Polydopamine Coatings in Confined Nanopore Space: Toward

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Polydopamine Coatings in Confined Nanopore Space: toward Improved Retention and Release of Hydrophilic Cargo Xianying Zheng, Jixi Zhang, Jie Wang, XueQiang Qi, Jessica M. Rosenholm, and Kaiyong Cai J. Phys. Chem. C, Just Accepted Manuscript • DOI: 10.1021/acs.jpcc.5b08558 • Publication Date (Web): 13 Oct 2015 Downloaded from http://pubs.acs.org on October 14, 2015

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The Journal of Physical Chemistry

Polydopamine Coatings in Confined Nanopore Space: toward Improved Retention and Release of Hydrophilic Cargo Xianying Zheng†, Jixi Zhang*,†, Jie Wang†, Xueqiang Qi‡, Jessica M. Rosenholm*,§, Kaiyong Cai† †

Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of

Bioengineering, Chongqing University, No. 174 Shazheng Road, Chongqing 400044, China. Email: [email protected]. ‡

Analytical and Testing Center of Chongqing University, Chongqing 400044, China.

§

Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi

University, Tykistökatu 6A, FI - 20520 Turku, Finland. Email: [email protected]

ABSTRACT: A composite nanocarrier system integrating the porous structure of mesoporous silica nanoparticles (MSNs) and the adhesive property of polydopamine for loading and release of hydrophilic drugs is reported. Amino group functionalization facilitates the oxidant-induced surface polymerization of dopamine in the confined space of mesopores by Schiff base/Michael addition reaction in a mild synthesis. As a consequence, to MSN@PDA particles with an average pore size of 4.0 nm, a particle diameter of ~ 70 nm, as well as a thin layer of polydopamine

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coating on the surfaces of MSNs. The MSN@PDA nanocarriers can effectively adsorb hydrophilic drugs with high loading capacities (380 µg/mg for doxorubicin hydrochloride (DOX) and 320 µg/mg for calcein), facilitated by the π–π stacking interactions between the abundant aromatic rings of PDA and the aromatic backbones of drugs. Interestingly, sustained and pHdependent drug release was observed for these drug loaded MSN@PDA particles, owing to the adhesive property of polydopamine like “molecular glue”. Moreover, a catechol-metal-drug coordination system can be easily constructed on the basis of the coordination bonding between catechols in polydopamine and transition metal ions (Fe3+, Zn2+), as well as that between metal ions and anthracycline drugs (i.e. DOX), resulting in an acid-triggered drug release.

KEYWORDS: Porous nanocarriers, Polydopamine coating, Molecular glue, Coordination bonding, Responsive release 1. Introduction Among nanoscopic therapeutic systems, mesoporous silica nanoparticles (MSNs) have emerged as robust nanovectors for drug delivery in the past decades.1 The characteristic mesoscopically ordered pore structure accompanied with the consequential high surface areas and pore volumes can not only provide the materials with a high loading degree capacity, but also lead to efficient rentention of the cargo, especially hydrophobic drugs.1 For hydrophilic drugs loaded by electrostatic interactions or physical adsorption, metabolites/ions in the body fluid can displace the drugs, resulting in premature drug release. Hence, nanoscopic surface engineering on MSNs was introduced as a means of regulating the movement of cargo molecules responding to specific external stimuli, such as pH, temperature, redox condition, etc.2 After a veritable explosion of research effort in constructing drug release nano-architectures on the basis


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of MSNs, two typical mechanics, i.e. on/off capping or gating on the outer surface of particles, and tunable host–guest interactions on the pore surface, have emerged as the most potential candidates for the driving forces of drug release. Usually, fabrication of the supramolecular nanomachines in the former mechanic involves tedious and intricate steps, whereas the later one holds the promise of simple fabrication and preservation of the outer particle surface for the integration of other functional entities like targeting agents. Successful surface modification of drug-interactive ligands is often an integrated and crucial part of material processing to construct the functionality of nanocarriers to control their interaction with drugs. Typically, the surface modification approaches of MSNs, i.e., cocondensation and post grafting on the basis of silane chemistry, are associated with certain drawbacks such as inhomogeneous surface coverage and limitation in the density of accessibility of the functional groups.3 Surface growth of polymers was thus developed to enable a precise control over the density and spatial arrangement of the functional groups incorporated in the pores while retaining an open porosity for the accommodation of guest molecules.4,

