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Interface Components: Nanoparticles, Colloids, Emulsions, Surfactants, Proteins, Polymers
Composite Nanotube Ring Structures Formed by Two-step Self-Assembly for Drug Loading/Release Junfeng Wang, Jiawei Li, Muhan Wang, Qiang Yao, Youguo Yan, and Jun Zhang Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.8b03787 • Publication Date (Web): 07 Feb 2019 Downloaded from http://pubs.acs.org on February 7, 2019
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Langmuir
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Composite Nanotube Ring Structures Formed by Two-Step Self-Assembly for
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Drug Loading/Release
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Junfeng Wang,† Jiawei Li,† Muhan Wang,† Qiang Yao,† Youguo Yan,†‡ and Jun
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Zhang*,†‡.
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†School of Materials Science and Engineering, China University of Petroleum, Qingdao
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266580, Shandong, China
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‡Institute of Advanced Materials, China University of Petroleum, Qingdao 266580,
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Shandong, China
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KEYWORDS: Nanotube ring; two-step self-assembly; drug loading/release.
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ABSTRACT: Nanotube rings are a barely reported novel structure formed by the self-assembly
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of soft matter, as compared with nanotube structures and ring structures. A two-step self-
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assembly of amphiphilic copolymer AB and solvophobic copolymer CDC was studied. We
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found that the nanotube ring can be formed from a certain mass ratio of copolymer CDC to
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copolymer AB and a block D of a certain rigidity. More interestingly, we discovered a new
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strategy for drug loading and release that is different from the usual strategies reported in the
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literature. The present study provides a new rationale for the self-assembly of copolymers.
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INTRODUCTION
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Polymeric nanomaterials have been widely utilized in many fields and applications, including
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energy,1-3 sensors,4-6 self-healing materials,7,8 and bioengineering.9,10 Amphiphilic copolymer
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self-assembly is an effective strategy for producing polymeric nanomaterials and has become
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something of a research “hot topic.” Generally, polymeric nanomaterials from copolymer self-
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assembly present three main morphologies: spheres, rods, and vesicles, and their applications,
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including smart gel and drug delivery, strongly depend on their morphological features.11-18
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Hence, better control of the micromorphology of polymeric nanomaterials makes it possible to
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achieve greater functionality. Recent advances in materials science have led to the development
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of numerous novel methods for the preparation of polymeric nanomaterials, which have been
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developed to realize more complex structures based on the foundation structures. For example,
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Gong et al. prepared robust patchy structures and colloidal polyhedra based on the sphere
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structure by adjusting the surface energy of the sphere micelles.19 Yang et al. prepared ring
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structures based on the rod structure by using poly(g-benzyl-l-glutamate)-graft-poly(ethylene
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glycol) (PBLG-g-PEG) graft copolymers in a two-step self-assembly process.20 Sun et al. could
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prepare nanotubes based on the vesicle structure by using poly(4-vinylpyridine)-b-polystyrenes
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(P4VP-b-PS) copolymers.21 Other researchers have prepared complex secondary structures based
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on the three foundation structures. The question is, can we obtain a more complex structure
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based on these secondary structures, such as a nanotube ring combined with a nanotube structure
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and a ring structure?
