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Tuning of Polymeric Nanoparticles by Co-Assembly of Thermoresponsive Polymers and a Double Hydrophilic Thermoresponsive Block Copolymer Qilu Zhang, Lenny Voorhaar, Sergey K. Filippov, Berin Fatma Yesil, and Richard Hoogenboom J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.6b03414 • Publication Date (Web): 04 May 2016 Downloaded from http://pubs.acs.org on May 6, 2016
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The Journal of Physical Chemistry
Tuning of Polymeric Nanoparticles by Co-Assembly of Thermoresponsive Polymers and a Double Hydrophilic Thermoresponsive Block Copolymer Qilu Zhang,1 Lenny Voorhaar,1 Sergey K. Filippov,2 Berin Fatma Yeşil,1 and Richard Hoogenboom1,* 1
Supramolecular Chemistry Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 S4, B-9000 Ghent, Belgium
2
Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic CZ – 162 06, Czech Republic
ABSTRACT: The co-assembly behavior of thermoresponsive statistical copolymers and a double hydrophilic block copolymer having a permanently hydrophilic block and a thermoresponsive block is investigated. By adjusting the hydrophilicity of the thermoresponsive statistical copolymers, hybrid nanoparticles are obtained with various ratios of the two species. Importantly, the size of these nanoparticles can be controlled in between 40 to 250 nm dependent on the TCP and the amount of statistical copolymers in the solution. Simultaneous analysis of static and dynamic light scattering data indicates that the possible structure of nanoparticles varies from hard sphere to less compact architecture and most probably depends on a difference between cloud point temperatures of individual components. This developed co-assembly method provides a simple platform for the preparation of defined polymeric nanoparticles. 1. Introduction Inspired by the highly ordered structures and functions of biological systems, scientists have been trying to create artificial selfassembled nano- or microstructures using synthetic materials for decades.1-3 Polymers with various architectures, e.g. diblock, triblock, comb-like or star shaped copolymers, have been reported to show complex self-assembly behavior resulting in different shapes of higher-ordered nano- or microstructures, which have found potential applications in many fields, like biomedical, micro-electronic, photoelectric and optical materials.4-9 Most of systems are formed by the self-assembly of block copolymers, due to their unique and excellent assembly behaviors.10-13 However, the synthesis of block copolymers requires sequential controlled/living polymerization14-16 or post-polymerization modification such as substitution17 and ‘‘click’’ reactions,18-19 which is time-consuming and a new polymer structure has to be prepared to vary and control the size of the micellar assembly, which is limited by the size of the utilize block copolymers. The self-assembly of much simpler statistical copolymers has also been demonstrated to result in high ordered nanostructures with different morphologies and morphological transitions.20 Compared to block copolymers, the synthesis of statistical copolymers is relatively easy, as they are typically achieved in a one-step copolymerization of two (or more) different monomers. For example, statistical copolymers containing tunable ratio of hydrophobic dodecyl chain and hydrophilic L-glutamic acid, prepared by simple copolymerization, have been reported to self-assemble into defined (giant) vesicular structures.21 We have recently reported a polyampholyte prepared by direct stoichiometric reversible addition−fragmentation chain transfer (RAFT) copolymerization of cationic, anionic as well as olig(glycol ethylene) (OEG) functionized monomers.22 Favored by the solvophilicity of the OEG side chains and solvophobicity of the polymer backbone, this statistical copolymer was found to form well-organized thermoresponsive
nanoparticles in ethanol or isopropanol. A limitation for the selfassembly of statistical copolymers is that an amphiphilic structure or strong inter/intra-chain supramolecular interactions are still required.20 Polymers with uniform solubility can hardly selfassemble into an ordered structure since the solvophobic aggregation cannot be stabilized leading to ill-defined phase separated agglomerates. In this contribution, we will present a straightforward method to assemble uniform statistical copolymers into higher order structures by co-assembly with a block copolymer (see Figure 1).23-24 The procedure is based on mixing of both a thermoresponsive block copolymer and a thermoresponsive statistical copolymer in solution. Temperature triggered co-assembly behavior of the resulting mixed polymer solutions was investigated by dynamic light scattering (DLS) and static light scattering (SLS). The influence of the cloud point temperature (TCP) and concentration of the thermoresponsive statistical copolymers with different TCP on the co-assembly behavior and the resulting nanoparticles will be discussed using one block copolymer of which the concentration was kept constant. During the course of this study, the group of O’Reilly also reported a related co-assembly methodology for tuning micellar properties by blending of block copolymers.25-26 2. Results and discussion The block copolymer and statistical copolymers with different TCPs were synthesized by reversible addition−fragmentation chain transfer (RAFT) polymerization and are listed in table 1.27-29 By altering the ratio of the two comonomers, namely methoxy di(ethylene glycol) acrylate (mDEGA) and ethoxy di(ethylene glycol) acrylate (eDEGA), statistical copolymers with various TCPs were obtained that were utilized for this co-assembly study (Table 1). The block copolymer with one permanent hydrophilic block, namely poly(ethylene glycol) (PEG, Mn=2000, Ð=1.06), and a P(mDEGA40-eDEGA60) thermoresponsive block was syn-
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The Journal of Physical Chemistry thesized using a PEG functionalized macro-CTA. The structures of the studied polymers are shown in Figure 1.
nately, the contrast was insufficient for detection by cryo-TEM most likely due to too high hydrophilicity of the particle core, which is not fully dehydrated in the collapsed state. Regular TEM is also not possible due to the very low glass transition temperature of these materials. o
25 C o 28 C o 29 C o 30 C o 32 C o 34 C o 36 C o 48 C
25
20
G(RH)
15
10
S
S O
O 44
O
S
40
O
60
O O
O
S
5
HO O
S
x
O
S
y
O O
O
0 1
O O
O O
O O
10
O
100
Size /RH.nm
O
80
Figure 1. Top: Schematic representation of the co-assembly of a thermoresponsive block copolymer and a thermoresponsive statistical copolymer; bottom: Structures of the studied block (left) and statistical (right) copolymers.
