The Configuration of Copolymer Ligands on ... - ACS Publications

Article pubs.acs.org/Langmuir

The Configuration of Copolymer Ligands on Nanoparticles Affects Adhesion and Uptake Yang Liu,†,‡ Bei Peng,*,†,‡,⊥ Salman Sohrabi,§ and Yaling Liu*,§,∥ †

School of Mechatronics Engineering, University of Electronic Science and Technology of China, Chengdu 611731, China Center for Robotics, University of Electronic Science and Technology of China, Chengdu 611731,China § Department of Mechanical Engineering and Mechanics, Lehigh University, Bethlehem, Pennsylvania 18015, United States ∥ Bioengineering, Lehigh University, Bethlehem, Pennsylvania 18015, United States ‡

S Supporting Information *

ABSTRACT: Nanoparticles (NPs) are promising carriers for targeted drug delivery, photodynamic therapy, and imaging probes. A fundamental understanding of the dynamics of polymeric NP targeting to bilayer membranes is important to enhance the design of NPs for higher adhesion, binding percentage, and efficiency. In this study, dissipative particle dynamics simulations are applied to investigate the adhesion and uptake processes of the rod, spherical, and striped NPs to cell membranes. It is observed that the striped ligands can prevent NPs from rotating even in active rotation. We further optimize striped NP to a more stabilized structure. Uptake processes of NPs with different configurations are thoroughly investigated in our simulations and among which Janus NP are indicated to improve the penetration rate to 100%. These findings provide better insight into patterned NP design and may help fabricate new NPs for biomedical applications.

■

INTRODUCTION In recent years the biomedical community has witnessed rapid development of bionanotechnology in clinical diagnostics and therapeutics.1−3 In particular, nanoparticles (NPs) of different sizes, shapes, and chemical properties have become widely used to deliver drugs to specific locations, improving the bioavailability during their circulation in the biological system.4−10 Therefore, understanding the fundamental mechanisms of how NPs interact with cellular membrane holds the key to unlocking their potential applications. NPs are small but have a high surface area and surface energy; thus, optimizing the design of surface structures has a significant effect on the interaction between cells and NPs.11−13 For example, peptide-functionalized NPs can act as efficient homing devices that are able to selectively target pancreatic cancer cells.12 It has also been found that nucleic acids can be delivered into the cell by functionalized gold NPs.14 Typically, the chemical properties and arrangement of the ligands on NPs are determinative factors in the NP−cell interaction,15−18 as these ligands can direct the assembly of NPs into hierarchically organized superstructures.19−22 Micellar structures with a hydrophobic core can be built by amphiphilic copolymers, when copolymers are immersed in hydrophilic solvents.23 The amphiphilic polymer hybrid NP composed of a lipid monolayer shell and a hydrophobic polymeric core can be used as a robust drug delivery platform, which has a tunable and sustained drug release profile and high drug encapsulation yield.24−26 The © 2016 American Chemical Society

influence of ligand structures on the penetration of NPs into cells is extremely important for designing drug carriers and regulating environmental exposure.15,27,28 Plenty of patchy and patchy-like micelles with high symmetry are assembled.29 Certain patchy arrangements of ligand patterns are realized by Poon et al.30 to enhance the specificity and efficiency of target drug delivery. Monolayers coated on NPs are built from a binary mixture of immiscible thiol surfactants containing different end groups.31−34 PonsSiepermann et al. (2012) enhanced the diversity of potential patterns by adding three or more surfactants to the mixture.35,36 NPs coated with striped amphiphilic polymers are assembled from quaternary monolayers on spherical nanoparticles.35,36The synthetic gold NPs coated with stripes of hydrophobic and anionic ligands are able to penetrate the cellular membrane without causing membrane disruption.9 The mixtures of linear ABC triblock and AC diblock copolymers are self-assembled in C-selective solvents and certain multicompartment NPs, such as the hamburger-like, reversed hamburger-like, and ring-coiledrod NPs are predicted in their simulations.37 Besides, the reversed hamburger-like is hierarchical self-assembled in experiment by Gröschel et al. (2012), and homogeneous Received: June 24, 2016 Revised: August 24, 2016 Published: September 8, 2016 10136

DOI: 10.1021/acs.langmuir.6b02371 Langmuir 2016, 32, 10136−10143

Article

Langmuir

Figure 1. (a) Schematic representation of the DPD model. The hydrophilic lipid heads (H) and hydrophobic lipid tails (T) are represented in purple and cyan, respectively, while the receptors on the membrane are lime. Functional ends, hydrophobic parts, and hydrophilic parts of the ligands are represented as yellow, red, and green beads, respectively. Part b illustrates that the z-rotation angle or x-rotation angle is the angle between the arrow on the NP and the axis. Parts b−g illustrate morphological and physical properties of ligand-coated NPs with different surface patterns. Parts b, c, d, e, f, and g represent spherical NP, striped NP (ligands are longer in the middle), hydrophobic NP (functional percentage is 50%), rod-shaped NP, hybrid NP, and Janus NP.

multicompartment micelles are synthesized through the intermediate preassembly of subunits.38,39 Studies indicate that large particles with sizes in the range of tens to hundreds of nanometers generally penetrate the membrane by endocytosis. Any larger or smaller NPs would lead to inefficient uptake.40,41 Thus, the design principles of synthetic small nanoscaffolds with amphiphilic polymers require further investigation. In this study, we perform dissipative particle dynamics (DPD) simulations42 of the direct penetration of both rod and spherical NPs into a lipid bilayer membrane. Several types of copolymer ligands are used to investigate the influence of surface properties on the uptake of spherical and striped NPs. Specifically, the effects of ligand arrangement on NP rotation during the adhesion and engulfment processes are studied. The engulfment percentage and binding percentage are used to quantify the influence of ligand arrangement.

