Mesoscopic Structures of Poly(carboxybetaine ... - ACS Publications

Subscriber access provided by UNIVERSITY OF MICHIGAN LIBRARY

Article

Mesoscopic Structures of Poly(carboxybetaine) Block Copolymer and Poly(ethylene glycol) Block Copolymer in Solutions Mingrui Liao, Hongyan Liu, Hongyu Guo, and Jian Zhou Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.7b01610 • Publication Date (Web): 09 Jul 2017 Downloaded from http://pubs.acs.org on July 10, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Langmuir is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

Mesoscopic Structures of Poly(carboxybetaine) Block Copolymer and Poly(ethylene glycol) Block Copolymer in Solutions

Mingrui Liaoa, Hongyan Liua, Hongyu Guo, Jian Zhou*

School of Chemistry and Chemical Engineering, Guangdong Provincial Key Lab for Green Chemical Product Technology, South China University of Technology, Guangzhou, Guangdong, 510640, P. R. China

*

Address correspondence to J. Zhou.

E-mail: [email protected] Fax: +86 20 87114069; Tel: +86 20 87114069. a. The authors contribute equally to this work. 1 ACS Paragon Plus Environment

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 39

ABSTRACT The anti-fouling property of exogenous materials is vital for the in vivo application. In this work, dissipative particle dynamics simulations are performed to study the self-assembled morphologies of two copolymer systems containing poly(ethylene glycol) (PEG) and polycarboxybetaine (PCB) in aqueous solutions. Effects of polymer composition and polymer concentration on the self-assembled structures of the two copolymers (PLA-PEG and PLA-PCB) are investigated, respectively (PLA represents poly(lactic acid)). Results show that whatever the copolymer composition is, PLA-PEG systems will self-assemble into core-shell structures; while onion-like and vesicle structures are also found for the PLA-PCB systems. Different morphologies are obtained at different polymer concentrations in both copolymer systems. Simulation results demonstrate that PCB is more stable than PEG to maintain self-assembled spherical structures of copolymer systems since PLA-PEG forms dumbbell-like structures while PLA-PCB is spherical under the same polymer concentration. Though both two copolymer systems can self-assemble into core-shell nanoparticles when the block ratio of PLA:PEG or PLA:PCB is 80:20, the core-shell structures of the nanoparticles are quite different. The shell layers formed by PEG in PLA-PEG nanoparticles are inhomogeneous in size due to the amphiphilicity of PEG; while shell layers in PLA-PCB nanoparticles are homogenous because of the strong hydrophilicity of the zwitterionic PCB polymer block.

KEYWORDS polymer self-assembly, molecular simulation, dissipative particle dynamics, zwitterionic, anti-fouling, drug delivery 2 ACS Paragon Plus Environment

Page 3 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

1. INTRODUCTION When entering the body, most polymers would experience interactions with proteins in blood or undergo phagocytosis by macrophage, which would discount the functions of polymers. The non-specific interaction between polymers and proteins is usually called as “bio-fouling” or “fouling”. The anti-fouling property of exogenous materials is vital for their in vivo applications. As effective anti-fouling materials, poly-(ethylene glycol) (PEG) has been widely investigated and zwitterionic polymers have drawn increasingly attention in recent years1-2. PEG is widely used as an anti-fouling polymer by now, based on its excellent properties such as non-toxicity and biocompatibility. The oxygen atoms in PEG chains can form hydrogen bonds with the hydrogen atoms in water, i.e., there is a hydration layer around PEG chains3-5, it is suggested that the steric repulsion between PEG and proteins is the main reason of the anti-fouling property of PEG with long flexible chains. However, it is found that PEG would auto-oxidize fairly rapidly, especially in the presence of oxygen and transitional metal ions. Without long-term stability, the practical application of PEG is limited6-7. Zwitterionic polymer, a neutral macromolecule which has equal anionic and cationic groups in the same polymer chain, is considered to have the potential to become the alternative to PEG. The biocompatibility of zwitterionic polymers is also favorable8-13, making it more competitive in biological applications. With super-hydrophilic anions and cations, there would be a stable hydration layer around the zwitterionic polymer, which is the key to its anti-fouling property14. Since the 3 ACS Paragon Plus Environment

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 39

hydration layer formed through ionic salvation is stronger than that formed by hydrogen bonds3-5, 15, the anti-fouling property of zwitterionic polymers is supposed to be stronger than that of PEG5. Experimental data demonstrate that zwitterionic polymers are ultra-low fouling materials. The amount of test proteins adsorbed on zwitterionic polymer materials is below 5 ng/cm2, much smaller than that on PEG. Besides, the long-term stability of zwitterionic polymers is also demonstrated to be outstanding16-17. Polycarboxybetaine (PCB) is one of the zwitterionic polymers which have ultra-low fouling property and long-term stability18-19. The carboxylate groups in its side chains render PCB potentials to be conjugated with targeted molecules containing amino groups through EDC/NHS chemistry20-22. Besides, the carboxylate group of PCB chain can withstand protonation and de-protonation under different environmental pH23. These features make PCB have more advantages than PEG to be used as drug carriers. As drug carriers, it is necessary to introduce hydrophobic polymer block to PEG or PCB polymer in order to enable the copolymer to phase separate in selective solvents and self-assemble into desired structures, such as core-shell nanoparticles. Biodegradable PLA24-25, PLGA26-28 and other materials29-32 can effectively degrade into small molecules which not only can be excreted rapidly without any adverse effects on the body, but also can contribute to the release of entrapped drugs. By now, the comparisons regarding the anti-fouling property between PEG and PCB in different applications have been reported33-34. Among them, Cao and Jiang35 designed and synthesized the copolymer PLGA-PCB with sharp contrast in polarity 4 ACS Paragon Plus Environment