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One

representative progress made in this field is surface hyperbranching polymerization which can be realized even on MSNs with small pore size.6, 7 In spite of the successful demonstrations of these dendrimer-modified MSNs in delivery of hydrophobic drugs, it is still challenging to circumvent organic synthesis conditions and sterically restricted polymerization in the pore space. Novel synthetic biomaterials through mimicking nature can be integrated on surfaces to serve as templates and building blocks for new generations of biocompatible coatings, owing to their environmental-benignity, high efficiency, controllability and universality. One of the most representative examples is bioinspired adhesion, also called mussel-inspired chemistry.8 Dopamine (DA), a mussel adhesive protein inspired molecule, has attracted strong interest in


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drug delivery especially after the discovery in the attenuation of the in vivo toxicity of biomaterials by polydopamine (PDA) surface modification.8 To some extent, polydopamine shows a higher degree of designability and flexibility in surface coating structures when compared to other polymers. This is mainly attributed to, at least in concept, four aspects as follows: (i) dopamine could undergo self-polymerization at mild conditions (alkaline or oxidants contained aqueous solutions), and adhere onto almost any solid surfaces without surface pretreatment; (ii) polydopamine is rich in catechol groups like mussel adhesive proteins, which endows the PDA versatile chemical reactivity for diverse secondary reactions. The bulk PDA powder is composed of irregular micro or nanometer clusters, this structure showed low surface area and poor efficient in practical application. Therefore, the template or substrate is needed to achieve PDA coated thin film or nano-layer. To date, there has been tremendous amount of effort dedicated to the generation of a polydopamine shell with a controlled shell thickness on nanoscale metal, metal oxides, and graphene, hydroxyapatite, etc.9,

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It may then appear a bit surprising that very few detailed

studies have been performed which aim at a detailed description of surface polymerization of dopamine in the nanopores of the nanocarriers for drug delivery. Polydopamine materials have been proposed as a good candidate for drug delivery, because of the π–π stacking interactions between the abundant aromatic rings of PDA and the aromatic backbones of drugs. However, the demonstrations of PDA’s drug delivery potential was only shown in polydopamine capsules using cavities to increase the drug payload.11,

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Noteworthily, polydopamine has a robust

chelating capability toward metal ions, which, unfortunately, was seldomly utilized for the development of facile drug delivery systems via tunable host–guest interactions. Previous studies by Che and the coworkers have demonstrated that porous nanocarriers can readily construct a


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typical “host-metal-drug” architecture through the coordination bondings between host surface and transition metal ions, as well as those between metal ions and drugs.13 The great advantage of PDA’s chelating capacity towards metal ions might provide ample scope for pH-responsive drug delivery systems on the basis of metal ion-mediated coordination bonding. Considerable room for improvement in the drug delivery potential might be exploited by the combination of MSN and PDA.

Figure 1. Schematic illustration of the progress in constructing polydopamine coated MSN particles for drug loading and release. Herein, we report on the construction of polydopamine coating on MSN surfaces mediated by oxidant induced surface polymerization, as depicted in Figure 1, with a focus on whether polydopamine coating can be exploited to improve the loading and release properties of hydrophilic drugs on porous nanocarriers. Three important features are associated with our composite nanocarrier system: (1) Amino group functionalization facilitates the surface polymerization of dopamine in the confined space of mesopores, leading to a thin layer of polydopamine coating on both the exterior particle surface and the internal pore surface. (2) The


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aromatic backbones in the polydopamine molecule impart the particles with strong affinity towards aromatic drugs, leading to a high loading capacity of guest molecules (i.e. DOX, calcein), as well as a sustained drug release, as compared with the MSN counterparts. (3) The catechol groups in polydopamine provide an ideal platform for constructing a catechol-metaldrug coordination system for a pH-responsive drug release. 2. Experimental section 2.1. Materials: Unless otherwise noted, all reagent-grade chemicals were used as received, and distilled water was used in the preparation of all aqueous solutions. Cetylmethylammonium bromide (CTAB, AR), ethylene glycol (AR) were purchased from Fluka. 1, 3, 5-trimethylbenzene (TMB, 99%) was purchased from ACROS. Decane (99%) was purchased from Alfa Aesar. Tetraethyl orthosilicate (TEOS, AR), 3-aminopropyltriethoxysilane (APTES, AR), NH4OH (30 wt%, AR), were purchased from Sigma. Dopamine hydrochloride (98%), ammonium persulfate (AR), iron nitrate nonahydrate (Fe(NO3)3·9H2O, AR), zinc nitrate hexahydrate (Zn(NO3)2·6H2O, AR), calcein (AR), doxorubicin hydrochloride (DOX, 98%), and 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid (HEPES) were purchased from Aladdin Industrial Inc. 2.2. Synthesis of Amino Group Modified MSNs (MSN-NH2): The starting particles were prepared by co-condensation procedure using TEOS and APTES as silica source according to a recipe reported by us.14 The molar ratio used in the synthesis was 1 TEOS: 0.19 APTES: 0.18 CTAB: 0.55 TMB: 1.6 decane: 5.9 NH3: 88.5 ethylene glycol: 1249 H2O. The reaction was allowed to proceed for 3 h at 70 ° C. Then, the heating was stopped and the as-synthesized colloidal suspension was then aged at 70 ° C without stirring for 24 h. After the suspension was cooled to room temperature, the suspension was separated by centrifugation. Ethanol was used to