■

Fi =

∑fC

+ f D + f R = [− aij(rc − rij) − γijωD( r ⃗/rij , vij)

i≠j

+ σijωR ζij(Δt )−0.5 ] r ⃗/rij ,

rij < rc

(1)

where aij denotes the repulsion factor; rij and vij are the distance and velocity vectors of the particle i with respect to the particle j, respectively; rc is the cutoff distance for conservative force; ωD and ωR are the weight functions (ωD = (ωR)2 = (rc − rij)2); εij is the Gaussian random number with zero mean and unit variance; and Δt is the simulation time step. σij and γij are the random noise strength and dissipation strength between beads i and j, respectively. These two are related via σij2 = 2γijkBT. We carry out the simulations for the frictional coefficients of γij = 4.5 and noise amplitude of σij = 3. Model Parameters. To simplify the model, we do not include other factors, such as charge,49 diffusivity,50 or detailed structure of ligands.31 This allows us to focus on studying the effects of different patterns of coating ligands on the adsorption and penetration processes. In our simulation the cutoff radius rc, the bead mass m, and the thermostat temperature kbT are set as unit elements. The reduced DPD units are converted to SI units by calculating the lipid diffusion coefficient and the membrane thickness. The simulated bilayer thickness is 5rc, and the lateral diffusion constants of lipid bilayer can be used to evaluate the effective time scale of the simulation;51 the typical experimental value of the DPPC bilayer thickness is approximately 4 nm, and the diffusion coefficient is 5 μm2 s−1. By comparison, the DPD length and the time units correspond to 0.8 nm and 24 ps in physical units, respectively. The dimension of the simulation box is 27rc × 48rc × 40rc, and the periodic boundary condition is assumed at all directions. The system is composed of 155 520 particles, 23 400 of which represent the bilayer membrane; the number density is 3. As illustrated in Figure 1, the ligands coated on the particle are composed of several connected beads; the number and hydrophilia of the beads can be varied based on specific conditions. Functional ends added at the end of the ligands can interact with membrane receptors. Each lipid is composed of one head and two tails. The head is composed of three hydrophilic beads, and the tail is formed by five hydrophobic beads. The membrane is composed of 50% receptors and 50% lipids.18 The NP with diameter

METHODS

DPD Formulation. The mesoscopic coarse-grain method of DPD is used in this study, where a cluster of atoms are treated as one single bead located at the center of mass of the cluster. In contrast to molecular dynamics, atoms or molecules in the system are denoted by a group of coarse-grain beads. Although DPD was originally developed to simulate fluid dynamics,43,44 it has also been successfully used to model hydrodynamic forces,43 to reproduce the phase behavior of lipid molecules,45 and to explore the interactions between biomembranes and NPs.16,46−48 DPD computes the evolution time of a system containing many bodies by numerical integration of Newton’s equation of motion. DPD applies both soft repulsive interactions and a momentum-conserving thermostat. The interaction forces between beads i and j in the DPD formulation consists of a conservative force f C, a dissipative force f D, and a random force f R. The total force on a bead i can be expressed as 10137


Article

Langmuir

Figure 2. Snapshots of the adhesion or uptake processes. Parts a−c represent the adhesion processes of spherical hydrophilic NPs, striped hydrophilic NPs, and rod-shaped hydrophilic NPs, respectively. Parts d−e represent the uptake processes of spherical hydrophobic NPs, striped hydrophobic NPs, and rod-shaped hydrophobic NPs, respectively. of 3.2 nm and ligand density 7 nm−2 is placed above the membrane. All simulations are performed in the NVT ensembles. The velocityVerlet algorithm with time step Δt = 0.02 τ is applied as the time integration method. The repulsive interaction coefficients between the different hydrophilias of beads within the membrane, ligands, and NPs are set as a = 100, while between the same hydrophilia they are set as a = 25. In addition, we keep the interaction coefficients between functional end and other beads (apart from receptor) at a = 45, while the receptor-functional end interaction parameter is set at a = 1 to model the attractive forces between receptors and ligands. As discussed in ref 52, an elastic harmonic force and a bending resistance force are used to connect two consecutive beads and constraint two consecutive bonds. Here, an elastic harmonic force is applied to link two consecutive beads, where ks and rs are the spring constant and equilibrium bond length, respectively. Take ks = 128, rs = 0.25rc for the copolymer ligands. Harmonic constrains are also applied to define the bending resistance force, where kθ and θ are the bending constant and equilibrium angle, respectively. For three consecutive ligand beads, we set kθ = 5 and θ = 180°. Parameters of elastic harmonic force and bending resistance force for lipids in the bilayer membrane can be found in.52