Page 5 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

between the two polymer blocks. Once added into aqueous solution, PLGA-PCB will easily self-assemble into nanoparticles with hydrophobic PLGA as cores and hydrophilic PCB as shells. With the addition of hydrophobic drugs docetaxel, the drugs can be encapsulated in the hydrophobic cores of nanoparticles. For PLGA-PCB system, the superhydrophilicity of PCB blocks make PCB segments stretch into aqueous phase only36. Therefore, they inferred that there would be great differences between the self-assembled structures of PLGA-PCB and those of PLGA-PEG in water. They believed that PLGA-PCB would self-assemble into perfect and regular core-shell structures with distinct interface between the PLGA core and the PCB shell; while PLGA-PEG copolymers will self-assemble into irregular core-shell structures with vague interface between the PLGA core and PEG shell. Computer simulations have long been used to study interactions between surfactants and vesicles, self-assembling behaviors of copolymers etc37-50. In this work, dissipative particle dynamics (DPD) simulations are performed to investigate the self-assembled structures of PLA-PCB copolymer as well as the structures self-assembled from PLA-PEG copolymer in aqueous solution. The effects of polymer composition and polymer concentration on the phase separated structures of both copolymer systems are studied. Comparisons of self-assembled morphology between PLA-PCB and PLA-PEG copolymer systems in aqueous solution are made. This work is expected to provide some insights into the microscopic origins of the structural differences of these two promising self-assembled drug delivery systems.

5 ACS Paragon Plus Environment

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 39

We expect to offer some guidelines for the design of polymer-based drug delivery systems. 2. METHODS Coarse-grained models. In this work, the phase behaviors of PLA-PCB and PLA-PEG copolymers in water are studied. The repetitive units of PLA and PEG polymer are coarse-grained into L and E beads. For PLA-PCB systems, we reduce the repetitive unit of PLA into L bead. As for the PCB polymer block, its repetitive unit was coarse-grained into two beads that are connected by a spring. One is denoted as Cb (the hydrophobic backbone) while the other as Cp (the hydrophilic pendant zwitterionic group). We still label the hydrophilic pendant group of the PCB repetitive unit as Cp bead after the carboxylate group of the hydrophilic pendant moiety is protonated; but we assign one positive charge to the Cp bead in DPD simulations when carboxylate group of the hydrophilic pendant moiety is protonated. In order to reproduce the tension of water better, three water molecules act as one W bead51. A schematic representation of coarse-graining is shown in Figure 1.

Simulation details. The simulation process contains two parts. First, we should acquire DPD parameters, then perform DPD simulations based on these parameters.

Parameters The repulsion parameter aij is the most important parameter which reflects the interaction between different beads. To obtain the repulsion parameter, Monte Carlo method52 and molecular dynamics method can be used. Molecular dynamics method 6 ACS Paragon Plus Environment

Page 7 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

mainly involves the mixing energy method53 and the solubility parameter method54; here we adopt the latter one. Materials Studio 4.4 was used to construct copolymer; then the solubility parameters δ of different species were obtained from the corresponding cohesive energy densities through molecular dynamics computation. Finally, the repulsion parameters aij were obtained according to the following equations39, 54-56, V (δ i − δ j ) 2 RT

(1)

aij = aii + 3.27 χ ij

(2)

χ ij =

aii = k BT

k −1 N m − 1 2αρ DPD

(3)

In equation (1), χij is the Flory-Huggins parameter that represents the interaction parameters between bead i and bead j. V is the reference molar volume. R is the ideal gas constant. δi and δj are the solubility parameters for bead i and bead j, respectively, T is the temperature of system. In equation (2), aii represents the repulsion parameter between beads of the same kind. In equation (3), α is a constant with the value 0.101±0.001, Nm is the number of water molecules that DPD bead represents. When Nm=3, the repulsion parameter between the same bead aii is 78.0055; k-1 is dimensionless compressibility and its value is about 15.98 at the room temperature56. ρDPD is the number density of system; kBT represents the energy unit in DPD simulations.


Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 39

Tables 1 and 2 list repulsion parameters among beads in PLA-PEG and PLA-PCB systems obtained through the corresponding solubility parameters (equation 1). From equations (1) and (2), we can know that repulsion parameters between different beads calculated through solubility parameter method must be larger than 78. The less deviation of the repulsion parameters from 78, the less χij value is and the better compatibility between the two beads is. From Table 1, it is easily found that the value of aL-W is about 2 times larger than 78, which means poor compatibility between L and W; that is to say L is hydrophobic, so parameters we calculated are qualitatively reasonable; while the repulsion parameter between E and W is much closer to 78 compared with those from L and G, indicating that the compatibility between E and W is much better, thus the bead E is somewhat hydrophilic; the repulsion parameters between E and other beads except W are found to be closer to 78 also, which means that E and L have good compatibility; that is to say, the bead E has the property of hydrophobicity in some extent also. Therefore, PEG is amphiphilic while PLA is hydrophobic. Table 2 shows repulsion parameters between beads in PLA-PCB system. We can observe that the repulsion parameter between Cb and W is 179.56 (much larger than 78), which means that the bead Cb is hydrophobic; while the repulsion parameter between Cp and W is very close to 78, demonstrating that Cp is hydrophilic. By comparing aE-W (114.01) with aCp-W(89.21), it is obvious that the hydrophilicity of Cp is stronger than that of E; after observing the value of aL-Cp, we come to know that the compatibility between Cp and hydrophobic beads is poor, i.e., Cp is hydrophilic only. 8 ACS Paragon Plus Environment

