Hybrid PLGA-Organosilica Nanoparticles with Redox-Sensitive

Jun 7, 2013 - ABSTRACT: A novel type of hybrid material based on a PLGA .... bAs-determined by TEM by measuring at least 200 particles: range (mean ...
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Hybrid PLGA-Organosilica Nanoparticles with Redox-Sensitive Molecular Gates Manuel Quesada, Carlos Muniesa, and Pablo Botella* Instituto de Tecnología Química (UPV-CSIC), Av. Los Naranjos s/n, 46022 Valencia, Spain S Supporting Information *

ABSTRACT: A novel type of hybrid material based on a PLGA nanoparticle core and a redox-responsive amorphous organosilica shell have been successfully synthesized. The outer layer is obtained by self-assembly of silicate ions with a silsesquioxane containing a disulfide bridge. These organic linkers work as molecular gates that can be selectively cleaved by reducing agents. This system is particularly suitable for storage and release of hydrophobic molecules, as the treatment with dithiothreitol leaves open doors that allow for the discharge of encapsulated molecules in the organic matrix. Using pyrene as a probe molecule, it has been shown that after partial disruption of the organic−inorganic coating, the release mechanism from PLGA particles fits pretty well into Higuchi’s model, corresponding to a diffusion-mediated process. These nanohybrids impose a better control and slower release of encapsulated molecules than bare PLGA nanoparticles, are reasonably stable in a physiological medium, and show great potential as stimuli-responsive vehicles for drug delivery. KEYWORDS: hybrid nanoparticles, core−shell, redox-responsive, PLGA-silica, controlled release

1. INTRODUCTION As knowledge on the pharmacological behavior of drug delivery nanoplatforms increases rapidly, more sophisticated devices are needed to comply with the new requirements generated.1−3 Due to this necessary continuous feedback, to date, there are only a few clinically approved nanoparticle-based therapeutic carriers.4 One of the most successful is based on biodegradable polymeric nanoparticles, in particular those based on poly(lactic-co-glycolic acid) (PLGA).5 Approved by the Food and Drug Administration, its hydrolysis leads to metabolites with minimal systemic toxicity and allows for long-term drug release. However, although variations on the hydrophobicity of the polymer chain show some control on the drug release rate, in most cases they all suffer from burst release.6 It is the accumulation of the drug on the surface of the particle that causes the premature release of more than 20−30% of the cargo, leading to increased toxicity and decreased therapeutic activity.7 Therefore, it is compulsory to implement accurate control over the release behavior of PLGA nanoparticles. In this sense, surface modification with organic coatings8−12 or with inorganic shells has been tried.13−16 However, most of these systems suffer from unspecific release, as drug discharge does © XXXX American Chemical Society

not respond to any specific stimulus. Therefore, drug delivery strategy must be focused on stimuli-responsive systems that promote controlled release of their payload under intracellular mechanisms.17−20 At this stage, redox-responsive, disulfidebased systems are some of the most effective biologically cleavable linkers as they benefit from the intra-/extracellular redox gradient, delivering the cargo upon entering the cell.21,22 This selectivity is not found either on the widely used acidlabile linkers, as low pHs can be encountered in the vicinity of tumors, or on enzyme-sensitive linking models, which are prone to be cleaved at the circulatory system.17,23 Herein, we present a novel hybrid material based in spherical PLGA nanoparticles containing hydrophobic molecules which have been covered by a thin layer (6−10 nm) of a redoxresponsive amorphous organosilica shell. We illustrate this concept by the self-assembly of tetraethyl orthosilicate and a silsesquioxane containing a disulfide bridge. As a consequence, the outer layer incorporates a number of disulfide bonds working as chemical doors that can be selectively cleaved by Received: March 1, 2013 Revised: May 20, 2013

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Scheme 1. Synthesis Layout of Pyrene-Loaded PLGA-Organosilica Nanoparticles with Redox-Responsive Disulfide Molecular Gates

Table 1. Compositional and Structural Characteristics of As-Synthesized Materials sample

TESPDS/TEOS (M)a

PSN POSN-1 POSN-2 POSN-3

0 0.10 0.20 0.66

diameter (nm)b

S (wt %)c

SiO2 (wt %)d

SiT/SiQ (at)e

YTESPDS (mol %)

± ± ± ±

0 0.471 0.582 0.883

21.16 15.22 12.51 12.41

0 0.062 0.096 0.154

0 31 24 12

98.3 99.7 71.2 73.3

31.8 64.5 31.1 17.0

a Molar ratio in synthesis gel. bAs-determined by TEM by measuring at least 200 particles: range (mean ± SD). cAs determined by elemental analysis. dAs determined by TGA measurements. eAtomic ratio between the silicon provided by TESPDS (SiT) and that coming from TEOS (SiQ).

