Composite Nanotube Ring Structures Formed by Two-step Self

Feb 7, 2019 - More interestingly, we discovered a new strategy for drug loading and release that is different from the usual strategies reported in th...
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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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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

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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-

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assembly step, and these holes are filled up following polymerization (Figure 7(a)). Therefore,

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the composite micelles can be used as a smart vehicle for carrying drugs. Figure 7(b) shows the

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strategy for applying drug loading and release. The drug model is used as a ideal solvophilic

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drug model, and repulsive interaction parameter is the same as the solvent bead. First, the porous

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vesicles are formed by the first self-assembly step of copolymer AB and copolymer CDC, and

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then the monomers and the drug are added to the system. Second, polymerization is conducted

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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

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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

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Figure 7(f) shows, as much as 28% of the drug in the carriers can be successfully released.

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CONCLUSIONS

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We have used computer simulations to assess a novel but simple strategy for preparing nanotube

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ring structures, which has scarcely been reported in the literature, by the self-assembly of soft

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matter, namely, the two-step self-assembly of copolymers AB and CDC. The use of a block D of

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a certain rigidity and of a certain mass ratio of copolymer CDC is the key to forming the

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nanotube ring structure. In addition, we have shown that this composite structure can be applied

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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

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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

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step two: Movie S2). (AVI)

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AUTHOR INFORMATION

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Corresponding Author

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* E-mail: [email protected] (J. Zhang).

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Notes

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The authors declare no competing financial interest.

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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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