pH-responsive Zwitterionic Copolymer DHA-PBLG-PCB for Targeted

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pH-responsive Zwitterionic Copolymer DHA-PBLG-PCB for Targeted Drug Delivery: A Computer Simulation Study Lingxia Hao, Lin Lin, and Jian Zhou Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.8b00626 • Publication Date (Web): 25 Apr 2018 Downloaded from http://pubs.acs.org on April 25, 2018

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pH-responsive Zwitterionic Copolymer DHA-PBLG-PCB for Targeted Drug Delivery: A Computer Simulation Study

Lingxia Hao, Lin Lin and 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. 1

ACS Paragon Plus Environment

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ABSTRACT

In this work, the self-assembled behaviors of zwitterionic copolymer docosahexaenoic acid-b-poly(γ-benzyl-L-glutamate)-b-poly(carboxybetaine

methacrylate)

(DHA-

PBLG-PCB) and the loading and release mechanism of the anti-cancer drug doxorubicin (DOX) was investigated via computer simulations. The effects of polymer concentration, drug content and pH on polymeric micelles were explored by dissipative particle dynamics (DPD) simulations. Simulation results show that DHA-PBLG15PCB10 can self-assemble into core-shell micelles; in addition, the drug-loaded micelles have a pH-responsive feature. DOX can be encapsulated into the core-shell micelle at the normal physiological pH condition; whereas it can be released at the acidic pH condition. The self-assembled behaviors of copolymer DHA-PBLG-PEG were also studied to have a comparison with those of DHA-PBLG-PCB. The DHA-PBLG15PCB10 system has a stable structure and it has a great potential to serve as drug delivery vehicles for targeted drug delivery.

KEYWORDS drug delivery; pH-responsive micelles; zwitterionic polymer; dissipative particle dynamics; molecular simulation

2


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1. INTRODUCTION Cancer is a disease caused by uncontrolled cell proliferation, which is a leading cause of death worldwide. 1 Over the past a few decades, the incidence of cancer has been increasing year by year; however, the current state of cancer therapy is still far from satisfactory. 2 Up till now, the commonly-used treatments for cancer include surgery, radiotherapy, chemotherapy3 and gene therapy4. Among them, chemotherapy drugs have poor water solubility, chemical instability, low permeability, serious toxicity and side effects 5, 6, the design of novel drug delivery system (DDS) is emergent. To improve the therapeutic efficiency and realize the targeted release of anti-cancer drugs, stimulusresponsive polymeric micelles7, including thermo-responsive8, 9, pH-responsive10, 11, light-responsive12, 13 and redox-responsive14, 15, have been widely used for DDS. Among these stimuli, pH-responsiveness is a commonly-used strategy to control self-assembly and disassemble for various applications, especially for targeted drug release. It is generally known that the pH in most cancer tissues and cells can reach as low as 4.5 (e.g., endosomes)16,17; however, the physiological pH3 of blood and normal tissues is about 7.4. Owing to the different pH values in various microenvironments of issues, pH-responsive micelles are attractive to realize the targeted drug delivery. Upon arriving at the periphery of cancer cells, the drug-loaded micelles rapidly disintegrate and release anti-cancer drugs. In the past several decades, polyethylene glycol (PEG) is a widely-used hydrophilic polymer and PEGylation has become the most commonly used method in DDS.18, 19 However, PEGylated nanoparticles are susceptible to be oxidized in biological media 3


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and lose their original properties, leading to significant decrease in cellular uptake20. In addition, the application and development of PEGylated nanoparticles are severely limited due to the lack of available reactive functional groups to be modified for targeted drug delivery.21 Among various types of DDSs, zwitterionic copolymer has attracted increasingly attentions, which serve as the alternative of PEG for the hydrophilic block.22,

23

methacryloyloxygethyl methacrylate) (PSB),

The popular zwitterionic polymers include poly(2phosphorylcholine)