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Amongst carbon materials, nanotube rings can be assembled from carbon tubes using ultrasonic
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irradiation or molecular templates.22,23 Chen et al. found that carbon nanotube rings coated with
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gold nanoparticles can significantly enhance Raman and other optical signals and can be used for
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imaging and imaging-guided cancer therapy.24 However, nanotube ring structures assembled
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from polymers have rarely been reported. Although it is possible to find reliable experimental
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methods for synthesizing polymer nanotube rings, as a result of the development of modern
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preparation techniques and strategies, their high cost and time-consuming procedures need to be
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carefully evaluated. Instead, dynamic simulation is an efficient technique for predicting new
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structures and for revealing the inner mechanism of ring formation.25-30 Therefore, simulation
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studies are important for guiding experiments for improving efficiency and lowering costs.31-34
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In this paper, strategies for preparing polymeric nanotube rings are explored using computer
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simulation, and we find that nanotube rings can be self-assembled by a two-step assembly of
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amphiphilic copolymer AB and solvophobic copolymer CDC when block D has a certain rigidity
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and length. Moreover, our simulation demonstrates that the nanotube ring can be readily utilized
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for drug delivery. During the first step of the assembly, we can obtain vesicles with some holes,
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and drugs can be loaded into the vesicles through holes. Following preparation of the nanotube
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rings, the drugs are sealed inside. Drug release can be simply realized by block D puncturing the
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nanotube ring wall. This strategy is different from traditional drug delivery methods, which
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provides new insights in this field.11, 35-38
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MODEL AND SIMULATION METHODS
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DPD Simulations. Dissipative particle dynamics (DPD) is a coarse-grained simulation method
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for studying complex hydrodynamic behavior in large systems, and was proposed by
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Hoogerbrugge and Koelman in 1992.39 In a DPD simulation, a coarse-grained bead represents
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one or more repeat blocks of a copolymer chain, or a cluster of atoms or molecules. All of the
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DPD coarse-grained beads are restricted by Newton’s equation of motion:
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𝑑𝑟𝑖 𝑑𝑡
= 𝑣𝑖
𝑑𝑣𝑖 𝑑𝑡
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𝑓𝑖
= 𝑚𝑖
(1)
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where 𝑟𝑖, 𝑣𝑖, and 𝑚𝑖 are the position, velocity, and mass of the 𝑖𝑡ℎ bead. The total interaction
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between the 𝑖𝑡ℎ and 𝑗𝑡ℎ beads is the summation of non-bonded and bonded interactions. The non-
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bonded interaction between each pair of particles includes the conservative force 𝐹𝐶, the random
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force 𝐹𝑅, and the dissipative force 𝐹𝐷. Thus, the pairwise non-bonded interaction force 𝐹𝑖
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between the 𝑖𝑡ℎ and 𝑗𝑡ℎ beads is the sum of the three forces:
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𝐹𝑖 = ∑𝑗 ≠ 𝑖(𝐹𝐶𝑖𝑗 + 𝐹𝐷𝑖𝑗 + 𝐹𝑅𝑖𝑗)
(2)
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For the 𝑖𝑡ℎ bead, the non-bonded interaction is contributed by all other beads within a cutoff
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radius 𝑅𝐶. The three non-bonded interaction forces 𝐹𝐶, 𝐹𝑅, and 𝐹𝐷 are:
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𝐹𝐶𝑖𝑗 = 𝛼𝑖𝑗𝜔(𝑟𝑖𝑗)𝑟𝑖𝑗
(3)
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𝐹𝐷𝑖𝑗 = ―𝛾𝜔2(𝑟𝑖𝑗)(𝑟𝑖𝑗 ∙ 𝑣𝑖𝑗)𝑟𝑖𝑗
(4)
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𝐹𝑅𝑖𝑗 = 𝜎𝜔(𝑟𝑖𝑗)𝜃𝑖𝑗𝑟𝑖𝑗
(5)
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where 𝛼𝑖𝑗 is the repulsion interaction parameter between each two beads, which can be estimated
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using the Flory–Huggins parameter 𝜒𝑖𝑗 from the equation:
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𝛼𝑖𝑗 = 𝛼𝑖𝑖 +3.5𝜒𝑖𝑗
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where 𝜒𝑖𝑗 represents the compatibility between two different kinds of DPD beads, and larger
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values of 𝜒𝑖𝑗 indicate less compatibility between two different kinds of DPD beads. For the same
(6)
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kind of DPD bead, 𝛼𝑖𝑖 = 25 and 𝜒𝑖𝑖 = 0. γ is the friction coefficient and σ is the noise amplitude.
