Dynamics and Populations of Micelles and Unimers - ACS Publications

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Tuning Biocompatible Block Copolymer Micelles by Varying Solvent Composition: Dynamics and Populations of Micelles and Unimers Bryce E. Kidd,† Xiuli Li,† Rachele C. Piemonte,† Tyler J. Cooksey,‡ Avantika Singh,‡ Megan L. Robertson,‡ and Louis A. Madsen*,† †

Department of Chemistry and Macromolecules Innovation Institute, Virginia Tech, Blacksburg, Virginia 24061, United States Department of Chemical and Biomolecular Engineering, University of Houston, Houston, Texas 77004, United States

‡

S Supporting Information *

ABSTRACT: Optimization of micellar molecular encapsulation systems, such as drug delivery vehicles, can be achieved through fundamental understanding of block copolymer micelle structure and dynamics. Herein, we present a study of PEO−PCL block copolymer spherical micelles that self-assemble at 1% wt/vol in D2O−THF-d8 mixtures. Varying solvent composition as a function of cosolvent THF-d8 at constant polymer concentration (1% wt/vol) allows sensitive study of how small molecule additives influence micelle structure and dynamics. We conduct nuclear magnetic resonance spectroscopy and diffusometry on two block copolymer (2k series: PEO2k−PCL3k; 5k series: PEO5k−PCL8k) spherical micelles that show drastically different behaviors. Unimers and micelles coexist in solution from 10−60 vol % THF-d8 for the 2k series but only coexist at 60 vol % THF-d8 for the 5k series. At ≥ 60 vol % THF-d8 micelles disassemble into free unimers for both series. We observe relatively flat micelle diffusion coefficients (∼1 × 10−10 m2/s) with increasing THF-d8 below 60 vol % for both 2k and 5k series, with only small changes in micelle hydrodynamic radius (≈14 nm) over this range. We compare these results to a detailed SANS and microscopy study described in a companion paper. These fundamental molecular dynamics, unimer population, and diffusion results, as a function of polymer composition and solution environment, provide critical fodder for controlled design of block copolymer self-assembly.

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INTRODUCTION Self-assembly of block copolymers (BCP) into functional nanometer-length-scale structures is of interest for a number of applications involving the encapsulation, delivery, or reactions of molecules. These applications include delivering hydrophobic drugs with poor bioavailability1,2 and conducting chemistry in tailored “nanoreactors” that enable reduced use of harmful solvents.3−5 Wormlike micelles, spherical micelles, and vesicles represent an array of possible morphologies that are obtainable through careful polymer chain (unimer) and solvent system design.6 Polymer block molecular weights and block compositions, solution concentration of unimers, and solvent type (including mixtures) all modulate intermolecular interactions to govern unimer dynamics and ultimately micelle self-assembly.7,8 Typically, design of drug-carrying copolymer micelles begins with hydrophobic and hydrophilic blocks that result in self© XXXX American Chemical Society

assembly of the hydrophobic block to form a core−shell nanostructure that is highly stable in water.1 The core size and specific molecular interactions determine drug-loading capacity in the core “microreservoir”. Moreover, for cancer treatment the micelle should be no larger than ∼50 nm to enable microfiltration sterilization and penetration through a solid tumor vessel wall.1 Upon introduction into the human body (typically intravenous injection), nonspecific elimination of drug-carrying micelles becomes an issue, which includes processes such as enzymatic and nonenzymatic degradation prior to reaching the target site, followed by excretion through the kidneys. Assuming the micelle survives a myriad of biological roadblocks, drug delivery to tumor cells is possible. Received: November 29, 2016 Revised: March 31, 2017

A

DOI: 10.1021/acs.macromol.6b02579 Macromolecules XXXX, XXX, XXX−XXX

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Here we investigate two BCP spherical micelle systems, which we term 2k series (containing PEO2k−PCL3k, or a PEO block of 2 kg/mol and a PCL block of 3 kg/mol) and 5k series (containing PEO5k−PCL8k) that self-assemble at 1% wt/vol in mixtures of D2O and a more hydrophobic cosolvent, THF-d8. We vary the vol % of THF-d8, which can selectively partition into the micelle core, in order to explore effects of solvent environment and micelle cargo on micelle dynamics and structure. Figure 1 illustrates this micelle−solvent system.