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wash the centrifuged particle. The template removal was performed by a highly efficient ionexchange method. The final product was suspended in acetone for further use. 2.3. Preparation of PDA modified MSNs (MSN@PDA): Surface modification of MSNs was carried out by oxidant induced surface self-polymerization of dopamine. Typically, 10 mg of the as-prepared MSN-NH2 particles were dispersed in 5 mL HEPES buffer (25 mM, pH 7.4). After the addition of 2 mg dopamine hydrochloride and subsequent 5 min of sonication, 2.4 mg of ammonium persulfate was added to the reaction mixture to initiate the polymerization reaction, which was allowed to proceed overnight. The particles were then retrieved by centrifugation and washed three times with water. 2.4. Preparation of metal ion coordinated MSN@PDA (MSN@PDA-Zn/Fe): In a typical procedure, 10 mg MSN@PDA particles were then re-dispersed in 5 mL of ethanol, followed by adding 2 mg of Fe(NO3)3·9H2O/ Zn(NO3)2·6H2O. The mixture solution was stirred overnight. Finally, the particles were centrifuged, washed for three times with ethanol and then dispersed in HEPES buffer for subsequent use. 2.5. Particle characterizations. Transmission electron microscope (TEM) images were obtained by a JEM 2010 (JEOL, Japan) instrument with 200 KV acceleration voltages in order to investigate the size, morphology and integrity of the nanoparticles. Samples were dried on holey carbon-coated Cu grids. The hydrodynamic size distributions and zeta potentials of the samples were measured using dynamic light scattering (DLS) techniques by a Zetasizer Nano instrument (Malvern, UK) at 25 °C. Nitrogen sorption isotherms were measured with a ASAP2010 analyzer (Micromeritcs, USA). The specific surface areas were calculated by the Brunauer-Emmett-Teller (BET) method in a


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linear relative pressure range between 0.05 and 0.25. The pore size distributions were derived from the desorption branches of the isotherms by the NLDFT method. The FT–IR spectra were collected over the range of 4000–400 cm-1 on a Spectrum 100 infrared spectrophotometer (Perkin Elmer, USA) using KBr technique. X-ray photoelectron spectroscopy (XPS) measurements were performed on an ESCALABMKII spectrometer with Al Kα radiation as the X-ray source for excitation. Raman spectra were obtained by using a dispersive spectrophotometer Jobin-Yvon LabRam HR Evolution with 532 nm light for sample excitation and a CCD detector cooled to −70 °C. The laser power used was between 0.5 and 4 mW. 2.6. Drug loading and releasing experiments. For the determination of adsorption isotherm of drugs (DOX, calcein), 2 mg of MSN@PDA was ultrasonically dispersed in 1 mL of the drug solution in HEPES buffer (25 mM, pH 7.4) with various concentrations. The mixture was stirred at room temperature for 2 h, and then centrifuged (11000 rpm, 15 min) to collect the drug-loaded nanoparticles. The amount of drug loaded into M-MSNs was calculated by subtracting the mass of drug in the supernatant from the total mass of drug in the initial solution. The concentrations of the drugs in the solutions were analyzed with a UV-Vis Spectrophotometer (NanoDrop 2000c, Thermo) at the wavelength of 480 nm (DOX) and 485 nm (calcein). The release study was conducted as follows. First, 2 mg of drug-loaded nanoparticles were dispersed in 2 mL of PBS buffer (pH 7.4), or in sodium acetate buffer solutions (20 mM, pH 4.4) with the same ionic strength (150 mM) as the PBS solution. At the predetermined time intervals, 0.2 mL of solution was withdrawn from the solution and the amount of released drug was analyzed by UV-vis. For keeping a constant volume, 0.2 mL of fresh medium was added after each sampling. All drugs release results were averaged with three measurements.