26, 27

(PMPC),

24,

25

poly(sulfobetaine

poly(carboxybetaine methacrylate)(PCB)28, 29 and mixed-

charged materials. 30, 31 Compared with traditional systems, they have lots of prominent features including super-hydrophilicity, good biomimetic nature, excellent non-specific protein adsorption and prolonged circulation in the blood. PCB is an amphoteric polyelectrolyte containing both positive and negative charges, which has been used for controlled release and pH-responsive DDSs. 32, 33 At the same time, PCB is neutral in physiological environments and carries positive charges in acidic environments. 23 This unique pH-responsive property gives more advantages than PEGylated nanoparticles34 as the drug delivery carrier. Recently, some pH-responsive polymers containing zwitterionic polymer segments and polypeptide segments have been reported and tested in experiments. 35, 36 However, the drug release mechanism, molecular details of the mechanisms and pathways are not understood thoroughly. Owing to the rapid development of computation technology, coarse-grained molecular dynamics (CGMD) and dissipative particle dynamics (DPD) could be applied to explore the mechanism of complex systems.37, 38 4


39

Those studies

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undoubtedly deepen our understanding of the details and provide a design guideline for novel DDSs. In previous computer simulation works, Luo et al. investigated the selfassemble process of grafted copolymer PAE-g-PEG and the loading/release mechanism of DOX in PAE-g-PEG polymersomes.40 Guo et al. explored the structure-property relationship of the pH-responsive nanoparticle PLGA/HP55 at different conditions.41 Su et al. investigated the loading and release behaviors of DOX by drug delivery carrier poly(amidoamine) (PAMAM) dendrimers.42 Polypeptide ingredients show great promise regarding the treatment of various health-endangering diseases.43 Poly(γ-benzyl-L-glutamate) (PBLG) is one example of efficient carrier materials due to its biocompatibility and biodegradability. 44 Moreover, PBLG can be utilized to form micelles and to pack hydrophobic drugs. 45 Polypeptidederived block copolymer appears as an attractive carrier for DOX and can assemble into higher ordered structures, such as micelles, vesicles, tubules and so on. They hold a great significance not only in fundamental research, but also in different potential biomaterial applications.46 Docosahexaenoic acid (DHA) is an indispensable highly unsaturated fatty acid for human body, which plays an important role in maintaining normal physiological activity of nerve cells.47 In this work, we constructed a novel tri-block copolymer DHAPBLG-PCB for DDS that was stable under the physiological conditions and responsive to cancer-relevant pH, to improve the therapeutic efficiency of DOX. On one hand, we took full advantage of coarse-grained model and DPD simulation to investigate the formation of drug-loaded micelles and the release mechanism of DOX at different pH5


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conditions. On the other hand, we also explored the self-assembled behavior of copolymer DHA-PBLG-PEG in order to compare the differences between PEG and amphoteric polymeric systems. Results show that the DPD method can provide some valuable information about the structure-property relationship of amphoteric polymeric systems, which can further promote the development of practical DDS. In the following sections, firstly, the simulation method and relevant details are briefly described; secondly, we analyze the obtained results under different conditions; finally, the conclusions based on the analysis are drawn. 2. METHOD AND SIMULATON DETAILS 2.1 DPD Method DPD is a particle-based mesoscale simulation technique, which was first introduced by Hoogerbrugge and Koelman48 in 1992 and later improved by Groot et al.49-51. This method is particularly useful for phenomena and systems occurred on the mesoscopic time and length scale, such as polymers, lipids and biopolymers systems. In DPD, coarse-grained model is used. Polymers can be regarded as soft beads connected by springs. The momenta and position vectors of these beads are governed by the Newton’s equations of motion. 52, 53 dv dri  vi , mi i  fi dt dt

(1)

where ri, vi, mi and fi denote the position, velocity, mass and total force acting on bead i, respectively. For simplicity, the reduced unit is used in DPD method.54 The total force fi acting on each pair of beads is defined as the sum of five contributions: the dissipative force FijD , the conservative force FijC , the random force FijR , the spring force FijS and 6


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the electrostatic force FijE . Hence, the total force fi runs over all other particles is given by55, 56

fi 

 F

C ij

i j

 FijD  FijR  FijS  FijE



(2)