9600g for 10 min and washed twice with miliQ water to remove the excess CTAB. Preparation of PLGA-Organosilica Nanoparticles (POSN). PLGA nanoparticles covered with a thin layer of a redox-responsive amorphous organosilica shell containing intercalated disulfides bridges (POSN) were prepared by the self-assembly of tetraethyl orthosilicate (TEOS) and bis[3-(triethoxysilyl)-propyl]disulfide (TESPDS) in the presence of PLGA@CTAB particles. For this purpose, as-made, pyrene-loaded PLGA@CTAB spheres were resuspended in 100 mL of an isopropanol/water mixture (iPrOH/H2O = 1:9, v/v). Then, TEOS, TESPDS, and NH4OH (0.52 M) were added with vigorous stirring in order to grow the organosilica wall. Typically, the molar composition of the initial gel was 1:0.20:0.15:58:2232 SiO2/TESPDS/NH4OH/ iPrOH/H2O. The density of disulfide gates along the inorganic coating was controlled by changing the molar ratio of TESPDS/TEOS in the range 0.05−0.66. The solution was left stirring for 96 h. Particles were recovered by centrifugation (9600g, 30 min), washed with H2O and ethanol (EtOH), and freeze-dried. POSNs of a diameter ranging 35− 165 nm were obtained. Depending on the molar ratio between TESPDS and TEOS used, three different POSN materials were prepared (see also Table 1): POSN-1 (TESPDS = 0.10 M), POSN-2 (0.20 M), and POSN-3 (0.66 M). Preparation of PLGA-Silica Nanoparticles (PSN). For the sake of comparison, PLGA nanoparticles covered with a thin layer of an amorphous silica coating (PSN) were prepared by polymerization of TEOS over PLGA@CTAB particles. Here, as-made, pyrene-loaded PLGA@CTAB spheres were resuspended in 100 mL of deionized water, and TEOS and NH4OH (0.52 M) were then added. The molar composition of the initial gel was 1:0.15:2232 SiO2/NH4OH/H2O. The reaction was left stirring for 48 h. Particles were recovered by centrifugation (9600g, 30 min), washed with H2O and EtOH, and freeze-dried. Materials Characterization. Carbon and sulfur contents in assynthesized POSN samples were measured by elemental and thermogravimetric analysis, respectively, in a FISONS, EA 1108 CHNS-O apparatus and a NEST instrument.

reducing compounds, as those found on entrance to the cell, leading to disassembly of the silica wall. In this core−shell architecture, the cover seals the particle, allowing no encapsulated molecule to be released before reduction of the disulfide bridges, and subsequently, the PLGA matrix controls the release rate through diffusion. The coating also adds to the nanohybrid characteristics of silica based materials such as chemical inertness, postmodification, easy regulation of the coating process, transparency, porosity, and biocompatibility.24 As a proof of principle, we have primarily focused on testing the feasibility of this novel PLGA-organosilica nanohybrid as a bioresponsive drug delivery system using a simple in vitro release study with pyrene as probe molecule.