Thus, the unique ability to tune self-assembly and drug-loading capacity of micelles holds powerful potential in developing next-generation drug delivery vehicles. Understanding unimer and micelle dynamics as well as drug cargo loading and delivery properties will aid in judicious design of BCP micelles. Most BCP micelles for drug delivery use poly(ethylene oxide) (PEO) as the hydrophilic block due to weak cellular adhesion of the PEO corona onto cells, which minimizes protein adsorption into the core and protects the hydrophobic core from enzymatic degradation.9 Biodegradable and hydrophobic polycaprolactone (PCL) has shown promise in forming the core of BCP micelle systems.10,11 Increasing the PCL block length allows increase in the core volume to optimize drug capacity. Since PCL is more hydrophobic than commonly used poly(propylene oxide), one may expect higher hydrophobic drug capacity when using PCL. Drug release kinetics can also be tuned through varying block lengths due to changes in unimer chain dynamics and exchange rates in solution.12−14 Unimer exchange and equilibrium phenomena, such as fusion/fission and aggregation, critical micelle concentration (CMC), and critical micelle temperature (CMT), depend strongly on block chemistry, solvent type, and other molecules in solution, and thus we seek to understand and quantify such properties.13 Dynamic light scattering (DLS) and small-angle neutron scattering (SANS) are commonly used to characterize BCP micelles.15 DLS can give information on micelle size and shape distributions but lacks chemically specific information. SANS can yield core and corona size as well as unimer exchange dynamics through time-resolved contrast-matching experiments.16−18 Here we complement these techniques with nuclear magnetic resonance (NMR), which can probe equilibrium and nonequilibrium dynamics with chemical specificity across a range of time scales and thus provide a larger breadth of information.19−29 In addition to NMR spectroscopy providing chemical structure information and chain dynamics, NMR diffusometry can probe the fundamental translational dynamics properties of small molecules and micelles in these systems. We can use NMR diffusometry to separately resolve dynamics of free unimers, small solute and solvent molecules, and micelles. These different species become distinguishable through the observation of more than one spectral component or diffusion coefficient component. NMR diffusometry has shown previous utility in mapping phase behavior and relative populations of unimers and micelles under a variety of different conditions.30−33 Furthermore, we can assign and quantify the size of different diffusing molecular species via the Stokes−Einstein equation22−24,34 D=

Figure 1. At 1% wt/vol block copolymer in D2O/THF-d8, unimers self-assemble into spherical micelles where PEO and PCL reside in the corona and core, respectively. Varying the D2O/THF-d8 solution composition provides a model system to build understanding of free unimer, micelle, and small molecule cargo dynamics.

We study a wide range of cosolvent compositions using NMR spectroscopy and diffusometry to reveal molecular dynamics and diffusion coefficients of unimers in solution and within micelles, including quantifying coexisting populations of each type. We further extract micelle hydrodynamic radii rmicelle and compare these results with complementary H SANS measurements of micelle radius, corona and core radii, and aggregation number (see companion paper).35 We observe drastic differences in micelle and unimer dynamics and populations between the two series when increasing THF-d8 content. We sensitively derive viscosity for each specific solution composition using eq 1 and the measured diffusion coefficients for the solvent molecules, along with known selected reference points for the viscosities and hydrodynamic radii of D2O and THF-d8. We then extract rmicelle for both 2k H and 5k series. We observe coexistence of free unimers and micelles over the range 10−60 vol % THF-d8 for the 2k series, but only at 60 vol % THF-d8 for the 5k series. We see that as THF-d8 content increases, there are no drastic changes in rmicelle H from 10 to 50 vol % THF-d8, and at >60 vol % THF-d8 the micelles disassemble into free unimers for both systems. Both series of data also show a decrease and then increase in diffusion coefficient for the solvents and polymer chains with increasing vol % THF-d8, and this correlates well with changes in ηsolution. These results provide fundamental information on BCP micelle dynamics and unimer associations. Expanding such NMR methods to better quantify how micelle cargo uptake influences unimer dynamics across a broad range of environments will give materials scientists new tools to understand micellar systems. This will have direct implications for developing and optimizing new BCP micelles for e.g. controlled drug delivery, advanced chemical separations, and the performance of chemistry inside micelle nanoreactors.