The conservative force FijC signifies the excluded volume effect; the dissipative force FijD describes vicious drag while the random force FijR depicts the stochastic impulse, which are determined by the positions and velocities of beads. They are given as follows:

aij(1  rij )rîj (rij  1) FijC   0 (rij  1) 

(3)

F ijD    D rij ( rîj  v ij )rîj

(4)

FijR   R rij  ij rîj

(5)

where aij is the repulsive parameter between the bead i and bead j, /

,

,

, γ is the dissipation strength governing the magnitude of the

dissipative force FijD ; σ is the noise parameter (

2

)

and

is the

Gaussian fluctuating variable and its mean value is 0. Drij  and R rij  are dimensionless weighting functions of FijD and FijR , which satisfy, 2 1  r   r  1   r     r      r  1  0 D

R

2

(6)

where kB is the Boltzmann’s constant and T is the thermodynamics temperature. In DPD simulations, kBT is chosen as the reduced unit of energy, γ is set to 4.5 and σ is set to 3. The spring force between the bonded consecutive beads of a chain is expressed as

FijS 

Cr

(7)

s ij

where Cs is the spring constant between beads i and j, which is set to 4. 7


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Since the DPD repulsive force is a kind of soft potential, DPD beads might have an overlapping probability in space during the simulation process. If the electrostatic effect is treated completely by point charge, then when two charged beads overlap, the electrostatic potential energy would be infinite, thus causing the system to collapse. Hence, the charge must be spread out over a finite volume by using a smearing charge distribution to avoid this issue. We adopted the Slater-type distribution, f (r ) 

q



3

exp(

FijE 

2r



) , electrostatic force between beads i and j is represented as,

Γq i q j 4r 2 ij

1  exp( 2  r )1  2  r 1  ij

ij

 rij rîj

where Γ  e2 /(kBT 0 r Rc ), e is the elementary charge,

r

57

0

(8)

is the vacuum permittivity,

is the relative permittivity of medium, q is the charge number,   5rc / 8 ,  is the

decay length of charge42. 2.2 Coarse-Grained Models In this work, the structure-performance relationship of DHA-PBLG-PCB for drug delivery was studied. DHA-PBLG-PEG system was also investigated for comparison. DOX is the drug. In the tri-block copolymer (DHA-PBLG-PCB and DHA-PBLG-PEG), docosahexaenoic acid (DHA) is the hydrophobic block, poly(γ-benzyl-L-glutamate) (PBLG) is the poly-peptide block, poly(carboxybetaine methacrylate) (PCB) and polyethylene glycol (PEG) act as hydrophilic blocks. Both DHA and PBLG have good biocompatibility with human body. The coarse-grained schemes for DHA-PBLG-PCB, DHA-PBLG-PEG and DOX are illustrated in Fig. 1. According to the attribute of each monomer, the hydrophobic block DHA is composed of two kinds of beads, DH1 and DH2; the polypeptide block PBLG 8


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is divided into two beads, P and A. There are a positively charged quaternary ammonium group (NH4+) and a negatively charged carboxylate group (COO-) in the PCB monomer. The carboxylate group carries a negative charge in the physiological condition; whereas it becomes neutral (-COOH) after the protonation under the acidic condition. Hence, PCB can be separated into three types of beads, the backbone (B) and the side chain (N under the physiological pH or C under the acidic pH). The repetitive unit of PEG is reduced into E bead. As for the anti-cancer drug doxorubicin (DOX), according to the principle of trying not to separate the bridge rings as possible, DOX is coarse-grained into three parts: D1, D2 and D3. In addition, water molecule is expressed as W and the counter ions (CI) are added into the simulation system to keep the whole system electrically neutral.

Fig. 1. The coarse-grained models. (a) DHA-PBLGn-PCBm; (b) DHA-PBLGn-PEGm 9


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and (c) DOX.