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γ and σ can be unified by one formula:
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𝜎2 = 2𝛾𝑘𝐵𝑇
(7)
The weight fraction ω(𝑟𝑖𝑗) is given by the expression of Groot and Warren:40 𝑟 1 ― 𝑖𝑗 𝑟𝑐 𝑟𝑖𝑗 ≤ 𝑟𝑐 𝑟𝑖𝑗 > 𝑟𝑐
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ω(𝑟𝑖𝑗) = {0
(8)
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𝜃𝑖𝑗 is a randomly fluctuating variable with zero mean and unit variance.
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The bonded interaction force between each pair of bonded beads is regarded as a harmonic
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spring force:
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𝐹𝑆𝑖𝑗 = 𝐾𝑠(1 ― 𝑟𝑖𝑗 𝑟𝑠)𝑟𝑖𝑗
(9)
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where the value of 𝐾𝑠 is set to 50 to prevent the copolymer model from elongating excessively
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and 𝑟𝑠 = 0.8𝑟𝑐. In addition, 𝑟𝑐, m, and 𝑘𝐵𝑇 are the length unit, the mass unit and the energy unit ,
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which are set to 1. The unified time τ can be formulated as:
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2 τ = (𝑚𝑟𝑐 ) 𝑘𝐵𝑇
(10)
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As shown in Figure 1(b), the angle-restricted force acts on the angle between three neighboring
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beads to reflect the different degrees of rigidity of block D. The angle-restricted force can also be
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represented by a harmonic spring force:
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𝐹𝐵𝑖𝑗 = 𝐾𝑏(𝜃 ― 𝜃0)
(11)
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where the value of 𝐾𝑏 is set to be in the range 0 to 15 and 𝜃0 = 180°.
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Figure 1. Schematic illustration of the reaction model.
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Reaction Model. In 2015, Hiroshi Noguchi et al used a reaction model to study the self-
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assembly process induced by chemical reactions41. In 2016, Lin et al studied PISA of linear
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diblock copolymers by using the reaction model42. According Lin’s work, as shown in Figure
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1(a), when the monomer M moves close to the active end of block B with a reaction radius R
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(R = 0.8𝑟𝑐), this active end has a certain probability (Pr) of bonding with the closest monomer M.
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Following this, the monomer M transforms to a solvophobic bead B. The reaction probability Pr
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is controlled by a series of random numbers. A random number between 0 and 1 is created by the
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computer for each step. If any one random number is smaller than the reaction probability Pr, the
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active ends will bond with their closest monomers; thus Pr can reflect the polymerization rate. In
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our simulation, the reaction probability was set to a value of 0.0001, which is consistent with our
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previous work and Lin’s work42, 43. In all of our simulations, the conversion rate of monomers
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was greater than 99%.
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Table 1. Parameters and their acronyms used in DPD simulation
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Parameter
Acronym
Repulsive Interaction Parameter
𝛼𝑖𝑗
Friction Coefficient
γ
Noise Amplitude
σ
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Length Unit
𝑟𝑐
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Time Unit
τ
Mass Unit
m
Energy Unit
kbT
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In the simulation, there were 1,536,000 beads in an 80𝑟𝑐 × 80𝑟𝑐 × 80𝑟𝑐 cubic system under
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periodic boundary conditions; the numerical density of beads was 3. The repulsive values of the
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interaction parameters between solvophilic bead A and solvent bead S (𝛼𝐴𝑆) were maintained at
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20, and those of the repulsive interaction parameters between solvophobic beads B, C, and D and
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solvent bead S were set to 80. The values of 𝛼𝐴𝐵, 𝛼𝐴𝐶, and 𝛼𝐴𝐷 were set at 60. To maintain the
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solvophilicity of monomer M, the value of 𝛼𝑀𝑆 was set at 25. The value of the friction coefficient
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γ was set at 4.5, and that of the noise amplitude σ was set at 3. The time step was 0.04τ, the total
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time was at least 4 × 106 steps, and each step of the self-assembly was run for 2 × 106 steps.