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Calculation of the corrected concentration of released DOX is based on the following equation: Cc = C t +

v t-1 ∑ Ct V 0

(1)

Where Cc is the corrected concentration at time t, Ct is the apparent concentration at time t, v is the volume of sample taken (0.2 mL), and V is the total volume of the release fluid (2 mL). 3. Results and discussion 3.1. Structural characterization of the hybrid nanocarriers Figure 2a shows a typical transmission electron microscope (TEM) image of the as-prepared amino-co-condensed MSNs (MSN-NH2). Particles are composed of uniform spherically shaped particles with an average diameter of ~70 nm, as well as radially aligned pore structures inside the particles. Amino groups were modified on the particle surface by a cocondensation approach to facilitate an efficient surface polymerization of dopamine through Schiff base formation and/or by Michael type addition involving quinone groups of oxidized dopamine with primary amino groups from dopamine and MSN-NH2.15, 16 The total amount of accessible primary amines on MSN-NH2 was determined to be 0.471 mmol/g, as determined by a ninhydrin test previously.17 TEM image of polydopamine modified MSN particles (MSN@PDA) is shown in Figure 2b. There is a reduction in the contrast of the mesopores. In light of that mesoporous silica is alkaline corrosive, typical pH-induced polymerization of dopamine was not used in our study and a high particle concentration (2 mg/mL) was used in the coating buffer (HEPES, pH 7.4). Hence, the surface degradation and/or corrosion was greatly inhibited.18, 19, 20 The reduction in the contrast should not be from the surface degradation of silica, consequently suggesting the presence of a thin polymer coating on the surfaces of the particles. In order to further confirm the presence of polydopamine on the surfaces of MSN, silver staining as a general route of revealing phenol


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groups was used, taking advantage of reducing ability of catechols toward noble metallic salts.21 After being in contact with a silver nitrate (AgNO3) solution, modified samples got darkened because of the formation of silver nanoparticles via a redox couple between Ag+ and the polyphenolic coating. The presence of small surface-bound silver nanoparticles were evident from the scattered black dots through composite particles (Figure 2c), while large silver nanoparticles were located on the exterior surface, implying that polydopamine was coated on both external pore surface and exterior particle surface. Energy dispersive X-ray spectroscopy (EDS) element mappings of Si, and Fe/Zn elements of MSN@PDA-Fe and MSN@PDA-Zn are shown in Figure 2d and e. Green dots indicative of metal ions were observed in the regions of particles with red silicon dots, demonstrating the distribution of metal element in MSN@PDA particles. The catecholic hydroxyl groups can interact with transition metal ions and form strong coordination bonds to give reversible noncovalent catechol–metal complexes when a catechol donates a non-bonding electron pair to the metal ions, which is well known in a variety of natural organisms.9,

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The amount of

coordinated metal ions, determined by inductively coupled plasma atomic emission spectroscopy (ICP‐AES), was 0.36 and 0.11 mmol/g, for MSN@PDA-Fe and MSN@PDA-Zn, respectively. The difference in these two metal ions might be ascribed to the discrepancy in their coordination bonding ability towards catechols in polydopamine.22 The stability of the catechol–metal complexes has been proven to be controlled by pH via the protonation of the catecholic hydroxyl groups.22,

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In the present study, two kinds of metal ions (Fe3+, Zn2+) which are more

metabolizable were chosen to investigate the controlled drug release behaviors based on coordination bondings (catechol–metal, and metal-drug), which will be shown in the following part.


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Figure 2. Typical TEM images of MSN-NH2 (a), MSN@PDA (b), MSN@PDA- Ag (c), MSN@PDA-Fe (d), and MSN@PDA-Zn (e). Arrows in c show the presence of silvered nanoparticles resulting from the reduction of catechols in polydopamine. Red and green dots in d and e stand for silicon and metal elements (Fe for d and Zn for e), respectively.


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Nitrogen sorption isotherms of MSN-NH2 and MSN@PDA (Figure 3a) were measured to investigate the influence of PDA incorporation on the mesostructure of MSN. All samples exhibit type IV isotherms with type H1 hysteresis loops, characteristic of a mesoporous material with 1D cylindrical channels. It is observed that the isotherm changes considerably after MSNNH2 coated by PDA. First, the adsorption capacity decreased after the incorporation of PDA. Second, the relative pressure, at which capillary condensation (i.e., mesopore filling) occurs, shifted systematically to lower relative pressure range (P/P0, 0.2-0.45). This was also reflected in a reduction of the mesopore diameter (from 4.9 nm to 4.0 nm in average) shown in Figure 3b. Furthermore, a reduction in the BET surface area (from 1043 m2/g to 471 m2/g) and the pore volume (from 0.85 cm3/g to 0.43 cm3/g) can be found for MSN@PDA, probably due to the surface growth of PDA inside the channels. The correlation between the slope of the adsorption–desorption hysteresis and the homogeneity of the pores can provide information about the distribution of polymers.26 The slope of the adsorption–desorption hysteresis for MSN@PDA showed a slight decrease indicating that the PDA polymer increased corrugation of the pores to some extent by forming thickness differentiation on local pore surfaces. As for the exterior surface of MSN-NH2, a shift of the isoelectric point from 10.2 in the case of MSN-NH2 to 7.5 for MSN@PDA was clearly observed from the zeta potential measurements (Figure S1). Moreover, MSN@PDA particles showed neutral surface potential at pHs below its isoelectric point, owing to the zwitterionic nature of polydopamine.12 These data support that PDA was successfully modified on the surfaces of MSN-NH2.