2.3 Simulation Parameters and details In DPD simulations, when the coarse-grained model of each molecule has been established, the bead-bead interaction parameter aij can be calculated and its value depends on the underlying atomistic interactions. Groot and Warren49 constructed a link between aij and Flory-Huggins parameter

ij in order to calculate the conservation

force by mapping the DPD model onto Flory-Huggins theory. aij can be calculated according to the following relation,

aij  aii  3.27ij

(9)

where DPD is the number density of beads in the system and is set to 3.

aii denotes

repulsive parameter between the same beads and its value is set to 25. For two different components i and j, Flory-Huggins parameter ij is either obtained from molecular simulation or experimental measurements depending on the availability. In computer simulation, Flory-Huggins parameter ij can be gotten through calculating the mixing energy between two molecular segments55, 1    Eij  2  Eii  E jj    ij  z   RT    

(10)

where z is the coordination number; E ij is the mixing energy of a pair of interacting beads i and j; T is the absolute temperature; R is the ideal gas constant. The FloryHuggins parameters for Equation (10) can be calculated by BLENDS module with the COMPASS II force field in Materials Studio 7.0.58 To obtain a reasonable value with sufficient statistics, the averaged mixing energy of each pair was calculated with 10


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200,000 samples by Monte Carlo method. The DPD interaction parameter aij for all bead pairs at 298 K are shown in Table 1. Among them, the DPD repulsive parameters of the counter ion (CI) with other beads are the same with those of W beads except that the CI bead carry one negative unit charge.41, 59, 60 Since the DPD repulsive interaction is short-ranged while the electrostatic interaction is long-ranged and more important, so it is fine to set the DPD repulsive parameters of the counter ion (CI) with other beads the same as those of W bead with other beads. Table 1. DPD Repulsion parameters between beads in the DHA-PBLG-PCB system and the DHA-PBLG-PEG system aij

DH1

DH2

P

A

B

E

N

C

D1

D2

D3

W

CI

DH1 DH2 P A B E N C D1 D2 D3 W CI

25 27.3 31.7 44.8 69.9 61.5 63.7 32.2 28.1 25.9 26.1 64.7 64.7

25 29.9 37.8 73.6 68.2 70.4 39.5 25.3 23.7 24.2 60.9 60.9

25 22.2 36.7 51.9 33.1 28.7 24.8 21.7 23.8 58.9 58.9

25 68.2 64.5 45.1 34.6 30.6 28.8 29.5 55.4 55.4

25 36.7 68.1 102.6 81.3 70.4 53.7 53.7

25 89.2 65.5 59.8 44.5 44.5

25 115.7 94.4 87.8 24.3 24.3

25 68.0 123.4 109.3 55.7 55.7

25 21.7 23.9 158.1 158.1

25 23.4 35.5 35.5

25 39.8 39.8

25 25

25

There is a relationship between the

, pH and the degree of protonation (α). It

follows the Hasselbach-Henderson equation 61： pK a  pH  log



(11)

1

In this work, the simulation box has the 40×40×40

dimension. There are 192,000

beads at DPD =3. The NVT ensemble was adopted. The particle mass m, the cutoff radius

and

are taken as the basic DPD unites, 62 11


1. The

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integration time step of t = 0.05  is employed, where is the reduced DPD time unit,

/

/

1. For electrically charged beads, long-range electrostatic

interactions are calculated by the Ewald sum method and the Slater-type charge density distribution is adopted to avoid the overlap of charged beads. Since the equilibrium state were jointly determined by temperature, pressure and self-assembly morphologies of polymers, a total of 300,000 simulation steps were performed to ensure equilibrium. The equilibrium of the system was judged by observing the fluctuation of total energy over time. All simulations in this work were conducted by DL_MESO 2.6 package63 and the temperature was set constant at 298K. In addition, all visualizations of simulation results were implemented with the VMD software.

3. RESULTS AND DISCUSSION 3.1 Effect of different compositions on self-assembled morphologies of DHAPBLG-PCB The copolymer can self-assemble and form nanoparticles in aqueous solution. Due to the repulsive effect with water, hydrophobic blocks aggregate to form inner core and hydrophilic blocks form outer shell with an ordered arrangement around the core. The micelle with core-shell structure provides as a perfect carrier for DOX. To find the suitable composition of the copolymer, we systematically study the effect of composition on self-assembly morphologies of DHA-PBLGn-PCBm in aqueous solution. In this section, the system comprises of 10% DHA-PBLGn-PCBm and 90% water. The polymerization degrees of PBLG and PCB blocks vary from 10 to 20. The simulation results are presented in Fig.2. By observing the self-assembled 12


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morphologies of DHA-PBLGn-PCBm at different compositions, we can better understand the formation characteristics of the micelle.

