. Possessing these properties by G3, specially due to its structural asymmetry, make penetration of water beads into the dendrimer feasible. But for higher generation G4 with its relatively structural symmetry, the encapsulation efficiency for water molecules can be enhanced by changing its core to DAH or BAPE. It is also observed that for the higher generation G4 the effect of core modification is more profound than G3 because the core modification promotes the structural asymmetry development of G4 more significantly. Comparing the number of water beads that penetrate into the PAMAM dendrimers for EDA, DAH, and BAPE cores indicates a significant increase when their cores have been modified with DAH or BAPE and substantiates the effective influence of the core nature in the dendrimer encapsulation efficiency.

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INTRODUCTION Dendrimers are uniformly hyper branched, treelike polymers1,2 and their chain-branched structure puts them in a high position as a potentially valuable materials for the targeted drug delivery applications.3 The dendrimers’ structure includes three basic parts, (i) the terminals that are from the molecular surface and have the greatest effect on the dendrimers’ behavior in the solutions; (ii) the repeating units of the branching chains, known as dendrones, which surround the core and form cavities in their structures and act as the host for encapsulation of guest drug molecules; and (iii) the core, which acts as a scaffold and keeps the branching chains together and determines the size and the shape of the dendrimers. The dendrimers are defined by the generations number (G) that indicates the chainbranched layers surrounding the core.4 Because of their sophisticated but suitable structure for guest molecules encapsulation, dendrimers have been extensively used in medical applications as antitumor agent,5,6 biosensors,7 and drug carriers. The dendrimers can attach the drugs and other materials to their surfaces8,9 or encapsulate the drug guest molecule in their internal structure.10,11 Among various © 2014 American Chemical Society

dendrimers, polyamidoamine (PAMAM, the molecular structure is shown in Figure 1), with good water solubility, uniform structure, and surface functionality3,12 has attracted much attentions for usage in drug delivery systems. It is found that grafting polyethylene glycol (PEG) to PAMAM increases the circulation lifetime and decreases the cytotoxicity of the drug delivery system.13 As mentioned, the advantage of PAMAM dendrimers are their ability to encapsulate smaller guest molecules in their internal structure.1,14 The PAMAM generation can affect its specifications such as encapsulation efficiency. Devarakonda et al.15 found that in aqueous solution the increase in solubility of the drug molecules nifedipine in higher dendrimer generations was due to the enhancement in encapsulation efficiency of the dendrimer interior cavities. To improve the encapsulation efficiency, PAMAM has been conjugated with several functional groups, for example, PEG-grafted PAMAM16 has been modified Received: September 13, 2013 Revised: January 24, 2014 Published: March 3, 2014 3257

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resulting complex has a smaller radii of gyration (Rg). Lee and Larson29 studied the structure of PAMAM conjugated with arginine and histidine at various pHs and found that with increasing the protonation at low pH on PAMAM surface, the PAMAM forms a dense-shell structure at pH 5 and a densecore at pH7. They also showed that at low pH, the PAMAM has more inner cavities in its interior structure and can encapsulate more guest molecules. To the best of our knowledge, no study has been done on the effect of core and its nature on the encapsulation capacity and structural change of dendrimers by coarsed-grained (CG) molecular dynamics simulation. Therefore, in this work a CG simulation of PAMAM dendrimer with different cores, ethylenediamine (EDA), 1,5-diaminohexane (DAH), and bis(3-aminopropyl) ether (BAPE), has been performed. The molecular structures of the above-mentioned cores are presented in Figure 2. These cores have been used in synthesis Figure 1. PAMAM dendrimer. The core, G0, and G1 are shown.

by changing its core. Watkins et al.17 spotted that with increasing the number of carbons in the PAMAM core up to 12, the aqueous solubility of the nile red compound in the dendrimers was enhanced. Kannaiyan et al.18 found that for generation 3 (G3) of poly(propyleneimine) dendrimer as the core of PAMAM-shell, and with increasing the generation of the PAMAM at high pH, the encapsulation capacity for pyrene was improved. pH sensitivity of PAMAM is one of its advantage in such a way that at low pH it forms an extended structure.19 By using this feature the release and encapsulation of the drug guest molecule can be controlled. For example, at low pH it is found that the PAMAM has higher release rate of furosemide drug molecule.20 Also greater solubility of 2-naphtol21 and nicotinic acid22 in the PAMAM dendrimer solutions was observed at high pH. Molecular dynamics (MD) has introduced an efficient and novel technique for molecular structure study especially for the PAMAM dendrimers and has provided promising results by its applications. Lee et al.23 performed an atomistic MD simulation on PAMAM of various generations and validated the existence of the extended structural and inner cavities variation of PAMAM. Maiti et al.24 simulated generations 4, 5, and 6 PAMAM dendrimer with ethylenediamine core in water and determined that G5 dendrimer swelled by 33% in the presence of water as the solvent. Carbone et al.25 studied the PAMAM dendrimer over a tempreture range of 200−400 K and reported stronger hydrogen bond formation in G4 than that of G3. They also reported the low effect of temperature on dendrimer properties such as gyration radius. Maiti et al.26 simulated PAMAM dendrimer generations 1 to 11 with EDA core by MD simulation and reported the structural properties of the dendrimer. Lee et al.27 studied size and internal structure of acetylated and unacetylated G5 PAMAM dendrimers in aqueous and in methanol solutions and found that the radius of gyration of the acetylated and unacetylated G5 in aqueous solution is more than that of methanol. All-atom simulation of dendrimers can be time-consuming, and the application of coarse-grained (CG) models can be considered as a reasonable choice for reducing the simulation time. Lee et al.28 simulated a PEG-grafted PAMAM with a CG model and observed that PEG-attached dendrimers possesses a larger size at low pH, but for longer PEGs with increasing number of the conjugated PEGs to PAMAM the chain back-folding occurs and the