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The simulations were performed by a coarse-grained molecular dynamics program based on
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LAMMPS, and the morphologies were observed by visual molecular dynamics (VMD).44, 45
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RESULTS AND DISCUSSION
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Figure 2. (a) The sketch map of two-step of self-assembly. (b) The table of the abbreviation used
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in the discussion.
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We developed a two-step self-assembly strategy for the preparation of nanotube rings, as shown
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in Figure 2(a). In the first step, amphiphilic copolymer AB2 and solvophobic copolymer
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C4D42C4 were assembled into composite micelles. In the second step, the monomers were added
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into the system, and block B could grow further from B2 to B5 by polymerization, contributing to
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the continuous self-assembly and increasing the solvophobic space around the micelles. In our
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work, the initial mass concentration of copolymer AB2 was set to 2% w/w, and block C is used
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to fix the copolymer CDC. As for copolymer CDC, the mass concentration, the chain lengthand
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the chain rigidity of block D can also influence the final morphologies, so all of these factors
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need to be studied under the two-step self-assembly strategy. The different mass ratios between
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copolymer CDC and copolymer AB are studied from 1:24 to 1:6. The different chain rigidities of
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block D are studied from Kb=0 to Kb=15. The different chain length of block D is studied from
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D21 to D84. Moreover, to understand the results and discussion better, the parameters and their
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abbreviations are shown in Figure 2(b).
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Figure 3. The final morphology of the micelles by the two-step self-assembly of amphiphilic
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copolymer AB and solvophobic copolymer CDC with different rigid of block D and mass ratio
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of copolymer CDC to copolymer AB (CmCDC : CmAB = 1:24, 1:12, 1:6).
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The effects of different mass ratios of copolymer CDC to copolymer AB and the different
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rigidities of the block D on the final morphologies were first studied. As shown in Figure 3(a),
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for a highly rigid block D (Kb = 15kbT/rc), copolymer CDC tends to assemble into a rod-like
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structure in the first step. During the second step as shown in Figure 3(b), the micelles fuse
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together further, and the larger solvophobic space of the micelles makes the ring-like structures
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disappear and promotes the formation of rod-like structures. When the rigidity of block D is
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Kb = 5kbT/rc, copolymer CDC tends to surround and spread inside the micelles. In the second
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step, the dispersion and surrounding of copolymer CDC can be promoted because of the larger
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solvophobic space of the micelles. When the block is soft (Kb = 0kbT/rc), copolymer CDC tends
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to form a coil-like structure and is distributed mainly in the micelles. The second step has less
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influence on the distribution and structure of copolymer CDC. In addition, when Kb = 15kbT/rc
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and Kb = 5kbT/rc, increasing the mass ratio of copolymer CDC will promote it to form a rod-like
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structure, although the space around the micelles has increased following the second step. When
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Kb = 0kbT/rc, the mass ratio of copolymer CDC has no influence on the structure of copolymer
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CDC. In Figure S1, when Kb = 5kbT/rc and the mass ratio of copolymer CDC is 1:24, copolymer
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CDC and copolymer AB can form a symmetrical structure following the two-step self-assembly.
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Figure 4. (a) The radius of gyration (gr) and the angle between the two ends and the center (θ) of
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gravity of block D in first step of self-assembly. (b) The radius of gyration (gr) and the angle
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between the two ends and the center (θ) of gravity of block D in the second step of self-
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assembly.