Fig. 2. The self-assembled morphologies of DHA-PBLGn-PCBm at different compositions: (A) overall views; (B) sectional views. Water beads are not shown for clarity. It can be seen from Fig. 2A that, when the composition ratio (n/m) of PBLG and PCB segments varies in a certain range, the morphology of DHA-PBLGn-PCBm in aqueous solution is ever-changing, such as spherical, gourd-like, cross-linked micelles and irregular aggregates. With the ratio gradually decreases, the micelles with non-spherical shapes are formed due to the strong adhesions in different directions. When the composition ratios of DHA-PBLGn-PCBm copolymers are 2:1 (a) and 3:2 (b), the spherical micelles come in sight. Although both DHA-PBLG15-PCB10 and DHAPBLG20-PCB10 can form spherical micelles, there are still some differences between them. Compared with DHA-PBLG20-PCB10, the DHA-PBLG15-PCB10 forms a stable spherical micelle with a well-organized core-shell structure. From the sectional view of DHA-PBLG15-PBC10 (expressed as D-15-10) in Fig. 2B, the hydrophilic PCB block 13


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(cyan) is located in the outermost layer of the micelle and forms the protective hydrophilic shell. Hydrophobic DHA forms the inner core and polypeptide block PBLG is the middle layer of the micelle, which can be jointly used to encapsulate hydrophobic anti-cancer drug DOX. Therefore, DHA-PBLG15-PCB10 is selected as the suitable composition and we would focus on copolymer DHA-PBLG15-PCB10 in the subsequent discussion.11, 33 3.2 Effect of copolymer concentration on self-assembly morphology of DHAPBLG-PCB To find the suitable concentration of copolymer, the morphologies of drug-loaded system containing copolymer DHA-PBLG15-PCB10 and DOX are investigated in detail. Fig. 3 shows the self-assembly morphologies and their corresponding sectional views of copolymer at different concentrations: 5%, 10%, 15%, 20% and 25%, respectively. The copolymer concentration in aqueous solution is defined as the ratio of bead amount between copolymer beads and all beads in the simulation box.

Fig. 3. The DOX-loaded copolymer morphologies of DHA-PBLG15-PCB10 at different polymer concentrations: (A) overall views; (B) sectional views. Water beads are not 14


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shown for clarity. For the DHA-PBLG15-PCB10 system, with the increase of the copolymer concentration, the self-assembly morphologies gradually change from spherical to cylindrical micelles. When the polymer concentration is lower than 15%, the system can self-assemble into the spherical micelle with a core-shell structure, in which PCB is the shell, DHA, PBLG and DOX act as the core. However, at the low concentration of 5%, the studied system forms the spherical micelle with an uneven surface due to the incomplete surrounding of PCB blocks, a few drug molecules are exposed to the solution. Although both 10% and 15% can form spherical micelles, the former has a smooth surface and a well-ordered structure. When the concentration is up to 20% and 25%, cylindrical structures are formed. It can be seen from the sectional view (Fig. 3B) that the distributions of each component in micelles at different concentrations are similar, PCB is located in the outmost layer, DHA and DOX are distributed in the inner, and PBLG constitutes the middle layer. Their distributions are mainly dependent on their hydrophobicity. Among them, PCB are superhydrophilic whereas DHA and DOX are hydrophobic. 31,

55

Based on the above analysis, the suitable concentration of

copolymer is around 10% to obtain the spherical micelle with a core-shell structure. 3.3 Effect of DOX content on self-assembly morphologies of DHA-PBLG-PCB and DHA-PBLG-PEG To further explore the DOX-loaded system, the self-assembled morphologies of DHA-PBLG-PCB system containing different drug contents are investigated. Meanwhile, the morphologies of DHA-PBLG-PEG system were also explored for 15


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comparison. In this section, we choose the same composition and concentration so as to make a direct comparison between the DHA-PBLG-PCB system and the DHAPBLG-PEG system. To spot the reasonable drug content, the concentrations of copolymer in two systems are kept at 10%. Then by adding different amounts of drug molecules, the effect of drug content on self-assembled structures is investigated. Selfassembled morphologies of DOX-loaded copolymer under different drug contents (0.01, 0.03, 0.05, 0.07 and 0.09, respectively) are shown in Fig. 4. The definition of drug content is the ratio of bead amount between drug beads and all beads in the simulation box.

