Thermoresponsive Layer-by-Layer Assemblies for Nanoparticle

Article pubs.acs.org/Langmuir

Thermoresponsive Layer-by-Layer Assemblies for NanoparticleBased Drug Delivery Jing Zhou,† Michael V. Pishko,*,‡ and Jodie L. Lutkenhaus*,†,§ †

Department of Materials Science and Engineering, Texas A&M University, College Station, Texas 77843-3003, United States Department of Biomedical Engineering, Texas A&M University, College Station, Texas 77843-3120, United States § Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, Texas 77843-3122, United States ‡

S Supporting Information *

ABSTRACT: Layer-by-layer (LbL) capsules, known for their versatility and smart response to environmental stimuli, have attracted great interest in drug delivery applications. However, achieving a desired drug delivery system with sustained and tunable drug release is still challenging. Here, a thermoresponsive drug delivery system of solid dexamethasone nanoparticles (DXM NPs, 200 ± 100 nm) encapsulated in a model LbL assembly of tunable thickness consisting of strong polyelectrolytes poly(diallyldimethylammonium chloride)/poly(styrenesulfonate) (PDAC/PSS) is constructed. The influence of various parameters on drug release, such as number of layers, ionic strength of the adsorption solution, temperature, and outermost layer, is investigated. Increasing the number of layers results in a thicker encapsulating nanoshell and decreases the rate of dexamethasone release. LbL assemblies created in the absence of salt are most responsive to temperature, yielding the greatest contrast in drug release. Relationships between drug release and LbL architecture are attributed to the size and concentration of free volume cavities within the assemblies. By tailoring the properties of those cavities, a thermoresponsive drug delivery system may be obtained. This work provides a promising example of how LbL assemblies may be implemented as temperature-gated materials for the controlled release of drug, thus providing an alternative approach to the delivery of therapeutics with reduced toxic effects.

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INTRODUCTION To date, effective cancer treatments include chemotherapy, surgery, radiation, and immunotherapy.1 Recently, combination therapy under remote physical control has received great attention as an approach to decrease systemic toxicity and avoid overdosing. External stimuli, including light, magnetic field, electric field, and heat, have been used to trigger, control, and enhance localized cancer therapies.2 Because heat can be utilized to directly destroy cancer cells,3 the delivery of anticancer drug triggered by temperature is of special interest for combined cancer treatment. Drug delivery systems are designed to improve the therapeutic efficacy of conventional “free” drugs, in which free drugs are primarily encapsulated within or attached to lipids or polymers. Examples of problems associated with free drugs include poor drug solubility, unfavorable pharmacokinetics, and poor biodistribution.4 Efficient drug delivery systems allow for precisely controlled pharmacokinetics and preferentially localized delivery to reduce systemic side effects and required dosage.5 Numerous polymer-based delivery systems have been developed to encapsulate therapeutics.6 By selecting appropriate polymers, various properties such as formulation, particle size, permeability, and sustained release may be tuned to suit specific needs. It remains a challenge to address these needs comprehensively, so a versatile strategy is of great interest. One © 2014 American Chemical Society

such option is the layer-by-layer (LbL) approach, which allows one to design both reservoir7 and matrix8 drug delivery systems with great tunability. LbL assembly is a technique for the construction of nanoscale films from the alternate adsorption of complementary polyelectrolytes from aqueous solution.9 LbL core−shell particles have been demonstrated, in which an LbL shell is deposited onto a spherical core, attracting great interest for use as multifunctional therapeutic delivery vehicles.10,11 By removal of the sacrificial particle core, hollow LbL capsules can be obtained.12−14 Therapeutics including small molecule drugs, peptides, proteins, and growth factors can be loaded into capsules and released at a desired rate. The highly versatile LbL assembly technique allows one to engineer the size, shape, permeability, and surface functionality of capsules and shells by simply selecting layer species, core shape,15,16 and assembly conditions, such as ionic strength,17 pH,18,19 and temperature.20−22 For controlled drug release using LbL assemblies, the permeability of the drug through the LbL membrane is critical.23 It is proposed that the diffusion of solute through an LbL assembly occurs through water-filled cavities existing Received: March 21, 2014 Revised: April 30, 2014 Published: May 1, 2014 5903