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We explored the effect of copolymer CDC during polymerization to gain further insight into its
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structural properties. Figure 4 shows the radius of gyration (gr) and the angle (θ) between the
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two ends and the center of gravity of block D following two-step self-assembly to reflect the
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structure transformation of copolymer CDC. For the first step, when Kb = 15kbT/rc, at the low
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mass ratio of copolymer CDC, most of the block D units remain straight, although a few of them
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curl into a ring-like structure, which reduces the value of gr. With increasing mass ratio of
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copolymer CDC, the ring-like structure disappears and the values of gr of block D were
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concentrated around 32.5, with the straight length of block D being 33.6 and the values of θ of
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block D concentrated around 180°. When Kb = 5kbT/rc, the distribution of values of gr is larger
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than when Kb = 15kbT/rc or Kb = 0kbT/rc, and the copolymer CDC surrounds the vesicles in the
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solvophobic inner space, as shown in Figure 1. Increasing the ratio leads to a reduction in the
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distribution of gr and the value of gr increases. Then the copolymer CDC self-assembles into a
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rod-like structure, as for the behavior when Kb = 15kbT/rc, as shown in Figure 1. When
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Kb = 0kbT/rc, the values of gr are much smaller and the change in θ is more acute. At the same
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time, Figure 1 shows that all of the copolymer CDC curl up into a ball and disperse in the
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solvophobic space of the micelles. In the second step, the increasing length of block B has no
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influence on the values of gr and θ of block D when Kb = 15kbT/rc and Kb = 0kbT/rc. When
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Kb = 5kbT/rc, the increase in the solvophobic space results in a wider distribution of gr values of
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block D. Therefore, under a certain mass ratio (1:24) and rigidity of block D (Kb = 5kbT/rc),
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copolymer CDC has a modest rigidity for use as a support structure to form the composite
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micelles.
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Figure 5. (a) The final morphology of the nanotube ring. (b) The distribution of the copolymer
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CDC in the micelle. (b) The section of the nanotube ring. (d) The radial density (D(r)) of the
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nanotube ring.
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More interestingly, when Kb = 5kbT/rc, the observed structure of the nanotube ring is that as
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shown in Figure 5(a). Figure S7(a) and (b) shows the root mean square deviation (RMSD) and
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the number of clusters (Nm) in each step. The RMSD eventually converges after completing the
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simulation in each step of the self-assembly, and the Nm remained unchanged for a long period
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of time, which indicates that the nanotube ring is a stable structure. Figure 5(d) shows the radial
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density of amphiphilic copolymer AB in the nanotube ring. The inner density is larger than the
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outer density, which leads to a larger membrane tension, and the center hole tends to disappear to
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offset the tension difference due to the Marangoni effect.46, 47 Therefore, it is difficult to form the
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nanotube ring structure without solvophobic copolymers CDC, as shown in Figure S5.
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Moreover, we also investigated two-step self-assembly using different lengths of block D (D21,
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D84) at the same mass ratio of copolymer CDC (Figures S2 and S4). Our study shows that
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nanotube rings can only be produced for a certain length and rigidity of block D and a certain
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mass concentration of copolymer CDC.
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The necessity of two-step self-assembly was also studied. As shown in Figure S6, because of the
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more solvophobic block B, the self-assembly progress is more intense, so that it is difficult to
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form micelles with the regular morphology; thus, one-step self-assembly of copolymer C4D42C4
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and copolymer AB5 assembles only into composite vesicles with complex cavities. Moreover,
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polymer with a rigidity of Kb = 5kbT/rc has been experimentally prepared,48 which suggests that
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the nanotube ring structure could be prepared by a two-step self-assembly experimental process.
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Figure 6. (a) The first step self-assembly of producing the nanotube ring. (b) The second step
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self-assembly of producing the nanotube ring. (c) The fusion progress of two cavities during
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forming the nanotube ring. (d) The transformation progress of the micelle’s outside after fusion
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of two cavities during forming the nanotube ring (the micelle is thicker, the blue is darker.).