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Figure 3. Nitrogen sorption isotherms (a) and the corresponding pore size distributions (b) of MSN-NH2 and MSN@PDA. To generate the polydopamine coatings within the pore channels, rather than outside of MSNs, we utilized the amino-functionalized MSNs to provide an effective bonding between amines on the pore surface of the solid template and quinone/catechol groups of polydopamine. Actually, if we just simply used the blank MSNs in the absence of amino group modification, we found that a large amount of the polydopamine nanospheres formed separated from the MSNs (Figure S2). Additionally, the hysteresis loop in the nitrogen sorption isotherm for MSN@PDA disappeared, indicating that the pore channels were sealed/blocked by the polydopamine coatings on the exterior particle surface. The pore blocking in the case of MSN without the presence of amino modification is in line with two recent studies.27, 28 All these results demonstrate the importance of the amino modification in MSN-NH2 for the successful preparation of the MSN@PDA with accessible polydopamine layer on the pore surface. X-ray photoelectron spectroscopy (XPS) was then applied to evaluate the PDA coating detail and the chemical bonds formed on the surfaces of the functionalized MSN particles. As shown in


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Figure 4a, typical peaks of O (1s), N (1s), C (1s), Si (2s), and Si (2p) were found in both MSNNH2 and MSN@PDA. However, there was a ~20% reduction in the silicon signals (154 eV for Si 2s, 103 eV for Si 2p)). Previous studies on the surface modification of dopamine on varying two-dimensional substrates all found a complete signal loss of the substrates after coating.16, 29 The continued presence of the Si signals after PDA modification on MSN-NH2 indicates that the thickness of the polymer coating was less than the escape depth of photoelectrons (ca 10 nm), which is in agreement with the analysis results from the nitrogen sorption isotherms.30, 31 In the high-resolution spectra of nitrogen shown in Figure 4b, the N(1s) band observed for the aminosilylated surface is a doublet, of which the major peak is known as that from free amine (399.7 eV) and another peak is known as that from the protonated amine (401.5 eV).32 PDA polymer in MSN@PDA can be deduced from two additional peak components at the BE of 399.2 eV for the secondary amine species and 400.3 eV for the partially protonated -N-H species.33 The secondary amine species should be dominantly resulted from the formation of 5,6dihydroxyindolinewhich was generated in the polymerization process of dopamine (Figure 1). It should be noted that the detailed structure of PDA is still under discussion and it was recently accepted that PDA is composed of dihydroxyindole, indoledione, and dopamine units.34 In combination with the results from UV absorption spectrum of MSN@PDA, where the typical absorption peak of quinone structure at 350 nm was observed (Figure S3),35 conclusion can be drawn that the dopamine molecules in the coating layer was polymerized in the oxidant-induced surface polymerization process.


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Figure 4. XPS wide spectra (a) and high-resolution spectra of nitrogen peaks (N1s) for MSNNH2 and MSN@PDA. To verify the metal ion coordination on surfaces of MSN, FTIR and Raman spectra of the samples during each modification step were determined and shown in Figure 5. The typical absorption peaks for silica were found at 800 cm−1 for the symmetric stretching vibration νs (Si– O–Si), at 1098 cm−1 for the asymmetric stretching vibration νas (Si–O–Si), and at 464 cm−1 for the Si–O–Si bending mode. In addition, the Si–OH stretching vibration was characterized at 953 cm−1 and 3450 cm−1. The stretching vibration at 1630 cm−1 indicated the successful modification of amine groups in MSN-NH2 particles.14 The characteristic adsorption peaks of PDA particles at 3220 cm−1, 3412 cm−1 (stretching vibration of phenolic O–H and N–H), 1630 cm−1 (stretching vibration of aromatic ring and bending vibration of N–H), 1518 cm−1 (N– H shearing vibration), 1395 cm−1 (the phenolic C–O–H bending vibration), and 1120 cm−1 (C–O vibration), were all found in the spectrum of MSN@PDA particles, suggesting the presence of


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many oxygen-containing functional groups and aromatic rings on PDA.36,

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The features of

characteristic peaks of dopamine and PDA microspheres suggest the successful polymerization of dopamine. The typical peak at 3220 cm−1 from the vibration of catechol –OH groups decreased remarkably after metal ion (Fe3+, Zn2+) coordination in the case of MSN@PDA-Fe, and MSN@PDA-Zn, which indicates deprotonation of the phenolic groups and coordination binding of the catechol to the metal ion.