2. EXPERIMENTAL SECTION PLGA PURASORB 5004 (lactide/glycolide = 53:47, Mw ∼ 20 000) was provided by Purac. Other reagents were purchased from Aldrich except HPLC solvents (HPLC grade from Scharlab). In brief, nanoparticles were synthesized in a two step process (Scheme 1). Initially, PLGA nanoparticles protected with a cationic shield of cetyltrimethylammonium bromide (CTAB) were prepared by a modified oil-in-water (o/w) emulsion procedure.25 Afterward, the resulting nanoparticles were covered with an amorphous organosilica layer through a sol−gel process under mild alkaline conditions, at room temperature. Preparation of CTAB-Coated PLGA Nanoparticles (PLGA@ CTAB). A total of 2 g of CTAB (5.49 mmol) was dissolved in 75 mL of miliQ water. A total of 250 mg of PLGA was separately dissolved in 25 mL of CHCl3. A total of 15 mg of pyrene was then incorporated into the organic solution, which was then added drop by drop to the aqueous solution using a perfusion pump while vigorously stirring. Once added, the emulsion was sonicated (Branson, 70 W output power) in an ice bath at 5 min intervals with 30 s breaks for a total of 20 min. The emulsion was immediately rotaevaporated until most of the chloroform was eliminated. The particles were centrifuged at B

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Nanoparticles’ morphology and size were studied by transmission electron microscopy (TEM) in a JEOL JEM 2100F microscope operating at 200 kV. Samples were dispersed in methylchloride and transferred to carbon coated copper grids. Moreover, field-emission scanning electron microscopy (FESEM) micrographs were collected in a ZEISS Ultra 55 microscope operating at 2 kV, with a 2 × 10−9 A beam current and 2.5 mm as the working distance. Z-potential measurements were conducted in a Zetasizer Nano ZS (Malvern Instruments Ltd., Worcestershire, U. K.). Dried materials were resuspended in deionized water at a concentration of 5 μg/mL, and measurements were performed at 25 °C. Magic angle spinning−nuclear magnetic resonance (MAS NMR) spectra were recorded at room temperature on a Bruker AV400 spectrometer, with a 7 mm Bruker BL-7 probe at a sample spinning rate of 5 kHz. The single pulse 29Si spectra were acquired using pulses of 3.5 μs corresponding to a flip angle of 3π/4 rad and a recycle delay of 240 s and referred to tetramethylsilane (TMS). The 1H to 13C cross-polarization spectra were acquired by using a 90 pulse for 1H of 5 μs, a contact time of 5 ms, and a recycle of 3 s and referred to adamantine. Infrared spectra were recorded at room temperature in the 300− 3900 cm−1 region with a Nicolet 205xB spectrophotometer, equipped with a Data Station, at a spectral resolution of 1 cm−1 and accumulations of 128 scans. Finally, the silsesquioxane incorporation to the silica framework in the as-synthesized materials was calculated from S-elemental analysis (FISONS, EA 1108 CHNS-O) and thermogravimetric (TGA) measurements of the silica content (Mettler-Toledo TGA/ SDTA851e). Redox-Responsive Release of Pyrene. A total of 0.5 mg of the hybrid PLGA@organosilica material weighted in a microgram scale for each data point was suspended in 0.5 mL of PBS and placed in a SlideA-Lyzer Mini Dialysis Device (10 K molecular weight cutoff). Each microtube was dialyzed to 14 mL of PBS at 37 °C while gently shaking. Then, dithiotreitol (DTT) was added after 2 h up to 100 mM. At the corresponding time, the suspension was diluted with 0.5 mL of acetonitrile (ACN) and ultrasonicated for 30 min to ensure all the particles were dissolved and the remaining pyrene was totally released. Pyrene concentration was determined by reverse-phase high performance liquid chromatography (RP-HPLC, see the Supporting Information). Control experiments were done with PLGA@CTAB and PSN materials following the same procedure, but in the absence of DTT. Initial pyrene loading in the materials was calculated by ultrasonication (30 min) in ACN of a nondialyzed sample. Triplicate samples were run for every experiment.

The study by electronic microscopy reveals monodispersed nanoparticles with an average diameter in the range of 35−165 nm and a continuous organosilica corona 6−10-nm-thick (Figure 1 and Table 1). Such a particle size is very suitable for

Figure 1. Electronic microscopy images of hybrid PLGA@organosilica nanoparticles: (a, b) TEM images of as-synthesized POSN-2 material. The inset in a shows the amorphous nature of the organic−inorganic coating. Red arrow in b shows a collapsed bigger nanoparticle. (c) FESEM image of as synthesized POSN-2 material. Red arrows indicate some bigger nanoparticles. (d) TEM image of POSN-2 nanoparticles after pyrene release.