the NPs.15,16,53 Our simulations show that the striped NPs can effectively prevent NPs from rotation. The bonding processes of spherical and striped hydrophilic NPs are simulated as shown in Figure 2a and b. For hydrophilic NPs, ligands coated on the NP are composed of hydrophilic beads and functional ends. The NPs are initially placed above the cell membrane and then move randomly due to Brownian motion. As the functional ends of the NPs gradually bind to the membrane receptors, the NPs firmly attach to the membrane and reach equilibrium. The receptors on the membrane rearrange and are gathered under the projection of the NPs on the local area of bilayer membrane. Hydrophilic parts of NP ligands can adhere to the membrane surface and are completely wrapped by the membrane when receptor−ligand attraction is strong enough.54 For NPs with diameters of several nanometers, endocytosis is no longer an effective way to help NPs cross the membrane.40,55 After binding, the distance between NP and membrane remain constant, Dm/2.0 + Dp/2.0, where Dm represents the membrane thickness (calculated by number density profile as explained in the Supporting Information) and Dp represents the NP diameter. So no serious deformation of the membrane happens even around the NP adhesion area on membrane, as shown in Figure 2a and b. The NP wrapping is restrained due to the high energy cost of membrane bending when membrane tension is low. Because the membrane bending energy is very strong, the sizes of the NPs are small, and only moderate receptor−ligand attractions are considered. Lipids cannot fully engulf the NP. This result agrees with Tongtao et al.48 Thus, the NP partial wrapping by membrane instead of endocytosis takes place, when surface tension is close to zero.

■

RESULTS AND DISCUSSION A schematic representation of the DPD model is illustrated in Figure 1a. On the basis of the arrangement of NP chains, two types of NPs coated by copolymer ligands are classified as spherical and striped NPs, as shown in Figure 1b and c. The Adhesion of Hydrophilic NPs to Membrane. In some applications, such as photodynamic therapy in cancer treatment,2 NPs only require an external contact with the bilayer membrane, rather than entering into the target cells. Previous studies have also shown that the penetration of NPs into membrane is accompanied by a spontaneous rotation of 10138


Article

Langmuir To characterize the rotation process quantitatively, z-rotation angles, as defined in Figure 1b, were measured, as shown in Figure 3. It is observed that, after the binding process is

Figure 4. Binding percentages of striped hydrophilic NPs with different length ratios.

structure so that the functional ends on the long ligands can reach the receptors on the membrane. Therefore, the binding percentage increases with the length ratio and reaches its highest value for NPs with a length ratio of 10/6. As seen in Figure 4, increasing ligand length further is unnecessary, because binding percentage cannot be enhanced any more. It also suggests that 10/6 length ratio is the ideal structure. The Engulfment of Hydrophobic NPs to the Membrane. NPs with hydrophobic ligands can penetrate into membranes,57 while NPs with functional ligands can facilitate the bonding process to the membrane surface.18 But NPs with hydrophobic ligands decorated by functional beads on their ends are rarely studied. Figure 1d illustrates the structure of NP covered by two types of hydrophobic ligands on its surface: one is hydrophobic ligands with functional ends, and the other is just the ligands composed of hydrophobic beads. A similar structure can be found in ref 18; however, the researchers only considered the endocytosis. The engulfment percentage is the fraction of NP surface covered by the membrane. As shown in Figure 2d and Figure 5a, NPs covered with pure hydrophobic ligands can be fully engulfed by the membrane. For functional percentage smaller than 70%, the engulfment percentage decreases by an increasing functional percentage because the functional ends can bind to the receptors on the membrane surface and tend

Figure 3. Upper graph represents the z-rotation angle for different shaped ligands on hydrophilic NPs as functions of time. The lower graph expresses the z-rotation angle of striped hydrophilic NPs with different length ratios as functions of time.

triggered, the spherical NPs rotate randomly in both aqueous and lipid environments, whereas striped NPs almost maintain a fixed z-rotation angle after they contact membranes. Thermodynamically, the binding and wrapping process are dominated by the competitive factors of membrane bending energy and receptor−ligand binding energy. The membrane bending energy mainly depends on the membrane bending stiffness and surface tension, while the ligand density and the receptor−ligand attractive strength control receptor−ligand binding energy.48,56 So for the adhesion process of striped NPs, long ligands anchoring to membrane surfaces slow the rotation. The released free energy caused by the receptor−ligand interaction leads to the local wrapping of the bilayer around the long and half of the short chains surface, as shown in Figure 2b. Only when receptor−ligand binding energy exceeds the membrane bending energy, the free energy increases, and the warping process moves forward.47 In our simulation, due to the constant surface tension and limited receptor−ligand binding energy, the membrane bending energy is high, and the free energy cannot further increase. The striped NP can only be partially wrapped, which ensure the striped NP rotation would not happen after binding, as shown in Figure 3. Even though the rotation of striped NPs is restrained, its zrotation angle is large and unstable. To further optimize the structure of striped NPs, we study the effects of the length ratio of long to short ligands on rotation. Results present in Figure 3 indicate that the rotation angle decreases as the length ratio increases. However, the z-rotation angle cannot be further reduced as the length ratio reaches 10/6. Therefore, the length ratio of 10/6 is the best structure to prevent the rotation of striped NPs during NP-membrane interaction. The binding percentage is defined by the number of bonded functional ends divided by the total number of functional ends. As shown in Figure 4, striped NPs with a higher length ratio have increased the means while decreased the standard deviations of binding percentages. Higher binding percentages can benefit the binding stability and help NPs firmly adhere to membrane surfaces. Due to the high membrane bending energy, it was hard for membrane to bend along the curve of NP surface. But the long strip band has a higher degree of freedom and can bend itself along the plane membrane