Page 9 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

DPD simulations. DPD module of DL-MESO is used to perform the following DPD simulations. The system is a cubic box with the box length of 40 rc, the basic length unit in DPD simulation is rc; the periodic boundary condition was applied in all three directions. The spring constant Cs is set to 4. To ensure that final states of systems reach equilibrium, the simulation steps are at least 4×105. The counter ions are added to neutralize the systems. 3. RESULTS AND DISCUSSION The self-assembled morphology of these two copolymer systems in water will vary when polymer composition or concentration is changed. Here, we will compare the self-assembled morphologies of PLA-PCB with those of PLA-PEG under different conditions. a. Comparison of the morphologies between PLA-PCB and PLA-PEG formed at different polymer compositions In this part, PLA-PEG systems and PLA-PCB systems with different compositions are simulated at the concentration of 0.1. The definition of solute concentration in aqueous solution is the proportion of bead amount between PLA-PEG (or PLA-PCB) and all beads in the simulation box. Under the concentration of 0.1, the core-shell structures of both PLA-PEG and PLA-PCB systems can be guaranteed. Figure 2 and Figure 3 are sectional views of self-assembled PLA-PEG system and PLA-PCB system, respectively. Figure 2 shows the sectional views of self-assembled morphology of the PLA-PEG system at different compositions; the total number of blocks is 100, from a to i, the 9 ACS Paragon Plus Environment

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 39

number of PLA block increases from 10 to 90. For clarity, the solvent bead W is not shown. From Figure 2, we can conclude that whatever the copolymer composition is, PLA-PEG systems will self-assemble into spherical structures with similar radii, this phenomenon was also observed in some previous experimental works57-59. The sectional views indicate that hydrophobic PLA chains can assemble into cores; amphiphilic PEG chains distribute outside to form the shells. Since the hydrophilicity of PEG can protect the stability of the spherical structure in aqueous solution by avoiding the direct contact of the hydrophobic PLA with water, the self-assembled morphologies are all core-shell structures with PLA as cores and PEG as shells. When the composition is PLA10-PEG90, the size of core is small and the PEG shell is very thick (as shown in Figure 2a); with the increase of PLA block, the radii of cores become larger and the thickness of shells become thinner (as shown in Figures 2b to 2h); when the composition is PLA90-PEG10, as shown in Figure 2i, it is obvious to find that the radius of PLA core is almost the same as those of other self-assembled structures, while PEG is insufficient to fully cover the core, thus some of hydrophobic PLA blocks rest on the surface and contact with water, reducing the stability of the self-assembled core-shell structures. Figure 3 is sectional views of PLA-PCB systems with different compositions; the total number of blocks is also fixed at 100. The number of PLA blocks increases from 10 to 90 at Figures 3(a-i). Interestingly, different from spherical core-shell structures formed in PLA-PEG systems, PLA-PCB systems at different compositions could self-assemble into different structures, such as onion-like spherical structure, vesicle 10 ACS Paragon Plus Environment

Page 11 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

structure and core-shell structure. When the ratio of PLA-PCB is 10:90, the PLA-PCB systems can self-assemble into unique onion-like structure, as shown in Figure 3a. Six layers formed by Cb and Cp arrange alternately, and a few PLA aggregates are dispersed among these layers; when the composition becomes PLA20-PCB80 and PLA30-PCB70, the number of PLA aggregates and Cb/Cp layers decreases and the onion-like structure becomes irregular; some W beads appear in self-assembled structures as shown in Figures 3b and 3c. All systems will firstly form some small aggregates in the initial stage, those small aggregates then merge into lager aggregates. Since the stable hydration layer around the outer Cp layer will block different Cp layers to form a homogeneous shell structure, the final morphology will be perfect onion-like structure as shown in Figure 3a after the merging process if water in the hydration layer is excluded completely during the merging process; while the onion-like morphology will contain some water as shown in Figures 3b and 3c if water in the hydration layer is not excluded completely. With the increase of PLA block length, the number of PLA aggregates becomes fewer and the volume of PLA aggregates increase. When the composition is PLA50-PCB50, the self-assembled morphology is peanut-like ellipsoid. When the composition is PLA60-PCB40 and PLA70-PCB30, the final morphology are vesicles with core-shell structures, while water does not locate in the center but close to the edge of spheroid. The appearance of core-shell vesicle may be due to the hydration layers around the yet excessive amount of the hydrophilic PCB blocks after forming core-shell structure can prevent different layers to form a thicker homogeneous shell, thus we can see the vesicles 11 ACS Paragon Plus Environment

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 39

beside the core-shell structures. When the composition comes to PLA80-PCB20, the final morphology is a perfect core-shell sphere as the increment of core size and the reduction of PCB blocks make PCB just enough to cover the PLA core. As for the PLA90-PCB10 system, the size of core is too large and the amount of PCB is too limited, so the PCB is dispersed in the shell with low density to make up a complete shell to avoid the contact of the hydrophobic blocks with water. In conclusion, to ensure the stability of system, the most suitable composition is PLA80-PCB20 to form the core-shell structure. b. Effect of concentration on self-assembled morphology of PLA-PCB In this part, we will investigate the effect of concentration on the morphology. Here, we adopt PLA80-PCB20 as the composition of system; as a comparison, PLA80-PEG20 is also explored. Figure 4 shows overall views of self-assembled morphology of PLA-PEG copolymer at different concentrations. From Figure 4a to 4g, we can see that whatever morphology is, the hydrophilic E beads are all distributed outside and cover the hydrophobic L beads. When the concentration is less than 0.2, the final self-assembled morphologies are all regular spherical micelles; with the increase of concentration, it is obvious to see that the size of the sphere gradually increases. When the concentration is higher than 0.2, the nearby self-assembled particles adjoin each other in different directions to form complex structures, such as dumbbell-like structure (when the concentration is 0.3), perforated layer (when the concentration is 0.4) and network structure (when the concentration is 0.5). 12 ACS Paragon Plus Environment