biological applications, such as drug and gene delivery. In all cases, samples were highly homogeneous, presenting less than 5% of considerably bigger particles that tend to collapse (red arrows in Figure 1b,c). The size of the particles is strictly dependent on the initial o/ w emulsion step, as the shell formation process does not seem to considerably affect the diameter of the core. In this respect, it is the dimension of the forming droplets and their stability in solution that determines the final polymer particle size.26 In the experimental procedure presented herein, the application of ultrasound homogeneously reduces the size of the droplets, while the surfactant avoids coalescence.6,26 The CTAB templates the silica that forms a clear shell around the particles. Furthermore, it is noticeable that after exposure to reducing agents this outer shell breaks partially, as the erosion caused by disulfide bridges cleavage leads to severe destabilization, and particles collapse (Figure 1d). FTIR was used to confirm the presence of both PLGA and silica in the nanoparticles. The FTIR spectrum of PLGA nanoparticles (Figure 2) shows intense absorbance peaks at 737 and 1394 cm−1, corresponding to δ(CH), 1095 and 1185 cm−1 assigned to ν(C−O), and a very strong peak at 1750 cm−1 due to the stretching vibration of CO (ester). Also, the bands at 2953 and 2996 cm−1 correspond to the ν(C−H) of CH3, and a small band at 2927 is due to the ν(C−H) of methylene groups. A broad signal at 3550 cm−1 illustrates the stretching vibration of OH terminal groups.27,28 After endowing the particles with the organosilica coating, new peaks appear at 458 and 955 cm−1 corresponding, respectively, to νas(Si−O−Si) and ν(Si−O), and a broad band centered at 3430 cm−1 is due to OH stretching vibrations of Si−OH species and molecular water.29

3. RESULTS AND DISCUSSION PLGA nanoparticles dispersed in an aqueous medium show negative charge (ζ = −29.2 ± 7.3 mV), due to ionization of terminal carboxylic groups. However, the covering with CTAB leaves the cationic surfactant ammonium groups facing outside to change the zeta potential to a positive value (ζ = 31.3 ± 9.2 mV). This surface charge provides colloidal stability and is crucial for the posterior silica shell formation, promoting the attraction of the silicate oligomers that condense on the particle surface. The obtained POSN material presents a typical core− shell outline, with an organic core made of PLGA@CTAB and an organic−inorganic shell built with amorphous silica which intercalates a number of disulfide bridges within the framework (Scheme 1). Zeta potential determination confirmed stable colloids in aqueous medium with a negative charge on the surface due to partially ionized silanol groups (see Figure S1 in the Supporting Information). X-ray diffractograms (not shown) indicate that the hybrids PSN and POSN are amorphous. C

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that the organic fragment remains intact as in the initial TESPDS reagent. The assignment of the other carbon atoms from starting silsesquioxane is not possible as their signals overlap with those of PLGA. 29 Si MAS NMR spectroscopy is able to confirm that the organic−inorganic precursor is covalently bonded to silica units in the external shell. Figure 4 indicates a moderate silica

Figure 2. Representative FTIR spectra of as-synthesized materials: (a) PLGA@CTAB and (b) POSN-2.

One important target in the development of the amorphous organosilica coating is to monitor the co-condensation process between the silicon alkoxide and the silsesquioxane, controlling their rates of hydrolysis. The excessive polymerization degree of the silanols groups and/or a very low incorporation of the disulfide reagent would lead to a very dense wall that strongly hinders the diffusion of reducing agents and, as a consequence, spoils its redox-sensitive properties. First, the assembly of the silsesquioxane to the outer corona in the different materials has been determined by S-elemental analysis and TGA measurements. Table 1 and Figure 3 show the variation in the final

Figure 4. 29Si MAS NMR spectra of as-synthesized POSN-2 material.