Figure 5. FTIR (a) and Raman spectra (b) of MSN-NH2, PDA, MSN@PDA, MSN@PDA-Fe, and MSN@PDA-Zn. In Raman spectra (Figure 5b), polydopamine coating on MSN shows typical peaks of polydopamine at 1580 cm−1 and 1345 cm−1, which result from stretching and deformation of aromatic rings.37 In the case of MSN@PDA-Fe and MSN@PDA-Zn, a new broad peak at around 630 cm-1 which should be assigned specifically to the chelation of metal ions by the catechol


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oxygens of dopamine,38 was observed, accompanied with the distortion at the vibration peaks of aromatic rings. These results further confirm the successful coordination of metal ions on MSN@PDA. 3.2. Drug loading behavior of MSN@PDA Drug loading and release properties of MSN@PDA and MSN@PDA-Fe/Zn were examined by using DOX as a model drug. Figure 6 depicts the DOX adsorption kinetics (a) and isotherm (b) of MSN@PDA particles from HEPES buffer (pH 7.4). To elucidate the effect of PDA coating, pristine MSN particles without any surface modifications were also employed in drug loading/release evaluations as a reference, considering that MSN-NH2 cannot adsorb DOX because of electrostatic repulsion between amino groups in DOX and those on the surface of MSN-NH2 in solutions. As shown, the DOX loading amount for MSN@PDA underwent a remarkably fast increase in the first 5 h, and then this increment slowed down sharply. After 24 h, the changes of DOX concentration in the supernatant became negligible, suggesting the drug adsorption had reached an equilibrium. In comparison, the equilibrium time for a saturated DOX adsorption onto M-MSN was much shorter (only 3 h as shown in Figure 6c). To explore the mechanism behind the slow adsorption rate of DOX on MSN@PDA, the adsorption kinetics was then fitted by the pseudo-first-order model, pseudo-second-order model, and Weber–Morris intraparticle diffusion model, respectively (Figure S4).39 The relevant parameters were calculated and are listed in Table S1. From the correlation coefficients (R2) in Table S1, the adsorption of DOX onto MSN@PDA fits the pseudo-second-order rate model well, and the calculated value of Qe (192 mg/g) is in accordance with the experiment value. This suggests that the adsorption process of DOX seems to be controlled by a high strength sorption process rather than a common physical adsorption one via van der Waals interactions. The


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possibility of electrostatic attraction between MSN@PDA and DOX could be ruled out due to the neutral charge of the particles at the drug adsorption condition. Among other interactions which may happen between the PDA and drugs with aromatic backbones, π–π stacking interactions via sharing of π-electrons have been reported to be the most dominant driving force which has always been used to explain the mechanism of aromatic adsorbate to polydopamine surface.40, 41 The complete fluorescence quenching of DOX after adsorption into MSN@PDA (data not shown) are also indicative of such interactions. However, the linear plot (Figure S2c) for the Weber–Morris intraparticle diffusion model does not pass through the origin; such a deviated straight line from the origin point indicates that the pore diffusion is also a ratecontrolling step in the adsorption process.

Figure 6. DOX adsorption kinetics and isotherms on MSN@PDA (a, c) and MSN (b, d) from solutions in HEPES buffer (25 mM, pH 7.4) at room temperature. An initial concentration of 400 µg/mL was used for determining the adsorption kinetics.