dx.doi.org/10.1021/la501047m | Langmuir 2014, 30, 5903−5910

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within the membrane.24,25 Any factor which alters the size of these cavities, including polymer chain mobility, the size of the solute in relation to the size of the cavities, and the existence of charged groups on the polymer, will cause a variation in the diffusivity of the solute.26 “Smart” LbL assemblies are one such example, in which external stimuli such as salt,27 pH,28,29 heat,30 and light31 induce changes in permeability.32 For example, Möhwald and co-workers prepared hollow LbL capsules of poly(allylamine)/poly(styrenesulfonate) (PAH/PSS). The permeability of the capsule increased as the salt concentration of the incubating solution increased.27 Tsukruk and co-workers reported the pH-responsive permeability of hydrogen-bonded hollow microcapsules of tannic acid assembled with a range of neutral polymers: poly(N-vinylpyrrolidone) (PVPON), poly(N-vinylcaprolactam) (PVCL), and poly(N-isopropylacrylamide) (PNIPAM).33 Thermoresponsive LbL assemblies are particularly of interest because they offer future opportunities for localized drug delivery.34−36 In the case where the critical response temperature is beyond physiological conditions, a photothermal effect can be leveraged through the inclusion of metallic nanoparticles. Many approaches to thermoresponsive LbL assemblies have centered upon polymers that undergo coil−globular phase transitions. Quinn and Caruso34 assembled hydrogenbonded LbL films of PNIPAM/poly(acrylic acid) (PAA) and found a temperature-dependent dye loading and release behavior. Sukhishvili and co-workers35 incorporated triblock copolymers poly(N,N-dimethylaminoethyl methacrylate)-bpoly(propylene oxide)-b-poly(N,N-dimethylaminoethyl methacrylate) (PD−PPO−PD) into LbL assemblies. Because the dehydration temperature of the central PPO block was strongly dependent on pH, reversible swelling and deswelling triggered by dual pH and temperature response was observed. Very recently, a class of LbL assemblies has been found to exhibit a thermal transition, in which the assembly becomes more viscoelastic upon heating. This transition exhibits features typical of a glass transition but is instead related to the dehydration of ionic groups on the polyelectrolyte (to be reported in a forthcoming publication). At this thermal transition, it is thought that ion pairs break, oppositely charged polyelectrolytes rearrange, and water goes into or out of the film (depending on whether electrostatic or hydrophobic forces dominate the overall film, respectively). The overall affect of the LbL film’s transition is a change in permeability and mechanical properties as well as swelling (or shrinking). Mueller et al.37 reported that PDAC/PSS LbL capsules experienced a thermal transition at 35−40 °C in water, upon which the Young’s modulus decreased significantly. Köhler et al.38 observed an “odd−even” effect in PDAC/PSS LbL capsules, where PSSterminated capsules shrank at 35−40 °C upon heating and PDAC-terminated ones swelled at 55 °C. In our group, Vidyasagar et al.39 found a step increase in viscoelasticity at 49− 56 °C for hydrated PDAC-terminated PDAC/PSS LbL assemblies assembled with salt, coinciding with films’ transition temperature. On the other hand, films assembled without salt are highly ion-paired and do not undergo this transition. Here, we demonstrate a thermoresponsive core−shell drug delivery system consisting of a solid dexamethasone (DXM) core and a PDAC/PSS LbL nanoshell. Dexamethasone, a hydrophobic, synthetic gluococorticoid that suppresses inflammation and autoimmune conditions, is given to cancer patients undergoing chemotherapy40 and has low solubility (140 μg/mL in phosphate buffer solution) (Figure 1). The PDAC/PSS LbL

Figure 1. Chemical structure of DXM.

system is chosen because it represents a “model” pair of strong polyelectrolytes. We examine the effect of temperature, ionic strength of assembly solution, thickness, and outermost layer on DXM release. Motivated by prior work, we were interested in whether the thermal transition could be leveraged to control the release of small molecules. As it will be shown, the permeability of the PDAC/PSS LbL system is indeed responsive to temperature, but its responsiveness is more dramatic for films that do not undergo the aforementioned transition. The implication is that transport through the LbL membrane occurs via water-filled cavities and that such cavities are much larger in LbL films that undergo the thermal transition, hence the smaller degree of temperature responsiveness.