condensation level in the POSN-2 material, which is consistent with the mildly alkaline medium (pH 8−9) set in the synthesis. In this sense, the deconvolution of NMR signals leads to 8% of Q2 ((SiO)2Si(OH)2 at −92.8 ppm), 25% of Q3 ((SiO)3Si(OH) at −101.5 ppm), and 59% of Q4 ((SiO)4Si at −110.3 ppm), and the calculated (Q3 + 2Q2)/(Q2 + Q3 + Q4) ratio, which gives the total concentration of silanol groups at the surface, is 0.44, clearly higher than that found for calcined silica materials.30,31 Furthermore, at −57.9 and −66.5 ppm, two additional resonances are observed that can be assigned to the presence of (CH2)3Si(OSi)2OH (T2, 2%) and (CH2)3Si(OSi)3 (T3, 6%). The presence of Tn bands suggests the correct incorporation of the silsesquioxane in the silica network through covalent linkages. Of special interest is the amount of TESPDS integrated in the outer shell, as it determines the density of disulfide gates and, thus, the responsive property of the hybrid nanoparticle to an external reducing stimulus. This can be done by calculation of the intensity ratio (T2 + T3)/(Q2 + Q3 + Q4).30,31 The obtained value (0.087) is consistent with the SiT/ SiQ atomic ratio achieved by elemental analysis results (0.096, Table 1). In addition, the absence of a band at −45 ppm, characteristic of the free disilane, confirms the complete integration of the disulfide containing reagent within the silica framework. Besides the number of redox-sensitive chemical doors present in the coating, the release kinetics of transported molecules from the PLGA core depends strongly on the condensation degree between the lactide and glycolide units of the polymer.32 Here, the lactide/glycolide (L/G) composition has been determined by 1H NMR, obtaining a ratio of 53:47% (see Figure S4 at the Supporting Information).33 However, as the copolymerization between TEOS and TESDPS is catalyzed by ammonium hydroxide, some ammonolysis of the PLGA chain can happen, inducing partial degradation of the polymer due to the cleavage of ester bonds.34 Such PLGA degradation is reflected as an increase in the L/G ratio due to the higher hydrolytic reactivity of the glycolide ester linkage.32 In our case, a slight rise of the L/G ratio up to 59:41% is observed, indicating that the polymer degradation occurs through a chain

Figure 3. Influence of the initial TESPDS/TEOS molar ratio on the silsesquioxane incorporation to the organic−inorganic coating (SiT/ SiQ atomic ratio, □) and the silica content (●) in the as-synthesized materials.

samples of the atomic ratio between the silicon provided by TESPDS (SiT) and the silicon coming from TEOS (SiQ), and Figure S2 (see Supporting Information) presents the TGA reports. It is noticeable that the efficiency of silsesquioxane inclusion decreases for high TESPDS/TEOS ratios in the starting gel, which is due to the low solubility of this reagent in an aqueous medium. In any case, we have been able to introduce the silsesquioxane molecule in the shell up to a SiT/ SiQ atomic ratio of 0.154, which means that there is one disulfide bridge located within the silica framework for every 13 silicate ions (sample POSN-3). In addition, the TGA determinations in these materials display a significant decrease of the inorganic (silica) loading when increasing the TESPDS/ TEOS ratio (Table 1 and Figure 3). To asses that the silsesquioxane molecule is stable during the synthesis, 13C CP-MAS NMR was measured. The spectrum of POSN-2 material is shown in Figure S3 (see at the Supporting Information). The peaks assigned to carbons directly linked to the disulfide bridges are clearly displayed at 41 ppm, confirming D

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scission manner.33,35 This does not seem enough to affect the release kinetics of the encapsulated molecules after disruption of the organosilica wall, as it will be shown below. In this work, as proof of principle, we have incorporated a hydrophobic molecule, pyrene, within the PLGA core. After the self-assembly of silica and the silsesquioxane, the amount of pyrene loaded in the organic matrix reaches 0.8−1 wt %. Then, in order to check the redox-responsive character of these organic−inorganic composites, we have carried out a release experiment of the POSN-2 sample in PBS solution containing DTT (100 mM), monitoring the pyrene concentration by HPLC-FL analysis. Pyrene loaded PLGA@CTAB particles and PSN-1 material (with no disulfide gates in the silica coating) were used as controls. The process is tentatively depicted in Scheme 2.