Figure 2. EDA, DAH, and BAPE cores.

of dendrimers. The EDA core is a typical core for the PAMAM dendrimer, the BAPE core is for the PETIM dendrimer,30 and the DAH core is for PAMAM dendrimers.1,31 All these cores have similar chemical structures with two amines at their end groups; because the synthesis starts from a diamine core, the diamine can be of various lengths and spacer.32 The aim of our work was to investigate the PAMAM structural variations at pHs 5 and 7 and to study the effect of core on the structural properties of PAMAM dendrimers to observe how the encapsulation capacity of PAMAM dendrimer depends on its structural change due to replacement of the commonly used dendrimer cores.

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METHODS All simulations have been performed by GROMACS 4.5 simulation package33,34 and by utilizing the MARTINI coarsegrained (CG) force field (FF) developed by Marirink et al.35,36 In this force field, approximately four heavy atoms (except H) are represented by a single particle as a bead. The FF of the dendrimers has been previously optimized by Lee et al.28 In the CG model used in this work, the PAMAM core (EDA) lumped into two beads (3 carbons and 1 nitrogen atoms were included in one bead) and each bead was 3258

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MARTINI standard values of 0.470 nm and 1250 kJ mol−1 nm−2,35 respectively. In the DAH core, at pH 7 all of the beads have no charge but at pH 5, two tertiary amines are protonated (due to nonacidic structure of pentane) and are represented by Qd bead with the net charge of +1. For the BAPE core, the middle ether part is represented by a N0 bead, and at pH 7 the two tertiary amines on the sides are also represented by N0 with no charge. It is worth noting that in all simulations concerning the interaction of BAPE core with water both N0 and Nda bead types were examined and no significant differences were found, as will be explained in the Result and Discussion. The bond length for N0−N0, as has been approximated by energy minimization, is set to 0.380 nm and the force constant is set to the standard value of 1250 kJ mol−1 nm−2. For BAPE core at pH 5, the two tertiary amines are protonated and are represented by Qd with the net charge of +1. MARTINI water model was used to simulate the dissolving process of the dendrimer in water. In the water model, every four water molecules were represented by a P4 bead (polar type) and the dendrimers were solvated in ∼10 500 water beads (approximately 42 000 water molecules) in a periodic box with the size of 10.7 × 10.7 × 10.7 nm3. To neutralize the simulation system, Cl− were added to the simulation box. Each of Cl− ion was presented as a bead and the number of Cl− ions added to the simulation box depended on the pH of the solution; for pH 7 and G3 dendrimers, 32 Cl− ions were added, and for G4 dendrimer 64 Cl− ions (which is equal to the number of terminal amines) were added to the simulation box. At pH 5, for G4 dendrimers 126 Cl− ions were added due to presence of both tertiary amines and primary amines. It should be noted that the simulations for PAMAM G3 were performed at pH 7. The system pressure was set to 1 bar and the temperature at 310 K by applying Berendsen coupling method in the NPT ensemble.38 The periodic boundary conditions were used in all three dimensions. A 1.2 nm cutoff was used for the van der Waals interaction and the potential smoothly shifted to 0 between 0.9 and 1.2 nm. Electrostatic interactions were

represented by N0 (N0 is one of MARTINI bead type as listed in Table 1). N0 has very poor capability for hydrogen bond Table 1. MARTINI Bead Type37 bead type polar intermediate polar

nonpolar charged

description P1, P2, P3, P4, P5 (in terms of order of polarity) N0, Na, Nd, Nda N0: very poor hydrogen bond Nd: hydrogen bond donor Na: hydrogen bond acceptor Nda: both donor and acceptor capacities C1, C2, C3, C4, C5 (in terms of order of interaction strength) Q0, Qa, Qd, Qda Q0: very poor hydrogen bond Qd: hydrogen bond donor Qa: hydrogen bond acceptor Qda: both donor and acceptor capacities

formation. Amide group (CH2CONHCH2) is represented by a P3 bead (moderately polar type bead). The terminal groups including the surface primary amines are represented by Qd, which is a charged bead for protonated state with the net charge of +1 and N0 for the unprotonated state. The PAMAM coarsed-grained structure is shown in Figure 3. This model has been used successfully to predict the experimental results of Rg for PAMAM28 and the dense core as well as the dense shell of PAMAM structures in aqueous solution.29 All the surface-terminals in the PAMAM used in this work are primary amines and they are protonated at both pHs 5 and 7. At neutral pH (∼7), the inner tertiary amines of the dendrimer are unprotonated and are represented by N0, but at low pH ( BAPE > EDA. 3264