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RESULTS AND DISCUSSION First, we describe the successful assembly of LbL shells onto DXM NPs, and second, we describe the release of DXM. The effect of varying (i) number of layers, (ii) ionic strength of assembly solution, (iii) temperature, and (iv) outermost layer on DXM release was examined. As will be shown, the nature of DXM release is tied to the cavities, voids, and pores existing throughout the LbL film. Assembly of LbL Shells onto DXM NPs. DXM NPs were fabricated using a dual-solvent evaporation technique,55 described in the Supporting Information. Solid spherical DXM particles of an average size of 200 ± 100 nm were formed (Figure 2). Further optimization of emulsification

Figure 2. FE-SEM of bare DXM NPs. 4 nm of palladium/platinum was sputtered on the sample to minimize charging.

speed, surfactant type/concentration, and organic to water volume ratio may be performed to control the particle size distribution.41 The particles’ ζ-potential was −16 mV, which suggests a net negative charge on the DXM particle surface. The encapsulation efficiency (EE) of DXM NPs was calculated as the mass ratio of DXM mass encapsulated and the initial 5904


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DXM mass, eq 1. The encapsulation efficiency determined by eq 1 was 35.3%. EE% =

mass of DXM encapsulated in NPs × 100% mass of DXM initial fed

(1)

Layer-by-layer nanoshells were fabricated by assembling alternating layers of PDAC and PSS onto DXM NPs as described in Figure 3 and the Supporting Information. Because

Figure 5. (a) TEM of (PDAC/PSS)4.5 and (b) (PDAC/PSS)8.5 assembled at 0.5 M NaCl on DXM NPs at a magnification of 100 000.

possible that LbL bridges formed between particles during assembly and broke during sonication, resulting in excess material. Wrinkles in the shell arise possibly from drying. If the excess material is indeed LbL film, then it could affect the release rate. In the case that some of the shell is thicker than the majority, the overall rate of release would be lower than the case of a perfectly, uniformly coated particle. Influence of Number of Layers on DXM Release. Figure 6a,b displays the cumulative DXM release at 37 °C from bare NPs, (PDAC/PSS)4.5 LbL-coated DXM NPs, and (PDAC/PSS)8.5 LbL-coated DXM NPs in which the LbL nanoshells had been assembled in the presence of salt or in the absence of salt. Mt is the mass of DXM released at time t, and M∞ is the total mass of DXM in the original system (i.e., the total mass of DXM release at infinite time). It was observed that bare NPs exhibited a rapid release of 70% in 2 h, whereas encapsulation via LbL assemblies eliminated this burst effect. The rate of release decreased as the number of layers increased for both ionic strengths explored. Within 8 h, 65.3 ± 0.7% of DXM was released from (PDAC/PSS)4.5 LbL-coated DXM NPs assembled without NaCl; increasing the number of layer pairs to 8.5 decreased the cumulative release further to 30 ± 2%. For those LbL nanoshells assembled at 0.5 M NaCl, 93 ± 1% of DXM was released from (PDAC/PSS)4.5 LbL-coated DXM NPs, whereas 63 ± 8% was released from (PDAC/ PSS)8.5 LbL-coated DXM NPs over the course of the experiment. The trends confirm that the rate of DXM release is a function of the thickness of the encapsulating shell.42

Figure 3. A schematic of LbL assembly on DXM NPs.

each layer has its own characteristic elemental composition (PDAC has nitrogen and PSS has sulfur), X-ray photoelectron spectroscopy (XPS) was used to analyze the surface composition of each deposited layer (Figure 4a). The sulfur 2p band at 168 eV was present only when PSS was the outermost layer, confirming the successful deposition of alternating layers. (The peaks at 118 eV represent Al 2s, which arose from the aluminum foil substrate.) The successful LbL coating on DXM NPs was also demonstrated by ζpotential measurements (Figure 4b). A reversal in charge after each adsorbed layer suggested that polyelectrolytes were sequentially deposited. TEM images of DXM NPs coated with 4.5 and 8.5 layer pairs of PDAC/PSS assembled at 0.5 M NaCl are shown in Figure 5, visually demonstrating the existence of the LbL nanoshell on DXM NPs. The core appeared darker than the shell, which may be due to the difference in crystallinity of the materials. DXM NPs are crystalline, while the nanoshell is amorphous. At a magnification of 100 000, the dried nanoshells were clearly observed, having thicknesses of 41 and 72 nm for 4.5 layer pairs and 8.5 layer pairs, respectively. The shell appears to fully coat the DXM NP, and some excess material is also evident; it is