Fig. 4. The self-assembled morphologies of DOX-loaded copolymer DHA-PBLG15PCB10 and DHA-PBLG15-PEG10 at different drug contents: (a) 0.01; (b) 0.03; (c) 0.05; (d) 0.07 and (e) 0.09, respectively. Water beads are not shown for clarity. It can be seen from Fig. 4 that the self-assembly morphologies of DHA-PBLG15PCB10 and DHA-PBLG15-PEG10 vary with the drug content. Compared with the DHAPBLG15-PEG10 system, the self-assembly morphology transformation is less obvious in 16


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the DHA-PBLG15-PCB10 system. For the DHA-PBLG15-PCB10 system, when the content of DOX is lower than 0.07, the copolymer DHA-PBLG15-PCB10 can selfassemble into a spherical micelle. Specially, when the drug content is 0.03, a spherical micelle with a core-shell structure is formed, where PCB is the shell, DHA/PBLG and DOX are the core due to the repulsion with water. When the drug content varies from 0.05 to 0.07, it still forms a spherical micelle, but a small fraction of drug molecules is exposed to the surfaces of micelles, which is not suitable for the safe and effective drug delivery. When the content is up to 0.09, the self-assembled structure turned into cylindrical-like. However, for the DHA-PBLG15-PEG10 system, the transformation of the morphology changes faster and more obviously. With the drug content increases, the DHA-PBLG15-PEG10 system undergoes structural transformation from spherical to cylindrical and finally to perforated-layered micelles. When the concentration is less than 0.05, the final morphologies are regular spherical micelles. In spite of a spherical micelle with a core-shell structure is formed at the drug content of 0.05, the high content of drug may cause the exposure of drug molecules. Therefore, we think 0.03 as the suitable drug content for both DHA-PBLG15-PCB10 system and DHA-PBLG15-PEG10 system. The difference between the DHA-PBLG-PCB system and the DHA-PBLGPEG system is attributed to different hydration properties. PEG monomer possesses hydroxyl and usually achieves hydration via hydrogen bonding; however, zwitterionic PCB monomer has highly charged groups, which can bind water molecules stronger by electrostatically induced hydration.64 Moreover, at the same copolymer concentration and drug content, the adhesion phenomenon occurs earlier in the PEGylated system 17


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than in the zwitterionic system, suggesting that the zwitterionic system is more stable than the PEGylated system.33, 39 According to the above discussion, the self-assembled morphology is a well-defined spherical structure when the copolymer concentration and drug content are 10% and 0.03, respectively. Subsequently, we make a comparison between DHA-PBLG15-PCB10 system and DHA-PBLG15-PEG10 system in detail. The sectional views and density profiles of different beads for DHA-PBLG15-PCB10 system and DHA-PBLG15-PEG10 system are shown in Fig. 5. It can be seen from Fig. 5 (a) and (b) that, DHA segments aggregate to form the core; PBLG segments act as the middle layer and PCB/PEG segments form the hydrophilic shell. Interestingly, the distribution of DOX is totally different for two systems. In the DHA-PBLG15-PCB10 system, DOX is mainly distributed in the inner core; whereas in the DHA-PBLG15-PEG10 system, DOX is located in the middle layer. This is because that the hydrophilicity difference between PCB and PEG segments. Among them, PCB segments are superhydrophilic and PEG segments are amphiphilic due to different structural features (aN-W = 24.3, aE-W=44.5). The density profiles of different beads are shown in Fig. 5(c) and (d), it is straightforward to find that the distributions of DOX and PCB are hardly overlapped; whereas DOX and PEG have an overlapping region, suggesting that DOX is closer to the shell formed by PEG blocks in the DHA-PBLG-PEG system. The reason is that the system containing zwitterionic PCB possesses ionic groups and can form a strong hydration layer on the surface by the solvation effect, which can effectively encapsulate drug molecules; whereas PEG usually achieve hydration by hydrogen bonding and its 18