Page 13 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

Figure 5 shows overall views of self-assembled morphology of PLA-PCB copolymer at different concentrations. From Figure 5a to 5g, we can see that whatever the morphology is, the hydrophilic Cp beads are all distributed outside, the backbone of PCB in the middle and the hydrophobic L beads locate in the center. When the concentration is lower than 0.3, the final self-assembled morphologies are all spherical; with the increase of concentration, it is obvious that the size of sphere gradually increases; when the concentration is higher than 0.15, the appearances of spheres become imperfect; when the concentration is 0.4, the system self-assembles into dumbbell-like structure; when the concentration is 0.5, the final morphology is network structure. Comparing Figure 4 with Figure 5, we come to know that when the concentration is 0.3, the self-assembled morphology of PLA80-PCB20 is still spherical, while the PLA80-PEG20 system is dumbbell l-like structure. This result can somewhat demonstrate that the self-assembled morphology of PLA-PCB is more stable than that of PLA-PEG. This may result from the water layer formed through ionic hydration in PLA-PCB system; it is more stable than the one formed by hydrogen bonds in PLA-PEG system. When the spherical radius is too large, the more stable hydration layer still prevents them from adjoining with each other in PLA-PCB system, but different spheres will contact with each other and form dumbbell-like structure via hydrophobic interaction in PLA-PEG system. In terms of the interaction parameters in Table 1 and 2, the more approximative value of repulsion parameters with 78 between beads mean the better affinity. For 13 ACS Paragon Plus Environment

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 39

instance, in Table 1 for the PLA-PEG system, the repulsion parameter between E and W beads is 114.01; while the repulsion parameter between Cp and W beads is 89.21 in Table 2 for the PLA-PCB system; the repulsion parameter of W bead (water) with itself is 78. The different repulsion parameters between E-W and Cp-W suggest that the Cp bead in PCB has better affinity than E bead in PEG with W bead. So the hydration of the Cp will be stronger and more stable than that of E. In addition, in our previous work60, the different hydrophilicity determined by hydrations of OEG and zwitterion in all-atom molecular dynamics simulations were also investigated. The simulation results show that the order of underwater oleophobicity of SAMs is oligo(ethylene glycol) (OEG) < mixed-charged zwitterion (NC3+/COO-). c. Comparison of the morphology between PLA-PCB and PLA-PEG From previous discussion, we know that when the concentration of PLA80-PCB20 is 0.1, the self-assembled sphere is almost perfect. So, in this part, we will compare PLA80-PCB20 system with PLA80-PCB20 system at the same concentration of 0.1 in detail. Figure 6 is the sectional views and slices for self-assembled morphologies of PLA80-PCB20 and PLA80-PEG20. Figure 6a and 6c clearly show that PLA self-assembles as the core in both systems; PCB (comprised by Cb and Cp) and PEG form the shell. In Figure 6a, it is easy to observe that Cp is the outer shell and Cb is in the middle; every Cp bead is stretched into water to form the hydrophilic shell; while amphiphilic PEG chains entangle each other through hydrophobic interactions to protect the hydrophobic PLA core as shown in Figure 6c. Slices are created to show 14 ACS Paragon Plus Environment

Page 15 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

densities of different types of beads. From Figures 6b and 6d, we can see that the thickness of Cp layer in PLA-PCB system is homogeneous while the thickness of PEG shell is uneven. The self-assembly rates of PLA-PEG and PLA-PCB systems are important for their different morphologies35. If a system quickly forms a locally stable structure, there will be little possibility for it to adjust to a more optimized structure; oppositely, if the system is self-assembling at a relatively smooth rate, in the process of reaching the globally stable state, the nanoparticle can adjust itself to a more reasonable and stable structure. In terms of the parameters of these beads in PLA-PEG and PLA-PCB systems, we can also illustrate the self-assembling rate of the nanoparticles. The larger value difference between W-W(78) and E-W(114.01) than that of the W-Cp(89.21) and W-W(78) also suggests that the driving force of PLA-PEG system is larger than that of PLA-PCB system. The density distribution of various beads (like E and L beads in PLA-PEG system, L and Cp beads in PLA-PCB system) can indicate the structural features of the self-assembled nanoparticles (the calculation starts from the mass center of the nanoparticle to the outmost shell). Here, density profiles of the representative results in Figure 6 (the ratio of PLA and PEG (or PCB) is 80∶20 in concentration of 0.1) were analyzed. In Figure 7, it is straightforward to find that, the outmost PEG block has an obvious overlapping area with the inner hydrophobic core (Figure 7a); but in PLA-PCB system (Figure 7b, the outer hydrophilic block (Cp beads) has little connection with the hydrophobic inner core, namely the shell can fully and homogeneously enwrap the inner core. 15 ACS Paragon Plus Environment

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 39

The self-assembled nanoparticle sizes of PLA80-PEG20 (or PLA80-PCB20) at different concentrations (0.05-0.15) are also calculated and measured. From the data in Table 3, we can know that whatever the concentration is, the thickness of shell in PLA80-PCB20 systems is approximately double of that in PLA80-PEG20 systems under the same concentration. This difference can also provide an evidence for the more stable structure of PLA80-PCB20 system than that of PLA80-PEG20 system. Based on the above discussion, the morphology of PLA-PCB would be more proper for drug delivery system than PLA-PEG because of the key anti-fouling property. For the strong hydration of the outmost PCB, the PLA-PCB can resist adsorption of plasma proteins in blood vessels and keep stable structure. The experimental work19 also demonstrated that PCB can resist both immune response and immediate bodily clearance better than PEG. 4. CONCLUSIONS In this work, the self-assembled morphologies of PLA-PCB and PLA-PEG systems in aqueous solutions are explored through dissipative particle dynamics simulations. Firstly, the repulsion parameters are obtained through the solubility parameter method. The repulsion parameters indicate that PEG is amphiphilic and PCB is hydrophilic. Then, differences on self-assembled morphology of the two systems are investigated at different block ratios. Whatever the block ratio is, PLA-PEG systems can self-assemble into spherical core-shell structures; while some interesting structures such as onion-like, peanut-like, vesicles and core-shell structures could be observed at different block ratios in PLA-PCB systems. Chances are, the hydrophobicity of 16 ACS Paragon Plus Environment