Figure 4. (a) XPS survey scans of DXM NPs sequentially encapsulated with layers of PDAC and PSS, assembled at 0.5 M NaCl. (b) ζ-potential of two layer pairs of PDAC/PSS LbL nanoshells assembled at 0.5 M NaCl on DXM NPs. 5905


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Figure 6. Cumulative DXM release from LbL-coated DXM NPs in which the LbL nanoshell was assembled in the presence of (a) 0.5 M NaCl or (b) in the absence of NaCl. Bare NPs (triangle), (PDAC/PSS)4.5 LbL-coated DXM NPs (circle), and (PDAC/PSS)8.5 LbL-coated DXM NPs (square). Release experiments were carried out in PBS 7.4 at 37 °C.

Similar trends were observed elsewhere with paclitaxel NPs11 and furosemide microcrystals.25 With respect to film thickness, PDAC/PSS LbL films assembled at 0.5 M NaCl grow exponentially, whereas PDAC/PSS films assembled without NaCl grow linearly.39 With equivalent number of layers, PDAC/PSS films assembled at 0.5 M NaCl are much thicker than films assembled without NaCl. However, the trends in Figure 6 have shown that the release was faster from exponentially growing LbL nanoshells, which are thicker. This is attributed to the effect of ionic strength upon the structure of the resulting LbL nanoshell in which films grown in the presence of salt have more water-filled cavities as compared to those grown without salt, discussed next. Influence of Ionic Strength on DXM Release. Figure 6a,b also displays the cumulative DXM release from LbL-coated DXM NPs assembled at 0.5 M NaCl and LbL-coated DXM NPs assembled without NaCl. The rate of DXM release was higher for the case where the LbL nanoshells were assembled in the presence of 0.5 M NaCl, regardless of the number of layer pairs. For 8.5 layer pairs, 63 ± 8% of DXM was released from those assembled at 0.5 M NaCl, while 30 ± 2% was released from those assembled without NaCl over the course of 8 h. A similar trend was observed for 4.5 layer pairs. Such behavior has been reported elsewhere40 and is associated with cavities and voids in the LbL nanoshell. The effect of ionic strength on the growth7 and various properties of LbL assemblies has been widely discussed.43,44 At low ionic strength, strong polyelectrolytes are elongated and adsorb to form thin films; at high ionic strength, they are in a coiled conformation and adsorb with loops and tails, forming relatively thicker films.45 It has been suggested that the high ionic strength during the buildup process favors polymer chain interdiffusion,46 leading to an interpenetrated, loosely packed structure. Recent studies further demonstrated that for strong polyelectrolytes an increase in assembly salt concentration yielded the same free volume size but the free volume concentration increased.47 Hence, we postulate that the results observed in Figure 6 are likely attributed to the variation of free volume concentration, from many cavities at high ionic strength to fewer cavities at low ionic strength. Many have studied the nature of pores and cavities in LbL assemblies. Chavez and Schönhoff estimated the porosity of PAH/PSS LbL shells using NMR cryoporometry and found that the pore size was ∼1 nm.48 Quinn et al. made use of