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DOX adsorption isotherms of MSN and MSN@PDA are shown in Figure 6c and d. Both isotherms fit well with the Langmuir adsorption mode. The drug loading capacity of MSN@PDA was as high as 380 µg/mg, which is considerably higher than the loading amount using MSNs as carriers (130 µg/mg). When normalized against the surface area, the loading capacity of MSN@PDA (0.81 mg/m2) is nearly 7 fold to that of MSN (0.12 mg/m2). The polydopamine coating on the surfaces of MSN-NH2 contains abundant aromatic rings, which presumably offers a compatible “molecular glue” environment for the ring structure of DOX, leading to the high loading capacity of DOX in MSN@PDA. Molecular binding and adsorption onto MSN@PDA was also generalized to another type of aromatic molecule tested in this work, i.e. a fluorescent dye molecule (calcein). Although the degree of loading on MSN@PDA (120 µg/mg) determined from the isotherm curve at the same adsorption conditions is around 3 times lower than that for DOX, the loading capacity of calcein reached a comparable level of 320 µg/mg after lowering the adsorption pH to 5 (Figure S5). As a molecule bearing four carboxyl acid groups, calcein possesses lower pKa values as compared with DOX, which consequently leads to higher hydrophilicity at neutral pH and thus low affinity towards π-electron rich polydopamine surface.42 These results suggest that various types of small aromatic molecules with low water solubility can be loaded onto the surface of MSN@PDA in the aqueous phase via noncovalent π–π stacking interactions. The influence of transition metal ions on the loading capacity of the MSN@PDA was investigated. However, negligible difference was observed for the amount of the loaded DOX between MSN@PDA and MSN@PDA-Mn+. DOX adsorption in the absence of metal ions is driven by the π–π stacking interactions between the abundant aromatic rings of PDA and the aromatic backbones of drugs. After the introduction of metal ion coordination, the strong


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coordinative affinity of C=O and C-O bonds in anthracycline drugs towards metal ions would also influence the patterns of host-drug interaction.13 One possible reason for a similar loading capacity would be that the two interactions take place in a synergistic way irrespective of their different binding sites. 3.3. Evaluation of drug release behavior On the basis of advantageous drug loading properties of MSN@PDA, it is then quite interesting to investigate the release from the MSN@PDA nanocarriers. Cumulative DOX release profiles from drug loaded MSN and MSN@PDA were obtained and compared in Figure 7. There was a 52% DOX release from MSN at pH 7.4 up to 72 h, but over 90% of the loaded DOX was released after 1 h of incubation in the release medium. This trend was attributed to the increased hydrophilicity and higher solubility of DOX at lower pH caused by increased protonation of NH2 groups on DOX. In comparison, the DOX release from MSN@PDA show a sustained release at both pH values, indicated by a slow increase to 20% and 60% cumulatively at pH 7.4 and pH 4.4, respectively. The sustained release should be owing to the π–π stacking interactions with a higher loading strength. Interestingly, sustained release behaviors were also observed in the case of calcein, where a burst release from MSN-NH2 (100% release after 1 h at both pH 4.4 and pH 7.4, as shown in Figure S5) was retarded after polydopamine coating. The only difference is that calcein was released from MSN@PDA at high pH values, due to the increased hydrophilicity resulting from deprotonation of the carboxylic acid group on the molecule. All these results imply that such π–π stacking is sufficiently strong to prevent rapid desorption in normal physiological conditions. The pH-dependent drug release from MSN@PDA could be exploited for drug delivery


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applications since the micro-environments of extracellular tissues of tumors and intracellular lysosomes and endosomes are acidic.

Figure 7. DOX release profiles as a function of time for MSN (a) and MSN@PDA (b) in buffers with different pHs. Besides the molecular binding capacities, another valuable feature of polydopamine lies in its chemical structure that incorporates catechols with a great binding potential towards transition metal ions to form varying coordination complexes.9, 43, 44, 45, 46 Under physiological condition (pH 7.4), the strong coordinative affinity of C=O and C–O bonds in anthracycline drugs (i.e. DOX) towards metal ions has been well established previously.13 Taking advantage of the


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coordination bonding between catechols and metal ions, as well as that between metal ions and DOX, a “catechol-metal-drug” architecture was then constructed (Figure 8). Considering that catechol-metal-drug bonds are fairly stable under neutral condition but prone to be attacked by acids, one would expect a pH-controllable release of DOX loaded on MSN@PDA-Mn+ particles.

Figure 8. Schematic illustration of the “catechol-metal-drug” architecture for controlled release of DOX from MSN@PDA-Mn+ particles. The drug release behaviors of DOX from metal ion coordinated MSN@PDA-Fe and MSN@PDA-Zn particles were also examined. Indeed, as clearly shown in Figure 9, both the amount and the rate of DOX release in buffers highly depend on the pH values. Within 8 h, only 15% and 10% of the DOX adsorbed on the MSN@PDA-Fe and MSN@PDA-Zn particles, respectively, was released at pH 7.4. Lowering the pH to 4.4 increased the DOX release to 50%, and 85%, respectively. Further increase of cumulative DOX release with time was fairly slow up to 70 h, characteristic of the “onset” drug release behavior in the delivery systems based on coordination bonding.13 Compared with the low and sustained release in the absence of metal ions, coordination bonding based delivery system possess a more pH-responsive release property, where large amount of released drug was induced by short incubation time at weakly acidic conditions. The maximum DOX release level of MSN@PDA-Fe is significant lower than that of MSN@PDA-Zn, possibly due to a higher coordination strength of Fe3+ ion towards catechol groups and/or DOX molecules.13, 23