Figure 5. Graph a depicts the engulfment percentage of NPs with different functional percentage (proportion of ligands decorated by functional ends); graph b shows the z-rotation angle for spherical and striped hydrophobic NPs. 10139


Article

Langmuir not to contact with the inner hydrophobic part of membrane. So the hydrophobic lipids parts in the membrane cannot fully cover the ligands with receptors on the ends. The engulfment percentage increases with the functional percentage, when the functional percentage is larger than 70%. Since more functional ends can adhere to the membrane receptors on the surface and NP could be partially wrapped by the membrane. With the increase of the functional percentage, more ligands can bond to the membrane, so the engulfment percentage increases. Figure 2d and e demonstrates the engulfment processes of spherical and striped NPs. Only striped NPs with a length ratio of 10/6 and pure hydrophobic ligands are studied in latter simulations. In these simulations, the hydrophobic ligands are able to penetrate NP into the membrane and minimize the exposure of the hydrophobic NP to the hydrophilic solvent. At last, the NP is stabilized on the midplane of the membrane, swells, and splits the internal hydrophobic bilayer lipids in two. This mechanism is analogous to the selective swelling of block copolymer lamellar domains by NPs, 58 the mesoscale thermodynamic model of uncharged NPs,57 and the experimental phenomenon of hybrids of hydrophobic dodecanethiolcoated Au NPs.59 Yet, the final equilibrium state depends on ligand arrangement. The z-rotation angle is also calculated for these hydrophobic NPs, as shown in Figure 5b. Similar to spherical hydrophilic NPs, spherical hydrophobic NPs also rotate freely before and after binding, while striped hydrophobic NPs acquire the same fixed z-rotation angle, about 10 degrees, after engulfment. For striped NP, the long ligands on the NPs are caught in between these two layers of membrane, which stops NP rotation. The striped NP separates the two layers of the membrane to increase the contacts between its hydrophobic surface and the lipophilic surfactant tails, thus lowering membrane surface tension. The striped NP engulfment process is similar to the 3SNP (3-stripy NP, three is the total number of stripes), whose penetration process is featured with an insertion−rotation mechanism.60 The 3-SNP (λ = 26.4%) parallels its striped structure with the flat membrane, and only a small energy barrier corresponding to NP rotation is needed to overcome it. The Adhesion and Engulfment of NPs with Different Shapes. Both simulation and experimental results have shown that NP shape can strongly affect pharmacokinetics and pharmacodynamics.61 Rod-shaped NP is another typical NP and nanorod with aspect ratios of three62 was also studied in our simulation, as illustrated in Figure 1e. We investigated rodshaped NPs to ascertain the influence of NP geometry on the particle adhesion and uptake processes, as shown in Figure 2c and f. For rod-shaped hydrophilic NPs, the ligands on the long end of rod-shaped NPs are the first to bind to the membrane bilayer. Then, the ligands on the flank are gradually drawn and firmly adhered to the membrane. On the contrary, the rodshaped hydrophobic NPs are able to enter the membrane and stay in the “crevice” of the two layers of phospholipid. Nanorod maximizes binding force after laying down with its long axis aligned with a cellular wall.62 The rod-shaped NP in our simulation can still move on the membrane. We measured the x-rotation angle and compared the results with the striped NPs. As shown in Figure 6a, rod-shaped NPs can rotate freely with its long axis parallel to the membrane, while striped NPs always keep a 90° angle respect to the x-axis after reaching equilibrium. As shown in the Figure 6b, the binding time was also measured for NPs of different shapes. The binding time for rod NPs is shorter than spherical NPs, which agrees with previous

Figure 6. Graph a illustrates the x-rotation angle of different NP types. Graph b shows the binding time for different NP types. Parts a, b, c, d, e, and f represents rod-shaped hydrophilic NPs, rod-shaped hydrophobic NPs, striped hydrophilic NPs, striped hydrophobic NPs, spherical hydrophilic NPs, and spherical hydrophobic NPs, respectively.