positron annihilation spectroscopy (PAS) to measure the angstrom-scale free volume.47 They found that depending on the number of layer pairs and the assembly conditions selected, the free volume cavity diameter could be tuned from 0.4 to 0.6 nm, and the total free volume concentrations varied from 1.1 × 1020 to 4.3 × 1020 cm−3.47 Elsewhere, Köhler et al.49 estimated an apparent mesh size of 13 nm for PSS-terminated PDAC/ PSS LbL microcapsules by encapsulating fluorescent dextran of varying molecular weights and by quantifying the entrapped amount after release. Influence of Temperature on DXM Release. The release profiles of bare DXM NPs in PBS at 37 and 60 °C are shown in Figure 7a. The dissolution rate was enhanced at 60 °C, as 78 ± 2% of DXM was released in 1 h, as opposed to only 41 ± 4% of DXM at 37 °C. This could be due to an increase in DXM solubility50 or diffusion coefficient upon heating. According to the Noyes−Whitney equation,51 an increase in saturation solubility or diffusion coefficient increases drug dissolution rate. The preceding comparisons have demonstrated that LbL nanoshells reduce the rate of drug release from DXM NPs at a constant temperature. Accordingly, temperature was varied to probe its effect upon the release of DXM from (PDAC/PSS)4.5 and (PDAC/PSS)8.5 LbL-coated DXM NPs assembled at 0.5 M NaCl or without salt. The temperatures investigated were selected so as to explore cases above and below the transition temperature of the 0.5 M NaCl-assembled LbL film (51 °C) (Figure 7b,c). Results were compared to assemblies made without salt, which yield dense, highly ion-paired films that do not have a detectable thermal transition (Figure 7d,e). Generally, the release rate increased as temperature increased for all systems. However, the change in release rate with respect to temperature was more extreme for LbL-coated DXM NPs assembled without NaCl. Within 8 h, the cumulative DXM release from (PDAC/PSS)8.5 LbL-coated DXM NPs assembled without NaCl increased by ∼40%, whereas it increased by only 23% for (PDAC/PSS)8.5 LbL-coated DXM NPs assembled with 0.5 M NaCl when temperature increased from 37 to 60 °C. The observation that PDAC/PSS LbL films assembled without salt are more responsive to changes in temperature can be explained by considering diffusion as it relates to free volume within the LbL nanoshell. In diffusion-controlled drug release, the diffusion of DXM occurs through water-filled cavities and is associated with a dynamic activation process. Considering Cohen and Turnbull free volume theory,52 the diffusing molecules, either DXM or water, reside temporarily in 5906


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On the other hand, for the case of PDAC/PSS LbL films assembled with 0.5 M NaCl, the chain configuration consists of more loops and trains and there is a higher concentration of free volume cavities.47 Upon heating, the film under goes a thermal transition, ion pairs are possibly broken and re-formed, and both the size and concentration of cavities are likely to increase. The relative increase in the DXM release rate was lower, which suggests that the LbL film rearranged in such a way so as to either reduce the concentration or sizes of the free volume cavities. The net effect, however, was that the PDAC/ PSS LbL film released DXM still had a higher finite release rate at 60 °C. The coexistence of open and closed pores and pore network morphology may also be considered as factors.54 Odd−Even Effect. Several groups have reported an “odd− even” effect for PDAC/PSS LbL capsules that had been assembled in the presence of salt.34,55,56 PSS-terminated capsules shrink upon heating, whereas PDAC-terminated capsules swell. Similarly, such behavior might influence DXM release for the present study. The preceding core−shell particles were terminated with PDAC, so it is of interest to compare the results to particles terminated with PSS. Figure 7f shows the release of DXM from (PDAC/PSS)4 LbL-coated DXM NPs assembled at 0.5 M NaCl, in which PSS is the outermost layer. In comparison to a similar system in which PDAC is the outermost layer (Figure 7b), the contrast in release with respect to temperature is much larger for the PSSterminated particle. At 37 °C, the release of DXM is slower from PSS-terminated LbL DXM NPs, as compared to PDACterminated LbL DXM NPs. The contrast in release with respect to outermost layer is significant, especially when considering that the PDAC-terminated nanoshell (4.5 layer pairs) is thicker than the PSS-terminated nanoshell (4 layer pairs). The origin of the odd−even effect arises from a competition between hydrophobic and electrostatic forces. Köhler and coworkers38,55 demonstrated that PSS-terminated capsules shrank upon heating tends because of dominating hydrophobic interaction; on the other hand, PDAC-terminated capsules swelled because of dominating electrostatic interactions. In turn, the mechanical properties of the nanoshell reflect the outermost layer, where PSS-terminated LbL films become more rigid and the hydrated mass decreases upon heating; in contrast, PDAC-terminated LbL films become more viscoelastic and the hydrated mass increases.39 Modeling of Release Kinetics. To understand the kinetics of release through the LbL membrane, the Korsmeyer−Peppas model57 (Mt/M∞ = ktn), which is a semiempirical relation describing the general solute release behavior of controlled release systems was applied. Mt/M∞ is the fractional drug release, t is the release time, k is a constant incorporating the coupling of solute diffusion and matrix relaxation phenomena, and n is the diffusional exponent, indicating the release mechanism. For release from a swellable sphere, solute release kinetics is dependent on drug diffusion and polymer relaxation. If the polymer swelling front advances faster than drug diffusion, Fickian diffusion kinetics are expected and n = 0.43. If drug diffusion is much faster than the swelling front, zeroorder kinetics is expected and n = 0.85.58 In other words, higher n indicates that the release is controlled more by viscoelastic relaxation of the matrix, whereas lower n indicates that release is controlled more by pure Fickian diffusion. Many release behaviors fall between these limiting cases, where 0.43 < n < 0.85.53 Because the model is valid for the first 60% of the normalized drug release, we were able to fit the release profiles