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amphiphilicity. In addition, the immiscibility of DHA-PBLG-PCB is larger than that of DHA-PBLG-PEG owing to the superhydrophilicity of PCB monomer and the amphiphilicity of PEG monomer, thus the regular and clear core-shell structure forms in the DHA-PBLG-PCB system; while the structure of the DHA-PBLG-PEG system has a fuzzy interface. Besides, according to comparative analysis on the density profile of the N bead and E bead, we can also clearly observe that the peak of E bead is relatively lower and wider than that of N bead. The distance between the N bead and the micellar center is ~14 while that of the E bead and the micellar center is ~15. This phenomenon further verifies that the PCB shell is compact and the PEG shell is fluffy. 33

In conclusion, the DHA-PBLG15-PCB10 would be more appropriate for the DDS in

comparison with DHA-PBLG15-PEG10.

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Fig. 5. Comparison of self-assembly morphologies of DOX-loaded copolymer DHAPBLG15-PCB10 and DHA-PBLG15-PEG10: (a, b) sectional views and (c, d) density profiles of different beads.

3.4 The drug release behavior of DHA-PBLG-PCB system Compared with the PEGylated DDS, pH-responsive polymeric micelles have more advantages on safe and effective cancer treatment. The key of drug delivery is to realize the targeted release of DOX. Owing to the protonation/deprotonation in PCB monomer, the morphology of the studied system changes a lot in different pH environments, namely the system has a pH responsiveness. Hence, we investigate the drug release behavior under the acidic condition and simulation results are shown in Fig. 6. 20


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Fig. 6. pH-responsive drug release behavior of DHA-PBLG15-PCB10 in the acidic condition. Water beads are not shown for clarity. In this section, the copolymer concentration is maintained at 10% and the drug content is 0.03, respectively. The initial state for drug release is the drug-loading equilibrium state under the physiological pH condition (Fig. 6a). When the drug-loaded micelle approaches to cancer cells (Fig. 6b), the morphology of spherical micelle begins to deform and PCB segments are no longer tightly wrapped in the outside of hydrophobic core and some even has a trend of keeping away from the surface of the micelle due to electrostatic repulsive interactions. When the release simulation is going on (Fig. 6c, 6d), the micelle continues to extend outward over time, the same kind of charged beads repel each other and lead to the evident stretch of PCB and PBLG segments. We observed that the spherical micelle has an obvious deformation. After prolonged simulation (Fig. 6e), the self-assembly morphology basically remains unchanged, indicating that the drug release process reaches to the equilibrium and can realize the sustained release of drug through the further degradation of the carrier. It can be seen from Fig. 6a that the initial morphology is spherical micelle with a core-shell structure under the physiological pH condition. When the carrier is approaching to the tumor issue (acidic pH condition), the PCB monomer will be 21


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protonated and the electrostatic repulsion will dominate, thus leading to the deformation of the micelle. The PCB segments stretch into the surroundings and change from the initial condensed state to the extended state after the protonation, the sectional view of the final micelle is shown in Fig. 6e. Besides, we also observe that most drug molecules are dispersed in the outside of micelles, indicating that drug molecules are released successfully. To compare the DOX distribution before and after the drug release, density profiles of drug molecules are analyzed and shown in Fig. 7. It can be seen from Fig. 7 that the number density of drug molecules (blue line) in the micellar nucleus is high at the physiological pH, but the number density of drug molecules (red line) in the micellar nucleus significantly decreases at the acidic pH. Under the acidic environment, the distribution peak of drug molecules is shorter and wider. Drug molecules distributed in the region far from the center of the micelle (in the range of 8 to 12 DPD units) increase obviously, which further verifies the successful release of DOX. It should be noticed that DOX is not immediately fully released, the remainder in the inner of the micelle can be further released by micellar degradation due to the good biodegradability of DHA and PBLG, thus can realize the sustained release of DOX in the body. This study can be used to verify the pH responsiveness and sustained-release effect of the zwitterionic micelles.65