the pores created in the organic−inorganic wall. Then, POSN-2 exhibits a sustained release of pyrene that achieves about 80% after one week. The case of the PSN sample, with a pure silica external coating, is very different. Here, the thin inorganic layer suffers a slow degradation in PBS,36 and after 24 h the carried molecule slowly diffuses outside the hybrid structure. Both PSN and POSN-2 materials show the collapse of most nanoparticles after release experiments, due to degradation of the organic− inorganic coating (Figure 1d). As regards the biological applications of these materials, and especially in hydrophobic drug delivery by systemic administration, the silica sealed structure with intercalated disulfide molecular bridges is not a definitive locking system, but it is able to keep safe the therapeutic charge with enough time before reaching the target cells. Similar approaches of PLGA core−shell systems have been developed with organic8−12 or inorganic13−16 coatings, with significant improvement in the controlled release of the transported molecule. Nevertheless, the main benefit of our model is that it is potentially sensitive to intracellular redox mechanisms, as those mediated by protein reductases37 or glutathione.38 The release mechanism of pyrene for PLGA@CTAB particles fits pretty well into Higuchi’s square root model (Table 2),39 which means that release is mainly mediated

Scheme 2. Schematic Representation of the Release Mechanism in Pyrene-Loaded PLGA-Organosilica Hybrid Nanoparticles

Table 2. Kinetic Parameters of Higuchi’s Model for the Pyrene Release in PLGA and Hybrid Nanoparticles

Figure 5 shows the importance of the presence of the redoxsensitive chemical doors in the shell of the nanoparticles.

sample

pyrene (wt %)

k (h1/2)a

rb

PLGA@CTAB PSN POSN-2

1.0 0.8 0.8

7.25 ± 0.01 4.80 ± 0.26 6.44 ± 0.25

0.9773 0.9859 0.9863

Higuchi’s release constant (mean value ± SD). coefficient. a

b

Regression

through the diffusion process, with very little contribution from degradation. This is surprising for a low molecular weight PLGA that usually presents a zero order pattern with degradation playing a dominating role and controlling the release rate.40 However, the presence of a protecting shield made of a cationic lipid monolayer can be enough to protect the PLGA nanoparticles for rapid degradation in an aqueous medium.8 Similar behavior is observed in the organosilicaprotected composites after disruption of the outer coating, although values of the kinetic constant k are lower in these materials (Table 2). Such differences in the release behavior are related to strongly hindered diffusion of the aqueous phase into the organic matrix through the partially degraded hybrid wall, imposing a better control and slower release of the molecule transported in the PLGA core.

Figure 5. Cumulative release profiles of pyrene-containing materials in PBS at 37 °C. In the case of POSN-2 material, DTT (100 mM) was added at t = 2 h. Dashed vertical line at 6 h and the inset show a rough estimation of the release initial stage (see text). Initial pyrene loading is in the range 0.8−1 wt % in all cases. Results are presented as mean ± SD.

4. CONCLUSION Novel hybrid materials based in a PLGA nanoparticle core containing hydrophobic molecules, such as pyrene, and a redoxresponsive amorphous organosilica shell have been successfully synthesized. The outer layer incorporates a number of disulfide bridges working as molecular gates that can be selectively cleaved by reducing compounds, allowing the discharge of stored molecules in the organic matrix. Then, the release mechanism of pyrene from PLGA particles fits pretty well into Higuchi’s model, corresponding to a diffusion-mediated process, with very little contribution from degradation. These

Nonprotected PLGA discharges the probe molecule from the beginning, with a burst initial phenomenon of about 35% of the loaded pyrene, and completes its release in 4 days. In the case of the POSN-2 material, no pyrene release occurs before DTT addition (t = 2 h). After this point, release has some delay (about half a hour), as the degradation of the organosilica shell needs disulfide bridges reduction and water diffusion through E