Figure 7. Cumulative DXM release at 37 °C (square) and 60 °C (circle). (a) Bare NPs, (b) (PDAC/PSS)4.5 LbL-coated DXM NPs assembled at 0.5 M NaCl, (c) (PDAC/PSS)8.5 LbL-coated DXM NPs assembled at 0.5 M NaCl, (d) (PDAC/PSS)4.5 LbL-coated DXM NPs assembled without NaCl, (e) (PDAC/PSS)8.5 LbL-coated DXM NPs assembled without NaCl, and (f) (PDAC/PSS)4 LbL-coated DXM NPs assembled at 0.5 M NaCl. Release experiments were carried out in PBS 7.4.

a cavity, and diffusion occurs when the solutes overcome a certain energy barrier and jump into the next cavity or when two cavities meet each other and the solutes diffuse through one cavity to another.53 The diffusion coefficient may be related to an average jump distance, the thermal velocity of the solute, and the probability that there is a cavity adjacent to the solute. At a given temperature, the rate of diffusion is determined by the probability of finding a sufficient free volume cavity for a solute molecule to pass through.26 Both PDAC/PSS LbL films assembled with or without salt bear cavities of similar size (measured at room temperature); therefore, diffusion is more likely controlled by the relative concentration of these free volume cavities.47 PDAC/PSS LbL nanoshells assembled at 0.5 M NaCl perhaps have a higher concentration of free volume cavities, leading to accelerated release of DXM relative to films assembled without salt (Figure 6a,b at 37 °C). As the temperature increased from 37 to 60 °C, the relative rate of DXM release increased far more for PDAC/PSS LbL nanoshells assembled without salt as compared to assembled with 0.5 M NaCl. This observation suggests the possibility that there is a significant change in the size and/or concentration of free volume cavities within the LbL nanoshell. Assembled without salt, the LbL shell is highly ion paired and dense; upon heating, the film swells slightly.39 Assuming that the number of ion pairs does not change, then it can be concluded that swelling leads to larger cavities, thus accelerating DXM release. 5907


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Table 1. Korsmeyer−Peppas Model Fitting and Possible Mechanism of Diffusional Release from Swellable Controlled Release Systems sample

diffusional exponent, n

(PDAC/PSS)4.5 assembled without NaCl, 37 °C (PDAC/PSS)8.5 assembled without NaCl, 37 °C (PDAC/PSS)8.5 assembled at 0.5 M NaCl, 37 °C (PDAC/PSS)8.5 assembled without NaCl, 60 °C (PDAC/PSS)8.5 assembled at 0.5 M NaCl, 60 °C (PDAC/PSS)4 assembled at 0.5 M NaCl, 37 °C

0.43 0.43 < n < 0.85 0.85 0.58 ± 0.05 0.53 ± 0.02 0.57 ± 0.02 0.6 ± 0.1 0.39 ± 0.03 0.39 ± 0.04

spherical sample

kinetic constant, k/h−n

0.22 0.098 0.194 0.22 0.400 0.32

± ± ± ± ± ±

0.02 0.003 0.005 0.04 0.001 0.02

R2

release mechanism

Figure

0.99 0.99 0.99 0.94 0.99 0.96

Fickian diffusion non-Fickian transport case II transport non-Fickian diffusion non-Fickian diffusion non-Fickian diffusion non-Fickian diffusion Fickian diffusion Fickian diffusion

Figure 6b Figures 6b, 7e Figure 7c Figure 7e Figure 7c Figure 7f

including size and concentration, within exponentially growing LbL shells and linearly growing LbL shells at this present temperature window in future work.