results.8 The rod-shape NPs have a larger contact area, which leads to better binding capabilities.62 The binding time of striped NPs is also shorter compared to spherical NPs. This is because of the larger contact area of the striped NPs. The contact area of a spherical NP is independent of its orientation as shown in Figure 2a; thus, the binding area remains constant within the interacting distance. However, the contact area for striped NPs is related to orientation, and there is a higher chance of initiating first contact with the membrane due to its longer striped band. From Figure 6b, we find the binding efficiency of hydrophilic NPs to be higher than hydrophobic NPs. Compared with the interaction between hydrophobic NPs and membrane, the attractive force between ligands of hydrophilic NPs and the membrane hydrophilic surface is larger. The Penetration Processes of Hybrid NPs. The penetration process is achieved through the dynamic covalent bonds between the NP and the copolymer,17 which are selectively broken and reformed at equilibrium.18 These covalent bonds can be broken by applying pH-sensitive or thermosensitive materials. The polymers allow the manipulation of membrane attachment and detachment for different ambient conditions.52 Thus, NP can penetrate the membrane by varying amphiphilic polymer coatings. The structure of hybrid NP is demonstrated in Figure 1f, and specific parameters can be found in ref 17. Half of the beads on a single ligand are hydrophilic, and the other half are hydrophobic. Figure 7a−c illustrates the penetration processes of spherical hybrid NPs, striped hybrid NPs, and rod-shaped hybrid NPs. In these simulations, NPs penetrate into the bilayer of the membrane. The outer hydrophobic ligands are broken and detach from the hydrophilic segment of ligands. The detached ligands rearranged along the lipid distribution. Once the outer segments of ligands are totally separated from the NPs, which now have an exposed hydrophilic surface, they could not stay in the hydrophobic environment inside the bilayer. Thus, the NPs would be driven out of the bilayer via this hydrophobic interaction. However, the probability that the NPs enter into the cell cannot reach 100%. Our results agree with the research of Ding et al.17 The Penetration Process of Janus NP. After the hybrid NPs are attached to the cell membranes, they could either penetrate the membranes or be repelled. The penetration rate 10140


Article

Langmuir

Figure 7. Snapshots of the penetration processes of (a) spherical hybrid NPs, (b) striped hybrid NPs, (c) rod-shaped hybrid NPs, and (d) Janus NP.

is critical to drug delivery and is largely dependent on the penetration mechanisms of the NPs. For example, the penetration rate of the most ideal NPs can reach as much as 80%,17 while a 100% penetration rate for Janus NPs is found. Figure 1g shows the structure of Janus NP. Figure 7d illustrates its mechanisms and penetration process. Initially the NP would spontaneously enter the membrane, leaving the outer segment of the hydrophilic ligands (green) exposed to the liquid environment while the hydrophobic parts (red) are embedded in the membrane (Figure 7d, Stage 1 and Stage 2). After the ligands are broken in the middle, the hydrophilic parts of the striped NP contact directly to the hydrophobic lipid tails. Because the striped structure confines the rotation of the NP and the inner hydrophilic part exposes NP to the other side of the membrane (Figure 7d, Stage 3). Finally, after the inner segments of the ligands are broken, the hydrophilic NP is pushed out of the membrane through the breach caused by inner hydrophilic ligands and successfully enters the cell (Figure 7d, Stage 4). Each time when ligands break, lipid beads disperse and blend in membrane or liquid environment. Compared with the endocytosis process of Janus NP in ref 54, Janus NP proposed here does not rotate after adhesion, does not need external force to complete fission process, and does not attach any lipids after penetration. Besides, the endocytosed NPs in ref 54 are encompassed by the vesicles after translocation across the membrane, and it is still possible that NP cannot get out of endosomes and enter the cytosol. Therefore, Janus NP used here can lower the damage to the cellular membrane and directly act on cytoplasm after penetration. As shown in Figure 8, the penetration rate of Janus NP has reached 100%, while spherical hybrid NPs, rodshaped hybrid NPs, and striped hybrid NPs are approximately 50%, which agree with the research of Ding et al.17

Figure 8. Penetration rate of different NPs. Parts a, b, c, and d represent spherical hybrid NPs, striped hybrid NPs, rod-shaped hybrid NPs, and Janus NP.

length ratio of striped hydrophilic NPs increases the binding percentages. The length ratio of 10/6 is found to be the ideal structure for striped NPs. From the adhesion and engulfment processes, we show that hydrophobic NPs are able to enter the cell, whereas hydrophilic NPs can only adhere to the membrane. Functional ends on the hydrophobic ligands tend to drive the NPs into the internal environment. We also find that rod-shaped and striped NPs have a higher binding efficiency compared to spherical NPs. Our results provide some theoretical foundations for patchy NP design, which may contribute to generating improved ligands structure for drug delivery.

■

■

SUMMARY AND CONCLUSIONS In this study, DPD is used to study the adhesion and penetration processes of polymerized NPs to a cell membrane. The effect of NP shapes and ligand types on the penetration process are studied and discussed in detail. Our results indicate that spherical and rod-shaped NPs can rotate in liquid and lipid environments, while striped ligands are able to stop NPs from rotating after binding. Even when NPs have active rotation speeds, striped structure still can stop the NP rotation (as shown in Supporting Information). In addition, Janus striped ligands increase the penetration rate to 100%. Increasing the

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.langmuir.6b02371. Validation of membrane structure: surface tension, lateral density, bending moduli, and so forth are used to validate the structure of membrane. The active rotation of spherical and striped NPs: compare the effects of ligand configurations of NPs with initial speeds (PDF) 10141