kT cηsolutionrH

(1)

where D is diffusion coefficient, kT is average thermal energy, c (6π − 2π) is a constant that depends on the diffusing particle size, shape, and interaction type, ηsolution is bulk solution viscosity, and rH is hydrodynamic radius. We can access information such as unimer exchange rate, micelle size, and how such properties depend on solvent system and drug loading through careful experimental design. Thus, NMR offers the ability to probe a variety of structural and dynamical properties and can expand beyond common micelle characterization techniques. B

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not significantly produce differential signal intensity component weighting (including in two-component fits, see below) due to T1 and T2 relaxation. All NMR measurements were performed at 25 ± 1 °C.

EXPERIMENTAL DETAILS

Sample Preparation. Detailed synthetic procedures and basic characterizations for the BCPs are described in our companion paper.35 In brief, poly(ethylene oxide-b-ε-caprolactone) (PEO−PCL) BCPs were synthesized using monomethoxy-PEO as a macroinitiator for the ring-opening polymerization of ε-caprolactone.35−37 BCP molecular weights were characterized by gel permeation chromatography (GPC, Viscotek, GPCmax) and NMR end-group analysis (JEOL ECA-500 and ECX-400P), as shown in Table 1.

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RESULTS AND DISCUSSION Micelles, Unimers, and Solvent Molecules. To aid our understanding of how small molecule additives affect equilibrium and nonequilibrium dynamics of BCP micelles, we choose THF-d8 as a cosolvent that selectively partitions into the core (Figure 1). The present study investigates two spherical BCP micelles of similar block length ratio yet different molecular weights (2k series: PEO2k−PCL3k; 5k series: PEO5k− PCL8k). This allows us to simultaneously interrogate how modulations in cosolvent content, which directly influences interfacial tension,41,42 and how polymer molecular weights influence dynamics and transport of this class of micelles. We sample a range of solvent volume ratios for our binary solvent mixture starting with 10:90 vol/vol % THF-d8:D2O and increasing in steps of 10 vol % up to 100 vol % THF-d8, all at constant polymer concentration (1% wt/vol). By changing the solvent volume ratio, we gain insight into how micelle selfassembly depends on solvent environment. Use of deuterated solvents allows for clean resolution of polymer signals (Figure 2) in NMR spectra.

Table 1. Characteristics of the PEO−PCL Block Copolymers name PEO2k− PCL3k PEO5k− PCL8k

Mn_PEOa (kg/mol)

Mn_PCLb (kg/mol)

Đa

PCLb (wt %)

1.9

2.9

1.13

60

5.0

7.5

1.18

60

a Determined with GPC using universal analysis. bDetermined with 1H NMR.

Beginning with the naming definition for the polymers in Table 1, in the rest of the paper we will refer to micelle solution samples as 2kX% (corresponding to the PEO2k−PCL3k series) and 5k-X% (PEO5k− PCL8k series), where “X” refers to the vol % of THF-d8 in the solution, which varies from 10 to 100%. The 1% wt/vol BCP solutions were prepared by polymer dissolution in THF-d8 and subsequent slow addition of D2O with a syringe pump, followed by filtration (more details are provided in ref 35). The solutions were then transferred to a 5 mm NMR tube and sonicated (Fisher Scientific model FS140H, Hampton, NH) for 30 min prior to data acquisition to ensure minimal micelle aggregation. We note that we do not observe any nonequilibrium behavior in multiple measurements over 24 h postsonication, such as breaking apart and re-equilibration of micelles. Prior to each set of NMR experiments, DLS was also performed (see companion paper35) to verify the absence of micelle aggregation in solution. Pulsed-Field-Gradient (PFG) NMR Diffusometry. 1H PFG NMR diffusometry experiments were performed using a 400 MHz Bruker Avance III WB NMR spectrometer, equipped with a MIC probe coupled to a Diff60 single-axis (z-axis) gradient system. In the PFG NMR experiment, measured signal amplitude I as a function of gradient strength, g, was fit to the Stejskal−Tanner equation38−40