Page 17 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

amphiphilic PEG contributes to the partially compatibility in the formation of final core-shell structures with uneven shells, and the stable hydration layer formed through ionic solvation in PLA-PCB system contributes to other morphologies. Afterwards, the effects of concentration on self-assembled morphologies are studied. Both systems undergo the transition from spherical to dumbbell-like and network structures with the increase of concentration. PLA-PCB can maintain its spherical morphology when the concentration is high, while PLA-PEG become dumbbell-like. One possible explanation is that the hydration layer formed through ionic solvation in PLA-PCB is stronger than the one formed by hydrogen bonds in PLA-PEG, thus the self-assembled morphology is more stable. Finally, the self-assembled morphology of PLA80-PCB20 and PLA80-PEG20 are compared at the concentration of 0.1. Since Cp beads are super-hydrophilic, they extend into water to form a shell with uniform thickness; while E beads are amphiphilic, the hydrophobicity makes different PEG chains entangle with each other, so the thickness of PEG shell is uneven. This work can provide some useful internal structure information for the nanoparticles self-assembled by copolymers which contain PEG or zwitterionic PCB, and help for the development of drug delivery systems.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. ORCID Mingrui Liao: 0000-0002-9481-4026 17 ACS Paragon Plus Environment

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Jian Zhou: 0000-0002-3033-7785 Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENTS

Support from National Natural Science Foundation of China (Nos. 91334202, 21376089), the National Key Basic Research Program of China (No. 2013CB733500), Guangdong Science Foundation (No. 2014A030312007) and the Fundamental Research Funds for the Central Universities (SCUT-2015ZP033) are gratefully acknowledged. An allocation time from the SCUTGrid at South China University of Technology is gratefully acknowledged.

REFERENCES 1. Jiang, S.; Cao, Z., Ultralow ‐ Fouling, Functionalizable, and Hydrolyzable Zwitterionic Materials and Their Derivatives for Biological Applications. Adv. Mater. 2010, 22 (9), 920-932. 2. Blaszykowski, C.; Sheikh, S.; Thompson, M., A survey of state-of-the-art surface chemistries to minimize fouling from human and animal biofluids. Biomater. Sci. 2015, 3 (10), 1335-1370. 3. Shao, Q.; He, Y.; White, A. D.; Jiang, S., Different effects of zwitterion and ethylene glycol on proteins. J. Chem. Phys. 2012, 136 (22), 225101. 4. Leng, C.; Hung, H.-C.; Sieggreen, O. A.; Li, Y.; Jiang, S.; Chen, Z., Probing the Surface Hydration of Nonfouling Zwitterionic and Poly(ethylene glycol) Materials with Isotopic Dilution Spectroscopy. J. Phys. Chem. C 2015, 119 (16), 8775-8780. 5. Leng, C.; Hung, H. C.; Sun, S.; Wang, D.; Li, Y.; Jiang, S.; Chen, Z., Probing the Surface Hydration of Nonfouling Zwitterionic and PEG Materials in Contact with Proteins. ACS Appl. Mater. Interfaces 2015, 7 (30), 16881-16888. 6. Carr, L. R.; Zhou, Y.; Krause, J. E.; Xue, H.; Jiang, S., Uniform zwitterionic polymer hydrogels with a nonfouling and functionalizable crosslinker using photopolymerization. Biomaterials 2011, 32 (29), 6893-6899. 18 ACS Paragon Plus Environment

Page 18 of 39

Page 19 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

7. Xu, L. Q.; Pranantyo, D.; Neoh, K.-G.; Kang, E.-T.; Teo, S. L.-M.; Fu, G. D., Synthesis of catechol and zwitterion-bifunctionalized poly(ethylene glycol) for the construction of antifouling surfaces. Polym. Chem. 2016, 7 (2), 493-501. 8. Chien, H. W.; Tsai, W. B.; Jiang, S., Direct cell encapsulation in biodegradable and functionalizable carboxybetaine hydrogels. Biomaterials 2012, 33 (23), 5706-5712. 9. Chien, H.-W.; Xu, X.; Ella-Menye, J.-R.; Tsai, W.-B.; Jiang, S., High Viability of Cells Encapsulated in Degradable Poly(carboxybetaine) Hydrogels. Langmuir 2012, 28 (51), 17778-17784. 10. Ko du, Y.; Patel, M.; Jung, B. K.; Park, J. H.; Jeong, B., Phosphorylcholine-Based Zwitterionic Biocompatible Thermogel. Biomacromolecules 2015, 16 (12), 3853-3862. 11. Huang, C. J.; Chu, S. H.; Wang, L. C.; Li, C. H.; Lee, T. R., Bioinspired Zwitterionic Surface Coatings with Robust Photostability and Fouling Resistance. ACS Appl. Mater. Interfaces 2015, 7 (42), 23776-23786. 12. Chen, X.; Shang, H.; Cao, S.; Tan, H.; Li, J., A zwitterionic surface with general cell-adhesive and protein-resistant properties. RSC Adv. 2015, 5 (93), 76216-76220. 13. Min, W.; Zhao, D.; Quan, X.; Sun, D.; Li, L.; Zhou, J., Computer simulations on the pH-sensitive tri-block copolymer containing zwitterionic sulfobetaine as a novel anti-cancer drug carrier. Colloids Surf., B 2017, 152, 260-268. 14. Cheng, G.; Liao, M.; Zhao, D.; Zhou, J., Molecular Understanding on the Underwater Oleophobicity of Self-Assembled Monolayers: Zwitterionic versus Nonionic. Langmuir 2017. 15. Wu, J.; Lin, W.; Wang, Z.; Chen, S.; Chang, Y., Investigation of the Hydration of Nonfouling Material Poly(sulfobetaine methacrylate) by Low-Field Nuclear Magnetic Resonance. Langmuir 2012, 28 (19), 7436-7441. 16. Mahmud, G.; Huda, S.; Yang, W.; Kandere-Grzybowska, K.; Pilans, D.; Jiang, S.; Grzybowski, B. A., Carboxybetaine methacrylate polymers offer robust, long-term protection against cell adhesion. Langmuir : the ACS journal of surfaces and colloids 2011, 27 (17), 10800-10804. 17. Chou, Y. N.; Sun, F.; Hung, H. C.; Jain, P.; Sinclair, A.; Zhang, P.; Bai, T.; Chang, Y.; Wen, T. C.; Yu, Q.; Jiang, S., Ultra-low fouling and high antibody loading zwitterionic hydrogel coatings for sensing and detection in complex media. Acta Biomater. 2016, 40, 31-37. 18. Zhang, X. a.; Lin, W.; Chen, S.; Xu, H.; Gu, H., Development of a Stable Dual Functional Coating with Low Non-specific Protein Adsorption and High Sensitivity for New Superparamagnetic Nanospheres. Langmuir 2011, 27 (22), 13669-13674. 19. Yang, W.; Liu, S.; Bai, T.; Keefe, A. J.; Zhang, L.; Ella-Menye, J.-R.; Li, Y.; Jiang, S., Poly(carboxybetaine) nanomaterials enable long circulation and prevent polymer-specific antibody production. Nano Today 2014, 9 (1), 10-16. 20. Jia, G.; Cao, Z.; Xue, H.; Xu, Y.; Jiang, S., Novel Zwitterionic-Polymer-Coated Silica Nanoparticles. Langmuir 2009, 25 (5), 3196-3199.


Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 39

21. Wang, X.; Sun, X.; Jiang, G.; Wang, R.; Hu, R.; Xi, X.; Zhou, Y.; Wang, S.; Wang, T., Synthesis of biomimetic hyperbranched zwitterionic polymers as targeting drug delivery carriers. J. Appl. Polym. Sci. 2013, 128 (5), 3289-3294. 22. Leng, C.; Sun, S.; Zhang, K.; Jiang, S.; Chen, Z., Molecular level studies on interfacial hydration of zwitterionic and other antifouling polymers in situ. Acta Biomater. 2016, 40, 6-15. 23. Ramireddy, R. R.; Prasad, P.; Finne, A.; Thayumanavan, S., Zwitterionic Amphiphilic Homopolymer Assemblies. Polym. Chem. 2015, 6 (33), 6083-6087. 24. Oh, J. K., Polylactide (PLA)-based amphiphilic block copolymers: synthesis, self-assembly, and biomedical applications. Soft Matter 2011, 7 (11), 5096-5108. 25. Anderson, J. M.; Shive, M. S., Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv. Drug Delivery Rev. 2012, 64, Supplement, 72-82. 26. Jain, R. A., The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices. Biomaterials 2000, 21 (23), 2475-2490. 27. Ford Versypt, A. N.; Pack, D. W.; Braatz, R. D., Mathematical modeling of drug delivery from autocatalytically degradable PLGA microspheres — A review. J. Controlled Release 2013, 165 (1), 29-37. 28. Hines, D. J.; Kaplan, D. L., Poly (lactic-co-glycolic) acid− controlled-release systems: experimental and modeling insights. Crit. Rev. Ther. Drug Carrier Syst. 2013, 30 (3), 257-276. 29. Nicolas, J.; Mura, S.; Brambilla, D.; Mackiewicz, N.; Couvreur, P., Design, functionalization strategies and biomedical applications of targeted biodegradable/biocompatible polymer-based nanocarriers for drug delivery. Chem. Soc. Rev. 2013, 42 (3), 1147-1235. 30. Kumari, A.; Yadav, S. K.; Yadav, S. C., Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf., B 2010, 75 (1), 1-18. 31. Ma, J.; Ma, C.; Zhang, G., Degradable Polymer with Protein Resistance in a Marine Environment. Langmuir 2015, 31 (23), 6471-6478. 32. Ye, L.; Zhang, Y.; Wang, Q.; Zhou, X.; Yang, B.; Ji, F.; Dong, D.; Gao, L.; Cui, Y.; Yao, F., Physical Cross-Linking Starch-Based Zwitterionic Hydrogel Exhibiting Excellent Biocompatibility, Protein Resistance, and Biodegradability. ACS Appl. Mater. Interfaces 2016, 8 (24), 15710-15723. 33. Keefe, A. J.; Jiang, S., Poly(zwitterionic)protein conjugates offer increased stability without sacrificing binding affinity or bioactivity. Nat. Chem. 2012, 4 (1), 59-63. 34. Li, A.; Luehmann, H. P.; Sun, G.; Samarajeewa, S.; Zou, J.; Zhang, S.; Zhang, F.; Welch, M. J.; Liu, Y.; Wooley, K. L., Synthesis and In Vivo Pharmacokinetic Evaluation of Degradable Shell Crosslinked Polymer Nanoparticles with Poly(carboxybetaine) vs. Poly(ethylene glycol) Surface-grafted Coatings. ACS Nano 2012, 6 (10), 8970-8982. 35. Cao, Z.; Yu, Q.; Xue, H.; Cheng, G.; Jiang, S., Nanoparticles for Drug Delivery Prepared from Amphiphilic PLGA Zwitterionic Block Copolymers with Sharp Contrast in Polarity between Two Blocks. Angew. Chem. 2010, 122 (22), 3859-3864. 20 ACS Paragon Plus Environment