Article

Langmuir

■

(11) Verma, A.; Uzun, O.; Hu, Y.; Hu, Y.; Han, H. S.; Watson, N.; Chen, S.; Irvine, D. J.; Stellacci, F. Surface-structure-regulated cellmembrane penetration by monolayer-protected nanoparticles. Nat. Mater. 2008, 7 (7), 588−595. (12) Nel, A. E.; Mädler, L.; Velegol, D.; Xia, T.; Hoek, E. M.; Somasundaran, P.; Klaessig, F.; Castranova, V.; Thompson, M. Understanding biophysicochemical interactions at the nano-bio interface. Nat. Mater. 2009, 8 (7), 543−557. (13) Selvakannan, P.; Kumar, P. S.; More, A. S.; Shingte, R. D.; Wadgaonkar, P. P.; Sastry, M. Free-Standing Gold Nanoparticle Membrane by the Spontaneous Reduction of Aqueous Chloroaurate Ions by Oxyethylene-Linkage-Bearing Diamine at a Liquid-Liquid Interface. Adv. Mater. 2004, 16 (12), 966−971. (14) Ding, Y.; Jiang, Z.; Saha, K.; Kim, C. S.; Kim, S. T.; Landis, R. F.; Rotello, V. M. Gold nanoparticles for nucleic acid delivery. Mol. Ther. 2014, 22 (6), 1075−1083. (15) Li, Y.; Li, X.; Li, Z.; Gao, H. Surface-structure-regulated penetration of nanoparticles across a cell membrane. Nanoscale 2012, 4 (12), 3768−3775. (16) Yang, K.; Ma, Y. Q. Computer simulation of the translocation of nanoparticles with different shapes across a lipid bilayer. Nat. Nanotechnol. 2010, 5 (8), 579−583. (17) Ding, H. M.; Tian, W. D.; Ma, Y. Q. Designing nanoparticle translocation through membranes by computer simulations. ACS Nano 2012, 6 (2), 1230−1238. (18) Ding, H. M.; Ma, Y. Q. Role of physicochemical properties of coating ligands in receptor-mediated endocytosis of nanoparticles. Biomaterials 2012, 33 (23), 5798−5802. (19) Chen, L.; Klok, H. A. Multifaceted” polymer coated, gold nanoparticles. Soft Matter 2013, 9 (45), 10678−10688. (20) Mout, R.; Moyano, D. F.; Rana, S.; Rotello, V. M. Surface functionalization of nanoparticles for nanomedicine. Chem. Soc. Rev. 2012, 41 (7), 2539−2544. (21) Zhang, F.; Lees, E.; Amin, F.; Rivera Gil, P.; Yang, F.; Mulvaney, P.; Parak, W. J. Polymer-Coated Nanoparticles: A Universal Tool for Biolabelling Experiments. Small 2011, 7 (22), 3113−3127. (22) Lin, C. A. J.; Sperling, R. A.; Li, J. K.; Yang, T. Y.; Li, P. Y.; Zanella, M.; Chang, W. H.; Parak, W. J. Design of an amphiphilic polymer for nanoparticle coating and functionalization. Small 2008, 4 (3), 334−341. (23) Li, X. Shape transformations of bilayer vesicles from amphiphilic block copolymers: a dissipative particle dynamics simulation study. Soft Matter 2013, 9 (48), 11663−11670. (24) Zhang, L.; Chan, J. M.; Gu, F. X.; Rhee, J. W.; Wang, A. Z.; Radovic-Moreno, A. F.; Alexis, F.; Langer, R.; Farokhzad, O. C. selfassembled lipid? polymer hybrid nanoparticles: a robust drug delivery platform. ACS Nano 2008, 2 (8), 1696−1702. (25) Soto-Figueroa, C.; Vicente, L. Mesoscopic simulation of the drug release mechanism on the polymeric vehicle P (ST-DVB) in an acid environment. Soft Matter 2011, 7 (18), 8224−8230. (26) Nie, S. Y.; Lin, W. J.; Yao, N.; Guo, X. D.; Zhang, L. J. Drug Release from pH-Sensitive Polymeric Micelles with Different Drug Distributions: Insight from Coarse-Grained Simulations. ACS Appl. Mater. Interfaces 2014, 6 (20), 17668−17678. (27) Brown, D. M.; Kinloch, I. A.; Bangert, U.; Windle, A.; Walter, D.; Walker, G.; Scotchford, C.; Donaldson, K.; Stone, V. An in vitro study of the potential of carbon nanotubes and nanofibres to induce inflammatory mediators and frustrated phagocytosis. Carbon 2007, 45 (9), 1743−1756. (28) Sanchez, V. C.; Pietruska, J. R.; Miselis, N. R.; Hurt, R. H.; Kane, A. B. Biopersistence and potential adverse health impacts of fibrous nanomaterials: what have we learned from asbestos? Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2009, 1 (5), 511−529. (29) Kong, W.; Jiang, W.; Zhu, Y.; Li, B. Highly symmetric patchy multicompartment nanoparticles from the self-assembly of abc linear terpolymers in c-selective solvents. Langmuir 2012, 28 (32), 11714− 11724. (30) Poon, Z.; Chen, S.; Engler, A. C.; Lee, H. i.; Atas, E.; von Maltzahn, G.; Bhatia, S. N.; Hammond, P. T. Ligand-Clustered

AUTHOR INFORMATION

Corresponding Authors

*Tel.: +86 28 61831723. Fax: +86 28 61831723. E-mail: [email protected]. *Tel.: 1 610 758 5839. Fax: 1 610 758 6224. E-mail: yal310@ lehigh.edu. Present Address ⊥

No. 2006, Xiyuan Ave, West Hi-Tech Zone, Chengdu 611731, Sichuan, P. R. China. Author Contributions

Y.L. finished the model and analysis and acquired the original data in this article. B.P., Y.L., and S.S. have made the substantial contributions to conception and design for this article. B.P. and Y.L. contributed equally to this work. All the authors read and approved the final manuscript. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS The authors would like to acknowledge the partial support provided by the National Natural Science Foundation of China (No. 51575090), the Fundamental Research Funds for the Central Universities (No. ZYGX2014Z004), the National Youth Top-Notch Talent Support Program, NIH grant EB015105, NSF grant NSF CBET 113040, and NSF DMS1516236.