I = I0e−Dγ

Figure 2. 1H NMR spectrum of the 2k-10% (PEO2k−PCL3k micelle solution in 10:90 vol/vol % THF-d8:D2O) at 25 °C. We do not clearly resolve THF signal 8 at ∼3.7 ppm due to spectral overlap with PEO.

2 2 2

g δ (Δ− δ /3)

(2)

where I0 is signal amplitude at g = 0, γ is gyromagnetic ratio, δ is effective gradient pulse length, Δ is diffusion time between gradient pulses, and D is self-diffusion coefficient. The “b” factor, representing all the known NMR-specific parameters and useful for qualifying diffusion behaviors and artifacts, is given by b = γ2g2δ2(Δ − δ/3). The simple and robust pulsed-gradient stimulated echo (PGSTE) sequence39 was used with a 90° RF pulse length of 4.5 μs. A half sinusoid gradient pulse length of δ = 3.14 ms (effective rectangular pulse length = 2.00 ms), diffusion time Δ = 25 ms, and postgradient delay of 1.00 ms were used for 1H diffusion measurements. Maximum gradient strengths were adjusted in the range 5−600 G cm−1 to achieve 90−99% signal attenuation in 16−32 steps. Sufficient signalto-noise ratio (SNR) for each data point was achieved with 4−8 scans and acquisition times of 0.5 s (polymer signals) and 1.0 s (solvent signals) with 1 Hz line broadening. Relaxation delay times of 2.0 s were used for both polymer and solvent signals. Repetition times of 2.5 s (polymer signals) and 3.0 s (solvent signals) were used. Spin−lattice relaxation time (T1) measurements using the same RF pulse lengths as above, and the inversion−recovery sequence yielded T1 values in the range 0.4−4.0 s for all resonances. Spin−spin relaxation (T2) measurements using the same RF pulse lengths as above and the CPMG sequence yielded T2 values in the range 0.03−1 s for all resonances. Thus, the parameters used for the PGSTE experiments did

Figure 2 shows that the polymer signal line widths are broader (by a factor of ∼10) than the solvent signals (residual 1 H). This is related to the shorter spin−spin relaxation time (T2), which is the relaxation of net magnetization in the transverse (xy) plane,43,44 and which determines line broadening or full width at half-maximum (fwhm) = 1/πT2.45 Relative T2 gives information on how “rigid” or “mobile” is the molecular environment for a given nuclear site. That is, for the polymer signals, a shorter T2 value relative to the solvent signals indicates that the polymer chain environment is less mobile (slower tumbling) than the solvent molecules since the chains reside in the core and corona. Note that PCL signals (core) are also substantially broader (30 Hz) than PEO signals (corona) (10 Hz), demonstrating that PCL chain dynamics is significantly slower than for PEO. Compared to the solvent signals line width (500 ms) since we are able to measure unimers in two distinct F