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Fig. 7. Density profiles of DOX at the physiological pH and the acidic pH in the DHAPBLG15-PCB10 system

4. CONCLUSIONS The objective of the study is to develop a novel pH-responsive polymeric system which can effectively release DOX. To achieve this goal, a tri-block copolymer DHAPBLG-PCB for targeted drug delivery is investigated. Drug release efficiency can be regulated by adjusting the composition, concentration of copolymer and drug content. According to the simulation results, the suitable system comprises of 10% DHAPBLG15-PCB10, 3% DOX and 87% water, which forms a spherical micelle with a welldefined core-shell structure. In addition, we also make a comparison between DHAPBLG15-PCB10 and DHA-PBLG15-PEG10 systems, both two copolymers can selfassemble into spherical micelles; whereas the distribution of DOX is different for two systems. In the DHA-PBLG15-PCB10 system, DOX is mainly distributed in the inner core; whereas in the DHA-PBLG15-PEG10 system, DOX is located in the middle layer. The shell of the zwitterionic DHA-PBLG15-PCB10 is more compact than that of 23


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PEGylated DHA-PBLG15-PEG10. In addition, the pH-responsive characteristics and good biodegradability of copolymer DHA-PBLG15-PCB10 facilitate the sustained release of DOX, thus leading to reduced toxicity to normal tissues. Under the physiological pH condition, the copolymer can self-assemble into a spherical micelle with a stable structure; whereas the micelle disassembles in the acidic pH condition and can be further released by micellar degradation, most drug molecules spread in the solution. Overall, the DHA-PBLG15-PCB10 system would be more appropriate for DDS than the DHA-PBLG15-PEG10 system. Moreover, with the help of DPD simulation and theoretical analysis, researchers can be better guided for the design, preparation and optimization of drug carriers.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Fax: +86 20 87114069. Phone: +86 20 87114069

ORCID Lingxia Hao: 0000-0002-3083-5338 Lin Lin: 0000-0002-7481-5355 Jian Zhou: 0000-0002-3033-7785

Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENTS 24


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Support from National Natural Science Foundation of China (Nos. 21776093, 91334202, 21376089), 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.

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Fig. 1. The coarse-grained models. (a) DHA-PBLGn-PCBm; (b) DHA-PBLGn-PEGm and (c) DOX. 300x228mm (300 x 300 DPI)


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Fig. 2. The self-assembled morphologies of DHA-PBLGn-PCBm at different compositions: (A) overall views; (B) sectional views. Water beads are not shown for clarity. 319x140mm (72 x 72 DPI)


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Fig. 3. The DOX-loaded copolymer morphologies of DHA-PBLG15-PCB10 at different polymer concentrations: (A) overall views; (B) sectional views. Water beads are not shown for clarity. 319x140mm (72 x 72 DPI)


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Fig. 4. The self-assembled morphologies of DOX-loaded copolymer DHA-PBLG15-PCB10 and DHA-PBLG15PEG10 at different drug contents: (a) 0.01; (b) 0.03; (c) 0.05; (d) 0.07 and (e) 0.09, respectively. Water beads are not shown for clarity. 329x139mm (96 x 96 DPI)


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Fig. 5. Comparison of self-assembly morphologies of DOX-loaded copolymer DHA-PBLG15-PCB10 and DHAPBLG15-PEG10: (a, b) sectional views and (c, d) density profiles of different beads. 200x179mm (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

Fig. 6. pH-responsive drug release behavior of DHA-PBLG15-PCB10 in the acidic condition. Water beads are not shown for clarity. 250x60mm (96 x 96 DPI)


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Langmuir

Fig. 7. Density profiles of DOX at the physiological pH and the acidic pH in the DHA-PBLG15-PCB10 system 83x68mm (150 x 150 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

TOC image 160x79mm (96 x 96 DPI)


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pH-responsive Zwitterionic Copolymer DHA-PBLG-PCB for Targeted

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