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Figure 9. Comparison of DOX release profiles as a function of time for MSN@PDA-Fe (a) and MSN@PDA-Zn (b) in buffers with different pHs. 4. Conclusion In summary, an organic-inorganic porous nanocarrier system for improving the drug loading/release of MSNs has been developed by utilizing polydopamine coating on the surfaces of MSN as molecular glue. Facilitated by the co-condensed amino groups on MSNs, an oxidantinduced surface polymerization of dopamine was successfully enabled, as evidenced by TEM, nitrogen sorption, and XPS. The thin polydopamine coating on the pore surfaces significantly improves both drug loading in terms of large loading capacity and drug release properties in terms of sustained release, for aromatic molecules in the aqueous phase via noncovalent π–π stacking interactions. The abundant catechols in the coating endows the composite particle with


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the ability of metal ion binding and consequently led to a “catechol-metal-drug” architecture based on coordination bondings for more pH-responsive drug release. As the result of molecular engineering inspired by mussels, we anticipate that our findings may pave a facile and distinctive way for constructing biomimetic polydopamine on porous nanocarriers towards efficient retention and smart delivery of guest molecules.

Supporting Information. Zeta potential measurements, UV-vis absorption spectra, drug loading kinetic plots and calculations, and calcein loading and release curves. This material is available free of charge via the Internet at http://pubs.acs.org.” AUTHOR INFORMATION Corresponding Author *J. Zhang. Tel.: +86 2365102507. E-mail: [email protected]. *J. M. Rosenholm. Tel.: +358 2215 3255. E-mail: [email protected]. Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ACKNOWLEDGMENT This work was supported in part by the National Natural Science Foundation of China (NSFC, Grant No. 51502027, 21274169), Basic Advanced Research Project of Chongqing (Grant No. cstc2015jcyjA10051), 100 Talents Program of Chongqing University (J. Z.), and Academy of Finland grant# 260599 (J.M.R.). National Engineering Research Center for Nanotechnology


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(Shanghai) is greatly acknowledged for the help for TEM characterization. Dr. Qian Liu is acknowledged for the help in drawing schematic presentations. REFERENCES 1.

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Figure 1. Schematic illustration of the progress in constructing polydopamine coated MSN particles for drug loading and release. 56x37mm (300 x 300 DPI)


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Figure 2. Typical TEM images of MSN-NH2 (a), MSN@PDA (b), MSN@PDA- Ag (c), MSN@PDA-Fe (d), and MSN@PDA-Zn (e). Arrows in c show the presence of silvered nanoparticles resulting from the reduction of catechols in polydopamine. Red and green dots in d and e stand for silicon and metal elements (Fe for d and Zn for e), respectively. 127x211mm (300 x 300 DPI)



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Figure 3. Nitrogen sorption isotherms (a) and the corresponding pore size distributions (b) of MSN-NH2 and MSN@PDA. 50x33mm (300 x 300 DPI)


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Figure 4. XPS wide spectra (a) and high-resolution spectra of nitrogen peaks (N1s) for MSN-NH2 and MSN@PDA. 93x127mm (300 x 300 DPI)



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Figure 5. FTIR (a) and Raman spectra (b) of MSN-NH2, PDA, MSN@PDA, MSN@PDA-Fe, and MSN@PDA-Zn. 99x116mm (300 x 300 DPI)


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Figure 6. DOX adsorption kinetics and isotherms on MSN@PDA (a, c) and MSN (b, d) from solutions in HEPES buffer (25 mM, pH 7.4) at room temperature. An initial concentration of 400 µg/mL was used for determining the adsorption kinetics. 99x78mm (300 x 300 DPI)



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Figure 7. DOX release profiles as a function of time for MSN (a) and MSN@PDA (b) in buffers with different pHs. 99x155mm (300 x 300 DPI)


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Figure 8. Schematic illustration of the “catechol-metal-drug” architecture for controlled release of DOX from MSN@PDA-Mn+ particles. 25x9mm (300 x 300 DPI)



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Figure 9. Comparison of DOX release profiles as a function of time for MSN@PDA-Fe (a) and MSN@PDA-Zn (b) in buffers with different pHs. 102x165mm (300 x 300 DPI)


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Table of Contents Graphic and Synopsis 51x31mm (300 x 300 DPI)


Polydopamine Coatings in Confined Nanopore Space: Toward

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