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Macromolecules companion paper35). Here, NMR shows rmicelle consistently H higher than SANS, which again likely arises due to measurement technique differences. We then observe a sharp decrease in rmicelle to 5 nm at 60 vol % THF-d8. We note also that SANS H indicates aggregated micelles at 60 vol % (data not analyzed due to this fact), while NMR shows clean diffusion data. Thus, these results clearly show commonalities in size trends between NMR and SANS. We suggest that these observed differences in absolute size are due to averaging processes over micelle temporal or spatial variables for the two methods, which we will continue to explore. In the case of the 2k series, this disagreement may be due to unimers and solvent molecules that are hydrodynamically dragged along with the micelle but are too low in density to appear as significant SANS scattering density. Unlike the 5k series, the 2k series shows both unimers and micelles in solution from 10−60 vol % THF-d8, and furthermore Dmicelle increases (rmicelle decreases) between 30 H and 60 vol % THF-d8, which correlates with the rapid increase in the 2k series free unimer population between 30 and 60 vol % THF-d8 (Figure 4b). These changes also correlate with a significant increase of core polydispersity σRC and decrease in micelle aggregation number Nagg extracted from SANS data (see Supporting Information Figure S19 in the companion paper35). Furthermore, for both 2k and 5k systems, there is little change in rmicelle from 10 to 50 vol % THF-d8, which we H attribute to cosolvent-induced changes in aggregation number, solvent penetration of the core, and core and corona sizes observed via SANS.35 These results all reflect that these micelle systems (especially the 2k series) undergo major dynamical changes over the range of THF-d8 content, which we hope will provide fodder for further fundamental understanding of BCP micelles. Clearly, the dynamics and structure of the 2k and 5k series are quite different, and both NMR diffusometry and SANS report on different aspects of these micelle systems. In Figure 7, we conceptually summarize our conclusions regarding how micelle morphology depends on THF-d8 solvent content based on NMR diffusometry.

Figure 7. Illustration of BCP micelle morphology changes with THFd8 content. We see three distinct behavior regions for the 5k series: (1) micelles strongly dominate the solution at 60 vol % THF-d8, we observe only free unimers in solution. Note that micelles contain solvent molecules (THF and water), which we have omitted here for simplicity of presentation. Our companion paper35 describes solvent uptake and effects on micelle size in detail.

supramolecular systems. Collectively, these results show that we can fine-tune micelle self-assembly, which is critical for drug delivery and a host of other applications. In further related studies, we are currently exploring time-resolved NMR experiments as a sensitive tool to probe unimer exchange dynamics, which will complement time-resolved (TR) SANS experiments and potentially provide a new method for probing micelle behaviors in any NMR facility.

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CONCLUSIONS We have presented a detailed analysis of PEO2k−PCL3k and PEO5k−PCL8k block copolymer micelles, quantifying dynamics and populations of micelles and unimers on multiple time and length scales using NMR spectroscopy and diffusometry. Micelles self-assemble at 1% wt/vol in the D2O−THF-d8 mixed solvent system, and we vary the solvent volume ratio to explore free unimer and micelle structure, populations, and diffusion dependencies. The micelle radius rmicelle = 14 ± 3 nm H for the both 2k and 5k series at solvent compositions of 10−50 vol % THF-d8. For the 5k series, we observe coexistence of micelles and free unimers (rmicelle = 8 nm) at 60 vol % THF-d8 H followed by breakdown of micelles into free unimers. In contrast to the 5k series, the 2k series exhibits a coexistence region from 10 to 60 vol % THF-d8, wherein we observe a drastic increase in unimer content (12−45%) before breakdown into free unimers. We have compared and contrasted NMR and SANS35 characterizations and find substantial agreement overall, but notable disagreement between micelle radii measured with these two techniques. We are exploring new insights into such differences, which will serve to enhance our understanding of both techniques as well as our understanding of micelles and other macromolecular and

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.6b02579. Representative 1D spectra from pulse-acquire and diffusometry experiments, populations of free unimer and micelle fractions for 2k series, solution viscosities as a function of THF-d8 content (PDF)

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AUTHOR INFORMATION

Corresponding Author

*(L.A.M.) E-mail [email protected]. ORCID

Megan L. Robertson: 0000-0002-2903-3733 Louis A. Madsen: 0000-0003-4588-5183 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Science Foundation (NSF) under Awards CBET 1437767 and 1437831. Any G

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Macromolecules opinions, findings and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the NSF.

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DOI: 10.1021/acs.macromol.6b02579 Macromolecules XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.macromol.6b02579 Macromolecules XXXX, XXX, XXX−XXX