■ ■

ABBREVIATIONS NPs, nanoparticles; DPD, dissipative particle dynamics REFERENCES

(1) Sohrabi, S.; Zheng, J.; Finol, E. A.; Liu, Y. Numerical simulation of particle transport and deposition in the pulmonary vasculature. J. Biomech. Eng. 2014, 136 (12), 121010. (2) Bechet, D.; Couleaud, P.; Frochot, C.; Viriot, M. L.; Guillemin, F.; Barberi-Heyob, M. Nanoparticles as vehicles for delivery of photodynamic therapy agents. Trends Biotechnol. 2008, 26 (11), 612− 621. (3) Tan, J.; Keller, W.; Sohrabi, S.; Yang, J.; Liu, Y. Characterization of nanoparticle dispersion in red blood cell suspension by the lattice boltzmann-immersed boundary method. Nanomaterials 2016, 6 (2), 30. (4) Byrne, J. D.; Betancourt, T.; Brannon-Peppas, L. Active targeting schemes for nanoparticle systems in cancer therapeutics. Adv. Drug Delivery Rev. 2008, 60 (15), 1615−1626. (5) Davis, M. E.; Shin, D. M. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat. Rev. Drug Discovery 2008, 7 (9), 771−782. (6) Sutton, D.; Nasongkla, N.; Blanco, E.; Gao, J. Functionalized micellar systems for cancer targeted drug delivery. Pharm. Res. 2007, 24 (6), 1029−46. (7) McNeil, S. E. Nanotechnology for the biologist. J. Leukocyte Biol. 2005, 78 (3), 585−594. (8) Peng, B.; Liu, Y.; Zhou, Y.; Yang, L.; Zhang, G.; Liu, Y. Modeling Nanoparticle Targeting to a Vascular Surface in Shear Flow Through Diffusive Particle Dynamics. Nanoscale Res. Lett. 2015, 10 (1), 235. (9) Van Lehn, R. C.; Atukorale, P. U.; Carney, R. P.; Yang, Y. S.; Stellacci, F.; Irvine, D. J.; Alexander-Katz, A. Effect of particle diameter and surface composition on the spontaneous fusion of monolayerprotected gold nanoparticles with lipid bilayers. Nano Lett. 2013, 13 (9), 4060−4067. (10) Jiang, W.; Kim, B. Y.; Rutka, J. T.; Chan, W. C. Nanoparticlemediated cellular response is size-dependent. Nat. Nanotechnol. 2008, 3 (3), 145−50. 10142