Page 21 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

36. Cao, Z.; Jiang, S., Super-hydrophilic zwitterionic poly(carboxybetaine) and amphiphilic non-ionic poly(ethylene glycol) for stealth nanoparticles. Nano Today 2012, 7 (5), 404-413. 37. Mai, J.; Sun, D.; Li, L.; Zhou, J., Phase Behavior of an Amphiphilic Block Copolymer in Ionic Liquid: A Dissipative Particle Dynamics Study. J. Chem. Eng. Data 2016, 61 (12), 3998-4005. 38. Ye, H.; Wang, L.; Huang, R.; Su, R.; Liu, B.; Qi, W.; He, Z., Superior Antifouling Performance of a Zwitterionic Peptide Compared to an Amphiphilic, Non-Ionic Peptide. ACS Appl. Mater. Interfaces 2015, 7 (40), 22448-22457. 39. Prabhu, V. M.; Venkataraman, S.; Yang, Y. Y.; Hedrick, J. L., Equilibrium Self-Assembly, Structure, and Dynamics of Clusters of Star-Like Micelles. ACS Macro Lett. 2015, 4 (10), 1128-1133. 40. Goswami, M.; Borreguero, J. M.; Pincus, P. A.; Sumpter, B. G., Surfactant-Mediated Polyelectrolyte Self-Assembly in a Polyelectrolyte–Surfactant Complex. Macromolecules 2015, 48 (24), 9050-9059. 41. Wu, H.-L.; Chen, P.-Y.; Chi, C.-L.; Tsao, H.-K.; Sheng, Y.-J., Vesicle deposition on hydrophilic solid surfaces. Soft Matter 2013, 9 (6), 1908-1919. 42. Lin, Y.-L.; Chiou, C.-S.; Kumar, S. K.; Lin, J.-J.; Sheng, Y.-J.; Tsao, H.-K., Self-Assembled Superstructures of Polymer-Grafted Nanoparticles: Effects of Particle Shape and Matrix Polymer. J. Phys. Chem. C 2011, 115 (13), 5566-5577. 43. Chou, S.-H.; Wu, D. T.; Tsao, H.-K.; Sheng, Y.-J., Morphology and internal structure control of rod-coil copolymer aggregates by mixed selective solvents. Soft Matter 2011, 7 (19), 9119-9129. 44. Chou, S.-H.; Tsao, H.-K.; Sheng, Y.-J., Structural aggregates of rod–coil copolymer solutions. J. Chem. Phys. 2011, 134 (3), 034904. 45. Lin, C. M.; Wu, Y. F.; Tsao, H. K.; Sheng, Y. J., Studies of Drug Delivery and Drug Release of Dendrimer by Dissipative Particle Dynamics. AIP Conference Proceedings 2008, 982 (1), 525-527. 46. Lin, C.-M.; Chen, Y.-Z.; Sheng, Y.-J.; Tsao, H.-K., Effects of macromolecular architecture on the micellization behavior of complex block copolymers. React. Funct. Polym. 2009, 69 (7), 539-545. 47. Wu, S.-g.; Du, T.-t., Dissipative particle dynamics simulation of onion phase in star-block copolymer. Chem. Res. Chin. Univ. 2013, 29 (1), 171-176. 48. Guo, X.; Zhang, L.; Qian, Y.; Zhou, J., Effect of composition on the formation of poly(dl-lactide) microspheres for drug delivery systems: Mesoscale simulations. Chem. Eng. J. 2007, 131 (1–3), 195-201. 49. Chou, S.-H.; Tsao, H.-K.; Sheng, Y.-J., Morphologies of multicompartment micelles formed by triblock copolymers. J. Chem. Phys. 2006, 125 (19), 194903. 50. Sun, D.; Zhou, J., Dissipative particle dynamics simulations on mesoscopic structures of Nafion and PVA/Nafion blend membranes. Acta Phys. Chim. Sin. 2012, 28 (4), 909-916. 51. Huang, K.-C.; Lin, C.-M.; Tsao, H.-K.; Sheng, Y.-J., The interactions between surfactants and vesicles: Dissipative particle dynamics. J. Chem. Phys. 2009, 130 (24), 245101. 21 ACS Paragon Plus Environment

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 39

52. Djohari, H.; Dormidontova, E. E., Kinetics of Nanoparticle Targeting by Dissipative Particle Dynamics Simulations. Biomacromolecules 2009, 10 (11), 3089-3097. 53. Posocco, P.; Fermeglia, M.; Pricl, S., Morphology prediction of block copolymers for drug delivery by mesoscale simulations. J. Mater. Chem. 2010, 20 (36), 7742-7753. 54. Hongyan, L.; Hongyu, G.; Jian, Z., Computer simulations on the anticancer drug delivery system of docetaxel and PLGA-PEG copolymer. Acta Chim. Sin. 2012, 70 (23), 2445-2450. 55. Robert D. Groot; Timothy J. Madden, Dynamic simulation of diblock copolymer microphase separation. J. Chem. Phys. 1998, 108 (20), 8713-8724. 56. Groot, R. D.; Warren, P. B., Dissipative particle dynamics: Bridging the gap between atomistic and mesoscopic simulation. J. Chem. Phys. 1997, 107 (11), 4423-4435. 57. Riley, T.; Stolnik, S.; Heald, C. R.; Xiong, C. D.; Garnett, M. C.; Illum, L.; Davis, S. S.; Purkiss, S. C.; Barlow, R. J.; Gellert, P. R., Physicochemical Evaluation of Nanoparticles Assembled from Poly(lactic acid)−Poly(ethylene glycol) (PLA−PEG) Block Copolymers as Drug Delivery Vehicles. Langmuir 2001, 17 (11), 3168-3174. 58. Govender, T.; Riley, T.; Ehtezazi, T.; Garnett, M. C.; Stolnik, S.; Illum, L.; Davis, S. S., Defining the drug incorporation properties of PLA–PEG nanoparticles. Int. J. Pharm. 2000, 199 (1), 95-110. 59. Riley, T.; Govender, T.; Stolnik, S.; Xiong, C. D.; Garnett, M. C.; Illum, L.; Davis, S. S., Colloidal stability and drug incorporation aspects of micellar-like PLA–PEG nanoparticles. Colloids Surf., B 1999, 16 (1), 147-159. 60. Cheng, G.; Liao, M.; Zhao, D.; Zhou, J., Molecular Understanding on the Underwater Oleophobicity of Self-Assembled Monolayers: Zwitterionic versus Nonionic. Langmuir 2017, 33 (7), 1732-1741.


Page 23 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

TABLES.