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(17) Gao, W.; Chan, J. M.; Farokhzad, O. C. Mol. Pharmaceutics 2010, 7, 1913. (18) Strong, L. E.; West, J. L. WIREs Nanomed. Nanobiotechnol. 2011, 3, 247. (19) Ganta, S.; Devalapally, H.; Shahiwala, A.; Amiji, M. J. Controlled Release 2008, 126, 187. (20) Ulijn, R. V. J. Mater. Chem. 2006, 16, 2217. (21) Cheng, R.; Feng, F.; Meng, F.; Deng, C.; Feijen, J.; Zhong, Z. J. Controlled Release 2011, 152, 2. (22) Saito, G.; Swansonb, J. A.; Leea, K. D. Adv. Drug Delivery Rev. 2003, 55, 199. (23) Corma, A.; Diaz, U.; Arrica, M.; Fernandez, E.; Ortega, I. Angew. Chem., Int. Ed. 2009, 48, 6247. (24) Guerrero-Martínez, A.; Pérez-Juste, J.; Liz-Marzán, L. M. Adv. Mater. 2010, 22, 1182. (25) Chu, C.-H.; Wang, Y.-C.; Huang, H.-Y.; Wu, L.-C.; Yang, C. S. Nanotechnology 2011, 22, 185601. (26) Wischke, C.; Schwendeman, S. P. Int. J. Pharm. 2008, 364, 298. (27) Ganji, F.; Abdekhodais, M. J. Carbohydr. Polym. 2010, 80, 740. (28) Li, Y.-P.; Pei, Y.-Y.; Zhang, X.-Y.; Gu, Z.-H.; Zhou, Z.-H.; Yuan, W.-F.; Zhou, J.-J.; Zhu, J.-H.; Gao, X.-J. J. Controlled Release 2001, 71, 203. (29) Ding, Y.; Chu, X.; Hong, X.; Zou, P.; Liu, Y. Appl. Phys. Lett. 2012, 100, 013701. (30) Reale, E.; Leyva, A.; Corma, A.; Martinez, C.; Garcia, H.; Rey, F. J. Mater. Chem. 2005, 15, 1742. (31) Chen, C. Y.; Li, H. X.; Davis, M. E. Microporous Mater. 1993, 2, 17. (32) Fredenberg, S.; Wahlgren, M.; Reslow, M.; Axelsson, A. Int. J. Pharm. 2011, 415, 34. (33) Heo, S.; Lee, M.; Lee, S.; Sah, H. Int. J. Pharm. 2011, 419, 60. (34) Maulding, H. V.; Tic, T. R.; Coswar, D. R.; Fong, J. W.; Pearson, J. E.; Nazareno, J. P. J. Controlled Release 1986, 3, 103. (35) De Jong, S. J.; Ariasa, E. R.; Rijkersb, D. T. S.; van Nostruma, C. F.; Kettenes-van den Boschc, J. J.; Hennink, W. E. Polymer 2001, 42, 2795. (36) He, Q.; Shi, J.; Zhu, M.; Chen, Y.; Chen, F. Microporous Mesoporous Mater. 2010, 131, 314. (37) Brülisauer, L.; Kathriner, N.; Prenrecaj, M.; Gauthier, M. A.; Leroux, J.-C. Angew. Chem., Int. Ed. 2012, 51, 12454. (38) Balendiran, G. K.; Dabur, R.; Fraser, D. Cell Biochem. Funct. 2004, 22, 343. (39) Higuchi, T. J. Pharm. Sci. 1963, 52, 1145. (40) Mittal, G.; Sahana, D. K.; Bhardwaj, V.; Ravi Kumar, M. N. V. J. Controlled Release 2007, 119, 77.

nanohybrids impose a better control and slower release of encapsulated molecules than bare PLGA nanoparticles and are reasonably stable in a physiological medium and potentially sensitive to redox mechanisms. Ongoing research involves the development of similar nanohybrids responsive to different chemical and photochemical stimuli, as well as in vitro testing of current materials as carriers of hydrophobic antitumoral drugs.

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ASSOCIATED CONTENT

S Supporting Information *

General methods, Z-potential measurements, TGA reports, and 13 C CP MAS NMR spectroscopy and 1H NMR spectra of partially degraded PLGA (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are thankful for financial support by “CICYT” of Spain (projects CSD2009-00050 and MAT2012-39290-C0202). C.M. thanks the Spanish “Ministerio de Economiá y Competitividad” for an FPU Ph.D. studentship (AP200802851). We kindly appreciate the technical support of the Electronic Microscopy Service of UPV.

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dx.doi.org/10.1021/cm400700g | Chem. Mater. XXXX, XXX, XXX−XXX