Polymer
Polymer compoMn mDEGA TCP Ða sition (kDa)a %b / o Cc P(mDEGA20P20 17.5 1.09 14.3% 20 eDEGA80) P(mDEGA40P40 17.5 1.10 38.8% 26 eDEGA60) P(mDEGA50P50 15.0 1.11 49.2% 29 eDEGA50) P(mDEGA60P60 15.1 1.12 60.0% 33 eDEGA40) P(mDEGA80P80 14.7 1.11 78.6% 40 eDEGA20) PEG44-bBP P(mDEGA4018.4 1.14 40% 29d eDEGA60) a Determined by SEC; b Determined by 1H NMR spectroscopy; c Measured by turbidimetry at 5 mg/ml; d In this specific situation the phase transition temperature (PTT) was determined by DLS at 1 mg/ml. The temperature induced self-assembly of the block copolymer (BP) itself was first evaluated by DLS at 1 mg/ml in aqueous solution on Zetasizer Nano-ZS set-up. Figure 2 displays the volume weighted size distributions obtained at different temperatures and the evolution of cumulant fitted RH value with temperature of the BP solution during heating from 25 oC to 48 oC. A particle size of around 6 nm was observed below 28 oC indicating the presence of individually dissolved polymer chains, i.e. unimers of the BP. An increase of particle size was detected when the polymer solution was heated above 28 oC. After a gradual increase of particle size with increasing temperature, the particle size stabilized around 35 oC at about 130 nm with a very low polydispersity index (PDI=0.05) indicating the formation of nanostructures. Cryogenic transmission electron microscopy (cryo-TEM) was attempted to image the structure of the nanoparticles, but unfortu-
PDI
Rh/nm
Table 1 Characterization data of the copolymers synthesized for co-assembly behavior investigation
Rh
60
40
20
0
1,0 0,8 0,6 0,4 0,2 0,0 25
30
35
40
45
PDI
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
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50
o
Temperature / C
Figure 2. Volume weighted Ssize distribution of hydrodynamic diametersradii by CONTIN (top) and volume weightedcumulant fitted DRH value size versus temperature (bottommiddle) of BP in milliQ water at different temperatures (1 mg/mL) determined by DLS (Zetasizer Nano-ZS). To get insight on possible nanoparticle structure and additionally trace nanoparticles evolution we have performed more detailed study of BP solutions by DLS and SLS methods at different temperatures below and above TCP. From multi-angle DLS experiments (ALV), intensity-weighted distribution functions of apparent hydrodynamic radii together with relaxation times have been obtained. One can see that below TCP, the distribution function is clearly bimodal (Figure 3, top); in agreement with high the polydispersity index value at such temperatures (Figure 2, Figure S1). With increasing temperature above 30 oC only one peak remains that justifies the significant drop in PDI value. The dependence of relaxation rate as a function of q2 were of diffusive nature, that allows calculating an apparent diffusion coefficient DHapp of 3.9 x 10-8 m2/s corresponding to an apparent hydrodynamic radius RHapp of 81 nm (Figure S2,Supporting Information)
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and other compact nanoparticles with hyperbranched or similar Gaussian “soft sphere” structures.
0,1
172 nm 25C
Table 2. Refractive index increments, apparent molecular weights of nanoparticles, radius of gyration Rg, and ρ-ratio≡Rg/RHapp.
3.3 nm 0,0
RhW(Rh)
slow
fast
18 nm
0,2
30C
System
T, oC
dn/dc, cm3/g
Mwapp, g/mol
R g, nm
Rg/Rh
BP
35
0.129
1.47·108
80
0.99
3.0·107
23
0.78
6.5·107
29.5
0.81
2.0·108
78.4
0.99
0,0
81 nm
35C
0,2
0,0 -4 -3 -2 -1 10 10 10 10
10
0
10
1
10
2
3
10
10
4
10
5
10
6
7
10
10
8
10
9
BP+P50 (1:1)
Rh, nm
ln(Kc/Rθ), mol/g
-17,4 -17,6 -17,8
1,6x108
Rθ/Kc, g/mol
-17,2
BP+P80 (1:1)
1,2x108 3x10
8x107
-8
BP Gaussian coil hard sphere 7 Gaussian coil; Mw/Mn=24x10
10-2
-18,0
2x10-2
q, nm
2x10-8
-1
-18,2
Kc/Rθ, mol/g
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
The Journal of Physical Chemistry
-18,4 -18,6
1x10
-8
-18,8 0
100
200
300
400
500
600
700
q2, µm-2
Figure 3. Intensity-weighted distribution of hydrodynamic radii (top) of BP at different temperatures and SLS data in Zimm (open circles) and Guinier (filled squares) representation at 35 oC (bottom) determined by DLS/SLS methods (ALV) (c=1 mg/mL) Inset: fitting of SLS data by several models. Analysis of the static light scattering data shows that the partial Zimm diagram has strong non-linear behavior in the entire range of scattering angles (Figure 3, bottom). This can be ascribed to non-applicability of Guinier approximation (qRg