Table 1. Repulsion parameters between beads in PLA-PEG system

L

E

W

L

78.00

E

82.96

W

161.26 114.01

78.00 78.00

Table 2. Repulsion parameters between beads in PLA-PCB system L L

78.00

Cb

78.26

Cp

Cb

W

78.00

Cp 123.63 135.00

78.00

W

89.21

161.26 179.56

78.00

Table 3. Self-assembled sizes of PLA80-PEG20 and PLA80-PCB20 systems at different concentrations (unit：rc*) Radia of the nanoparticle Radia of inner core Thickness of shell Conc. PEG

PCB

PEG

PCB

PEG

PCB

0.05

9.26

9.47

8.70

8.32

0.56

1.15

0.1

11.59

11.76

10.84

10.29

0.75

1.47

0.15

13.20

13.40

12.34

11.65

0.86

1.75

rc*: the basic length unit in DPD simulation.


Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 39

FIGURES.

Figure 1. Coarse-grained models of the simulated PLA-PEG and PLA-PCB drug delivery systems. a represents PLA-PEG; b represents PLA-PCB; c represents water W.


Page 25 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

Figure 2. Sectional views of self-assembled morphology with different compositions. a to i represents PLA10-PEG90, PLA20-PEG80, PLA30-PEG70, PLA40-PEG60, PLA50-PEG50,

PLA60-PEG40,

PLA70-PEG30,

respectively.

represents bead E,

PLA80-PEG20,

PLA90-PEG10,

represents bead L. Every square above with

sides of 40 rc is same. 25 ACS Paragon Plus Environment

Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 39

Figure 3. Sectional views of PLA-PCB systems with different compositions. a to i represents PLA10-PCB90, PLA20-PCB80, PLA30-PCB70, PLA40-PCB60, PLA50-PCB50, PLA60-PCB40,

PLA70-PCB30,

represents bead L,

PLA80-PCB20, PLA90-PCB10, respectively.

represents bead Cb, and

represents bead Cp. Every

square above with sides of 40 rc is same.


Page 27 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

Figure 4. Overall views of self-assembled morphology of PLA-PEG copolymer at different concentrations: a=0.05, b=0.1, c=0.15, d=0.2, e=0.3，f=0.4, g=0.5. Every square above with sides of 40 rc is same.


Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 28 of 39

Figure 5. Overall views of self-assembled morphology of PLA-PCB copolymer at different concentrations: a=0.05, b=0.1, c=0.15, d=0.2, e=0.3, f=0.4, g=0.5. Every square above with sides of 40 rc is same.


Page 29 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

Figure 6. Comparison of self-assembled morphology of PLA80-PCB20 and PLA80-PEG20: a represents sectional view of PLA-PCB self-assembled morphology; b is the slice for PLA-PCB; c represents sectional view of PLA-PEG self-assembled morphology and d is the slice for PLA-PEG. Every simulating box of actual system above with sides of 40 rc is same.


Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 30 of 39

Figure 7. Density profiles of (a) PLA80-PEG20 system and (b) PLA80-PCB20 system at concentration of 0.1. L bead represents the PLA in red curve; E bead represent the amphiphilic PEG in green curve while the purple curve represents the hydrophilic Cp bead in PCB.


Page 31 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

Table of contents only


Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 1. Coarse-grained models of the simulated PLA-PEG and PLA-PCB drug delivery systems. a represents PLA-PEG; b represents PLA-PCB; c represents water W. 86x151mm (300 x 300 DPI)

ACS Paragon Plus Environment

Page 32 of 39

Page 33 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

Figure 2. Sectional views of self-assembled morphology with different compositions. a to i represents PLA10PEG90, PLA20-PEG80, PLA30-PEG70, PLA40-PEG60, PLA50-PEG50, PLA60-PEG40, PLA70-PEG30, PLA80PEG20, PLA90-PEG10, respectively. represents bead E, represents bead L. Every square above with sides of 40 rc is same. 129x321mm (96 x 96 DPI)


Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 3. Sectional views of PLA-PCB systems with different compositions. a to i represents PLA10-PCB90, PLA20-PCB80, PLA30-PCB70, PLA40-PCB60, PLA50-PCB50, PLA60-PCB40, PLA70-PCB30, PLA80-PCB20, PLA90-PCB10, respectively. represents bead L, represents bead Cb, and represents bead Cp. Every square above with sides of 40 rc is same. 108x272mm (95 x 95 DPI)


Page 34 of 39

Page 35 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

Figure 4. Overall views of self-assembled morphology of PLA-PEG copolymer at different concentrations: a=0.05, b=0.1, c=0.15, d=0.2, e=0.3，f=0.4, g=0.5. Every square above with sides of 40 rc is same. 449x888mm (95 x 95 DPI)


Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 5. Overall views of self-assembled morphology of PLA-PCB copolymer at different concentrations: a=0.05, b=0.1, c=0.15, d=0.2, e=0.3, f=0.4, g=0.5. Every square above with sides of 40 rc is same. 76x151mm (95 x 95 DPI)


Page 36 of 39

Page 37 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

Figure 6. Comparison of self-assembled morphology of PLA80-PCB20 and PLA80-PEG20: a represents sectional view of PLA-PCB self-assembled morphology; b is the slice for PLA-PCB; c represents sectional view of PLA-PEG self-assembled morphology and d is the slice for PLA-PEG. Every simulating box of actual system above with sides of 40 rc is same. 1013x925mm (71 x 71 DPI)


Langmuir

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 7. Density profiles of (a) PLA80-PEG20 system and (b) PLA80-PCB20 system at concentration of 0.1. L bead represents the PLA in red curve; E bead represent the amphiphilic PEG in green curve while the purple curve represents the hydrophilic Cp bead in PCB. 39x15mm (300 x 300 DPI)


Page 38 of 39

Page 39 of 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

TOC graphic 48x29mm (600 x 600 DPI)


Mesoscopic Structures of Poly(carboxybetaine ... - ACS Publications

Recommend Documents