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Watkins et al.17 investigated PAMAM dendrimer with primary amines as the surface groups. They found that in a fixed generation, by increasing the carbon atoms in the EDA core up to 12 and making a larger diamine core for the dendrimer, the capacity of the dindrimer for encapsulation of the nile red compound has been enhanced. This penetration enhancement can be attributed to the asymmetric structure of the dendrimer due to larger diamine core. The nile red compound is a bulky hydrophobic molecule and needs a large path way to penetrate into the created cavities of the dendrimer and it seems that the diamine core with 12 carbon provides the proper path way by forming an asymmetrical structure. But our simulation results indicate that the asymmetrical structural change of the dendrimer with only six carbon atoms (the DAH core) can also provide the sufficient path way for penetration of water beads into the dendrimer structure. Also Watkins et al.17 indicated that for a fixed core with 12 carbon atoms by increasing the generation up to 6 the encapsulation capacity for the guest molecule highly decreased. Our results show the same trend, which means that by increasing the generation of the dendrimer at a fixed core the probability of the water beads in the dendrimer decreased. This decrease can be explained by formation of symmetrical structure in higher generation of dendrimer (Figure 5) Sharma et al.31 investigated the encapsulation of 8-anilino-1naphthalene-sulfonic acid (ANS) in amine-terminated dendrimer with different core length. They found that the encapsulation of the ANS in amine-terminated PAMAM with the DAH core increased more than a 2-fold over EDA-core. These results can be explained by the fact that the DAH core created more cavities by forming an asymmetrical structure for penetration and accommodation of ANS into the PAMAM dendrimer compared with the EDA core. The difference in size between G3-EDA7 and G4-EDA7 (Table 9) is more than the size enhancement (as represented in

the probability of water beads in the G3 structure are more than G4, which means that the penetration of water beads into the open-shaped G3 dendrimer is higher than G4 but because of larger cavities in G4, the number of water beads which penetrated into G4 are higher than G3. In higher generation G4, due to presence of repulsion forces and the structural change from symmetry to asymmetry the effect of core on the dendrimer size is more profound. At a certain pH (5 or 7) for G3 or G4, by changing the core from EDA to BAPE, an increase in the dendrimer size (represented by Rg values in Table 2), structural asymmetry (Table 4) and the cavity volumes were observed. With DAH as the core, due to stronger repulsion forces between the nonpolar site and the dendrimer’s polar beads (protonated and unprotonated beads) the dendrimer structure changes to the highest structural asymmetry and this enhances the size and the encapsulation capacity of the dendrimers. At pH 7, the dendrimers show more back-folding of the terminals than at pH 5, which means more encapsulation capacity for the dendrimers at pH 5. The PAMAM with the DAH core significantly reduces the amount of back-folded terminals and shows higher inner cavities at both pHs 5 and 7. The ability of the guest molecule to pass through the surface groups and enter into the cavities is a two-step phenomenon. Our results show that the dendrimer core is influential in both steps. That is the core length and repulsive effect on the inner branching layers of the dendrimer can form an asymmetrical structure and by creating feasible path ways, facilitating penetration of guest molecules into the cavities around the dendrimer core. In turn, the core, by pushing away the nearby layers, makes larger cavities to accommodate the guest molecule. Therefore it can be stated that the type and the length of the core must be optimized in a PAMAM dendrimer to increase its encapsulation efficiency to a required level that is needed for desired application in drug delivery utilization.

Table 9. Percentage Increase of Rg for PAMAM Dendrimers with Generation, pH, and Core

Corresponding Author

generation -pH

EDA

BAPE

DAH

100 × (G4−7 - G3−7)/G3−7 100 × (G4−5 - G4−7)/G4−7

19 3.2

23 2.5

22 2.4

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AUTHOR INFORMATION

*E-mail: [email protected]. Tel: +982164543176. Fax: +982166405847. Notes

The authors declare no competing financial interest.

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Table 3) due to the core changing. The difference in the number of water beads penetrated in G4-EDA7 and G4-DAH7 (which is more than the same difference for G4-EDA7 and G4BAPE7) is approximately equal to the differences of water beads penetrated into G3-EDA7 and G4-EDA7. These results indicates that the length and the core type affect the cavity formation and the asymmetric structural change of the PAMAM dendrimer to enhance its encapsulation efficiency for guest molecules.

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CONCLUSION As drug carriers, drugs can be encapsulated into the dendrimers to be delivered to the targeted cells. The PAMAM dendrimers, because of inner cavities in their structure, can be used to encapsulate drug molecules. In this work, the effect of changing the core of PAMAM G3 and G4 dendrimers from EDA to DAH and BAPE at pHs 5 and 7 was investigated. It was observed that for specified core and pH for higher generation G4 the inner cavities become larger and the PAMAM structural asymmetry increases. Considering the RPDs in the dendrimers 3265

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