for some, but not all, of the LbL-coated DXM nanoparticle systems investigated (Table 1). The Korsmeyer−Peppas model fits the experimental data well with R2 > 0.94, enabling a further understanding of possible release mechanisms. Fickian transport is observed for (PDAC/PSS)8.5 LbL-coated DXM NPs assembled at 0.5 M NaCl at 60 °C and (PDAC/PSS)4 LbLcoated DXM NPs assembled at 0.5 M NaCl at 37 °C. All other cases exhibit non-Fickian transport. We next examined the influence of various parameters on the kinetic constant k in the power law. In the case of Fickian diffusion, k has a specific physical significance, k = 6(D/πa2)1/2, where D is the diffusion coefficient and a denotes the radius of a sphere.53 A decrease in k indicates either an increase in a or a decrease in D. For example, as the number of layers increased, the film’s inner structure remained the same but thickness increased, resulting in an increase in a and decrease in k (Table 1). The interpretation of k is more complex for the case of ionic strength. For a given number of layer pairs, PDAC/PSS LbL nanoshells assembled without NaCl are much thinner compared to those assembled at 0.5 M NaCl; therefore, a should increase and k should decrease with ionic strength, but this trend is contrary to observation. Therefore, the increase in k with respect to ionic strength is likely tied to an increase in D as ionic strength increases. With regard to changes in temperature, k doubled as temperature increased from 37 to 60 °C for both (PDAC/ PSS)8.5 LbL-coated DXM NPs assembled at 0.5 M NaCl and without NaCl. Interestingly, temperature has a significant effect upon the diffusional exponent n for the 0.5 M NaCl system. Upon heating from 37 to 60 °C, n decreases from 0.57 ± 0.02 to 0.39 ± 0.03. This significant shift from non-Fickian to Fickian diffusion suggests that the internal structure of the nanoshell changed with response to temperature. This observation is supported by the fact that this system is known to undergo a thermal transition at 51 °C, above which polymer relaxation outpaces drug diffusion, leading to Fickian transport. We postulate that the mechanism responsible for the differences in DXM release from LbL NPs assembled at different conditions may be associated with the properties of free volume cavities within the LbL nanoshell more than the mobility of polymer chains because the influence of thermal transition was not as pronounced. It has been demonstrated for LbL assemblies consisting of strong polyelectrolytes the number of layers does not change the free volume size.47 Therefore, the ionic strength and temperature must play a larger role in the nature of the free volume cavities. Thus, it will be interesting to examine the properties of free volume cavities,

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CONCLUSIONS A thermoresponsive core−shell NP-based drug delivery system was developed using PDAC/PSS LbL assemblies as the shell and DXM as the core. The influence of various parameters on DXM release from the core−shell NPs, such as number of layers, ionic strength of the adsorption solution, temperature, and outermost layer, has been investigated. The system exhibiting the greatest degree of thermoresponsiveness was (PDAC/PSS)8.5 assembled without salt, which does not exhibit a thermal transition. These results were explained in the context of the Korsmeyer−Peppas model, in which both non-Fickian and Fickian diffusion transport modes were observed, depending on the system’s parameters. A clear shift from non-Fickian to Fickian diffusion was observed upon heating for the LbL system bearing a thermal transition. Diffusion and release rate were attributed to the variation in the size and concentration of free volume cavities existing in the LbL nanoshell, suggesting a possible approach to control the thermoresponsive release of DXM. This thermoresponsive NP-based drug delivery system with tunable permeability may possibly realize an “on” or “off” drug release mechanism in response to temperature, thus providing an alternative approach to delivering therapeutics with reduced toxic effects. Future work will investigate similar LbL systems utilizing natural polymers, which are more favorable for biocompatibility. It will also be important to incorporate metallic nanoparticles so as to leverage photothermal effects for localized release.

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ASSOCIATED CONTENT

S Supporting Information *

Materials and methods. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail [email protected] (J.L.L.). *E-mail [email protected] (M.V.P.). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors gratefully acknowledge the National Center for Therapeutics Manufacturing, Materials Characterization Facility, and Microscopy & Imaging Center for use of HPLC, 5908


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SEM, XPS, and TEM. We thank Minchi-Hsieh, Choonghyun Sung, and Xiayun Huang for their valuable discussions. This material is based upon work supported by National Science Foundation under Grant No. 1049706.

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