Article

Langmuir “Patchy” Nanoparticles for Modulated Cellular Uptake and In Vivo Tumor Targeting. Angew. Chem., Int. Ed. 2010, 49 (40), 7266−7270. (31) Jackson, A. M.; Myerson, J. W.; Stellacci, F. Spontaneous assembly of subnanometre-ordered domains in the ligand shell of monolayer-protected nanoparticles. Nat. Mater. 2004, 3 (5), 330−336. (32) Jackson, A. M.; Hu, Y.; Silva, P. J.; Stellacci, F. From homoligand-to mixed-ligand-monolayer-protected metal nanoparticles: A scanning tunneling microscopy investigation. J. Am. Chem. Soc. 2006, 128 (34), 11135−11149. (33) Centrone, A.; Hu, Y.; Jackson, A. M.; Zerbi, G.; Stellacci, F. Phase Separation on Mixed-Monolayer-Protected Metal Nanoparticles: A Study by Infrared Spectroscopy and Scanning Tunneling Microscopy. Small 2007, 3 (5), 814−817. (34) Uzun, O.; Hu, Y.; Verma, A.; Chen, S.; Centrone, A.; Stellacci, F. Water-soluble amphiphilic gold nanoparticles with structured ligand shells. Chem. Commun. 2008, 2, 196−198. (35) Pons-Siepermann, I. C.; Glotzer, S. C. Design of patchy particles using quaternary self-assembled monolayers. ACS Nano 2012, 6 (5), 3919−3924. (36) Pons-Siepermann, I. C.; Glotzer, S. C. Design of patchy particles using ternary self-assembled monolayers. Soft Matter 2012, 8 (23), 6226−6231. (37) Sheng, Y.; Yan, N.; An, J.; Zhu, Y. Multicompartment nanoparticles from the self-assembly of mixtures of ABC and AC block copolymers in C-selective solvents. Chem. Phys. 2014, 441, 47− 52. (38) Gröschel, A. H.; Walther, A.; Löbling, T. I.; Schacher, F. H.; Schmalz, H.; Müller, A. H. Guided hierarchical co-assembly of soft patchy nanoparticles. Nature 2013, 503 (7475), 247−251. (39) Groschel, A. H.; Schacher, F. H.; Schmalz, H.; Borisov, O. V.; Zhulina, E. B.; Walther, A.; Müller, A. H. Precise hierarchical selfassembly of multicompartment micelles. Nat. Commun. 2012, 3, 710. (40) Gao, H.; Shi, W.; Freund, L. B. Mechanics of receptor-mediated endocytosis. Proc. Natl. Acad. Sci. U. S. A. 2005, 102 (27), 9469−9474. (41) Rajendran, L.; Knölker, H. J.; Simons, K. Subcellular targeting strategies for drug design and delivery. Nat. Rev. Drug Discovery 2010, 9 (1), 29−42. (42) Groot, R. D.; Rabone, K. Mesoscopic simulation of cell membrane damage, morphology change and rupture by nonionic surfactants. Biophys. J. 2001, 81 (2), 725−736. (43) Hoogerbrugge, P.; Koelman, J. Simulating microscopic hydrodynamic phenomena with dissipative particle dynamics. Europhys. Lett. 1992, 19 (3), 155. (44) Groot, R. D.; Warren, P. B. Dissipative particle dynamics: Bridging the gap between atomistic and mesoscopic simulation. J. Chem. Phys. 1997, 107 (11), 4423. (45) Rodgers, J. M.; Sorensen, J.; de Meyer, F. J.; Schiott, B.; Smit, B. Understanding the phase behavior of coarse-grained model lipid bilayers through computational calorimetry. J. Phys. Chem. B 2012, 116 (5), 1551−69. (46) Smith, K. A.; Jasnow, D.; Balazs, A. C. Designing synthetic vesicles that engulf nanoscopic particles. J. Chem. Phys. 2007, 127 (8), 084703. (47) Yue, T.; Li, S.; Zhang, X.; Wang, W. The relationship between membrane curvature generation and clustering of anchored proteins: a computer simulation study. Soft Matter 2010, 6 (24), 6109. (48) Yue, T.; Zhang, X. Molecular understanding of receptormediated membrane responses to ligand-coated nanoparticles. Soft Matter 2011, 7 (19), 9104−9112. (49) Dorairaj, S.; Allen, T. W. On the thermodynamic stability of a charged arginine side chain in a transmembrane helix. Proc. Natl. Acad. Sci. U. S. A. 2007, 104 (12), 4943−4948. (50) Singh, C.; Ghorai, P. K.; Horsch, M. A.; Jackson, A. M.; Larson, R. G.; Stellacci, F.; Glotzer, S. C. Entropy-mediated patterning of surfactant-coated nanoparticles and surfaces. Phys. Rev. Lett. 2007, 99 (22), 226106. (51) Li, X.; Liu, Y.; Wang, L.; Deng, M.; Liang, H. Fusion and fission pathways of vesicles from amphiphilic triblock copolymers: a

dissipative particle dynamics simulation study. Phys. Chem. Chem. Phys. 2009, 11 (20), 4051−4059. (52) Zhang, L.; Becton, M.; Wang, X. Designing Nanoparticle Translocation through Cell Membranes by Varying Amphiphilic Polymer Coatings. J. Phys. Chem. B 2015, 119 (9), 3786−3794. (53) Li, Y.; Yuan, H.; von dem Bussche, A.; Creighton, M.; Hurt, R. H.; Kane, A. B.; Gao, H. Graphene microsheets enter cells through spontaneous membrane penetration at edge asperities and corner sites. Proc. Natl. Acad. Sci. U. S. A. 2013, 110 (30), 12295−12300. (54) Ding, H. M.; Ma, Y. Q. Interactions between Janus particles and membranes. Nanoscale 2012, 4 (4), 1116−1122. (55) Zhang, S.; Li, J.; Lykotrafitis, G.; Bao, G.; Suresh, S. SizeDependent Endocytosis of Nanoparticles. Adv. Mater. 2009, 21 (4), 419−424. (56) Yue, T.; Zhang, X.; Huang, F. Membrane monolayer protrusion mediates a new nanoparticle wrapping pathway. Soft Matter 2014, 10 (12), 2024−2034. (57) Ginzburg, V. V.; Balijepalli, S. Modeling the thermodynamics of the interaction of nanoparticles with cell membranes. Nano Lett. 2007, 7 (12), 3716−3722. (58) Thompson, R. B.; Ginzburg, V. V.; Matsen, M. W.; Balazs, A. C. Predicting the mesophases of copolymer-nanoparticle composites. Science 2001, 292 (5526), 2469−2472. (59) Rasch, M. R.; Rossinyol, E.; Hueso, J. L.; Goodfellow, B. W.; Arbiol, J.; Korgel, B. A. Hydrophobic gold nanoparticle self-assembly with phosphatidylcholine lipid: membrane-loaded and janus vesicles. Nano Lett. 2010, 10 (9), 3733−3739. (60) Li, Y.; Zhang, X.; Cao, D. A spontaneous penetration mechanism of patterned nanoparticles across a biomembrane. Soft Matter 2014, 10 (35), 6844−6856. (61) Tao, L.; Hu, W.; Liu, Y.; Huang, G.; Sumer, B. D.; Gao, J. Shape-specific polymeric nanomedicine: emerging opportunities and challenges. Exp. Biol. Med. 2011, 236 (1), 20−29. (62) Tan, J.; Shah, S.; Thomas, A.; Ou-Yang, H. D.; Liu, Y. The influence of size, shape and vessel geometry on nanoparticle distribution. Microfluid. Nanofluid. 2013, 14 (1−2), 77−87.

10143