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In order to gain insight into the formation process of the nanotube ring structure, Figure 6 shows
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the two-step self-assembly process for preparing the nanotube rings. In the first step (Figure
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6(a)), the small-sphere micelles first appear. As the micelles fuse together, ring-like micelles and
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lamellar micelles are then observed. Finally, the ring-like micelles disappear through further
224
fusion, and the lamellar micelles curl up to form vesicles. In the second step (Figure 6(b)), as
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solvophobic block B grows, two vesicles can fuse to form the nanotube ring, whose details of
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formation were further studied. When the vesicles begin to fuse (Figure 6(c)), copolymer CDC
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first makes contact with the other cavity of the vesicle. Because copolymer CDC surrounds the
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cavity and obstructs it, it is difficult for the two cavities to fuse, and they have to squeeze
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together from the interspace of the network formed by the CDC copolymer. Then, the two
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cavities fuse together into a ring-like cavity, and copolymer CDC, acting as a support structure,
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keeps the ring-like structure stable. Following formation of the ring-like cavity (Figure 6(d)), the
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center of the micelle becomes concave, and finally the nanotube ring is formed (Figure S3,
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Movie S1, and Movie S2 show more details about the progress of two-step self-assembly).
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Figure 7. (a) The projected density of one half of a vesicle before and after the polymerization.
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(b) The sketch map of the design of smart carries for drug loading and release. (c) The drug
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loading progress over time. (d) The drug release progress over time. (e) The concentration of
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drug loading over time. (f) The percentage of drug release over time.
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Because solvophobic block B is short, holes remain in the vesicles following the first self-
240
assembly step, and these holes are filled up following polymerization (Figure 7(a)). Therefore,
241
the composite micelles can be used as a smart vehicle for carrying drugs. Figure 7(b) shows the
242
strategy for applying drug loading and release. The drug model is used as a ideal solvophilic
243
drug model, and repulsive interaction parameter is the same as the solvent bead. First, the porous
244
vesicles are formed by the first self-assembly step of copolymer AB and copolymer CDC, and
245
then the monomers and the drug are added to the system. Second, polymerization is conducted
246
after the drug diffuses into the vesicle, and then the holes in the vesicles are filled up. Finally, the
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vesicles are perforated by the D blocks when the solvophilicity of block D is changed so that the
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drug can diffuse out according to the concentration difference. At the same time, the short
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solvophobic block C hinders copolymer CDC from leaving the micelle. Figure 7(c) and (d)
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shows how this system can be used for drug loading and release. In this system, 4% w/w of the
251
drug is added to the solvent, and the concentration of the drug in the vesicle can reach as much as
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3.9% w/w, which is a little lower than the concentration in the solvent shown in Figure 7(e). As
253
Figure 7(f) shows, as much as 28% of the drug in the carriers can be successfully released.
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CONCLUSIONS
255
We have used computer simulations to assess a novel but simple strategy for preparing nanotube
256
ring structures, which has scarcely been reported in the literature, by the self-assembly of soft
257
matter, namely, the two-step self-assembly of copolymers AB and CDC. The use of a block D of
258
a certain rigidity and of a certain mass ratio of copolymer CDC is the key to forming the
259
nanotube ring structure. In addition, we have shown that this composite structure can be applied
260
effectively as a means of drug loading and release. This new strategy will facilitate the
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production of functional nanomaterials with complex structures for future experimental studies.
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ASSOCIATED CONTENT
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Supporting Information
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This material is available free of charge via the Internet at http://pubs.acs.org.
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Details about the dissipative particle dynamics method, the dynamic polymerization
266
model and the self-assembly progress and morphology. (PDF)
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Videos regarding the formation progress of nanotube ring structure (step one: Movie S1
268
step two: Movie S2). (AVI)
269
AUTHOR INFORMATION
270
Corresponding Author
271
* E-mail:
[email protected] (J. Zhang).
272
Notes
273
The authors declare no competing financial interest.
274
ACKNOWLEDGMENT
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This work is financially supported by the National Natural Science Foundation of China
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(51874332, U1663206, U1762212), the Climb Taishan Scholar Program in Shandong
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Province (tspd20161004), and the Fundamental Research Funds for the Central
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Universities (15CX08003A).
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Graphical Abstract:
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Nanotube ring produced by two-step self-assembly for drug loading and release.
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