Microporous and Mesoporous Materials 141 (2011) 94–101

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Microporous and Mesoporous Materials

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N,N0-diureylenepiperazine-bridged periodic mesoporous organosilicafor controlled drug delivery

Surendran Parambadath a, Vijay Kumar Rana a, Dongyuan Zhao b, Chang-Sik Ha a,⇑a Department of Polymer Science and Engineering, Pusan National University, Geumjeong-gu, Busan 609-735, Republic of Koreab Department of Chemistry, Advanced Materials Laboratory, Fudan University, Shanghai 200433, PR China

a r t i c l e i n f o a b s t r a c t

Article history:Received 29 July 2010Received in revised form 23 October 2010Accepted 31 October 2010Available online 4 November 2010

Keywords:Periodic mesoporous organosilica (PMO)Organic–inorganic hybrid materialsDiureylenepiperazineDrug delivery system

1387-1811/$ - see front matter � 2010 Elsevier Inc. Adoi:10.1016/j.micromeso.2010.10.051

⇑ Corresponding author. Tel.: +82 51 510 2407; faxE-mail address: csha@pnu.edu (C.-S. Ha).

N,N0-diureylenepiperazine-bridged periodic mesoporous organosilicas (PDPMOs) have been successfullysynthesized through co-condensation of bissilylated N,N0-diureylenepiperazine (BPDU) and tetraethylorthosilicate (TEOS), using a triblock copolymer (Pluronic P123) as a structure-directing agent in acidicconditions with various BPDU to TEOS ratios. These PMOs were characterized by small angle X-ray scat-tering (SAXS), N2 adsorption–desorption measurements, Fourier-transform infrared (FT-IR), solid-state29Si MAS and 13C CP-MAS NMR spectroscopy, transmission electron (TEM) and scanning electron micros-copy (SEM), X-ray photoelectron spectroscopy (XPS), and thermogravimetric analysis (TGA). It was foundthat the organic functionalities could be introduced at a maximum of 30 mol% in the wall structure of thediureylenepiperazine-bridged periodic mesoporous organosilica (PDPMO-30) with respect to the totalsilicon content. The PDPMO-30 was thermally stable up to 230 �C. The PDPMOs have an ordered meso-structure, a high surface area (ranging from 663 to 316 m2 g�1), a medium pore volume (1.26–0.66 cm3 g�1), and uniform pore sizes (7.7–5.4 nm). To test a potential application of the PDPMO,in vitro assays of captopril or 5-flurouracil adsorption and delivery were carried out at pH 7.4. Due tothe presence of hydrophilic urea moieties within the wall structure, the materials were shown to be par-ticularly suitable for adsorption and desorption of drugs and could be utilized for controlled drugdelivery.

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1. Introduction

Intense interest in surfactant-mediated synthesis and modifica-tion of periodic mesoporous organosilica (PMO) soon took shapeafter its discovery in 1999 [1–3]. Unlike surface-functionalizedmesoporous silica, the organic moieties in PMO are built directlyinto the walls of the channels. Introduction of organic functional-ities into the framework of the mesoporous silica materials ispotentially advantageous within various types of applications,including catalysis, ion exchange, encapsulation of transition metalcomplexes, chemical sensing, nano-material fabrications, andadsorption of metal ions and drugs [4–10]. It is possible to controlproperties such as adsorption capacity for metal ions, ion ex-changes, surface hydrophobicity, reactivity and thermal, as wellas mechanical properties, by changing the nature and distributionof the organic groups within the hybrid mesoporous silica. Eventhough many reports on the synthesis of PMOs having varioustypes of organic spacer groups, including alkanes, alkenes, phenyls,and aromatic molecules, are available, incorporation of multifunc-tional long chain organic moieties as bridging groups are reported

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in the literature in a limited capacity [11–16]. Although the devel-opment of PMO has led to great interest in the material sciences,owing to their specific composition and function, synthesis ofPMO with large and flexible organic bridging groups within themesoporous wall remains a challenging endeavor facing today’schemists [17]. Over the past year, the preparation of urea- or diu-rea-bridged bissilylated organic molecules for the exploitation ofPMOs has become a core point of interest among researchers[18–22]. Owing to the hydrophilic nature of the urea functionality,it can be easily embedded within the silica matrix of mesoporousmaterials. Moreover, the ease of the urea moiety used as part of or-ganic functionalities, such as alkyl, aromatic, alicyclic, and hetero-cyclic, through a simple organic reaction strategy of an isocyanatewith a primary amine, also adds to the immense synthesis of urea-containing organosilanes. Until this moment, only a few reports[18–22] were available regarding the preparation of diurea-con-taining bissilylated molecules and their utilization in PMOs.

The controlled release of active agents from an inert matrix hasbecome increasingly important for oral, transferal, and implantabletherapeutic systems due to the advantages of safety, efficiency, andpatient convenience. Several research groups have investigated thedrug adsorption and release properties of mesoporous silica mate-rials [23–30]. Among a variety of nanoparticle-based drug delivery

Scheme 1. Preparation of BPDU.

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systems, mesoporous silica nanoparticles have several advanta-geous features for use in the delivery of both water soluble andinsoluble drugs. These materials have large surface areas and por-ous interiors that can be used as reservoirs for storing the drug. Thepore size and environment can also be modified to selectively storedifferent molecules, while the size and shape of the nanoparticlescan be tuned to enhance cellular uptake process [31,32]. Further-more, robust inorganic materials do not swell in organic solventsand are stable at varying pH conditions. An ideal mesoporous car-rier with a high specific surface area, large pore volume, and appro-priate pore size (larger than the kinetic diameter of the drug)would be beneficial toward increasing the adsorption capacity. Inrecent years, captopril (highly hydrophilic drug) and 5-fluorouracil(weakly hydrophilic) have been documented [33–35] in select re-ports. Captopril/5-fluorouracil can easily be impregnated intoPMO silica materials by reacting the active groups of the drug withthe organo-functionality of the bissilylated organo-bridged mole-cule located in the mesopore framework, such as the hydrogenbond interaction of the carboxyl groups of the drug with the iminegroups of the urea [33]. It is well known that piperazine is thestarting material for the synthesis of a large spectrum of drugs.Giving emphasis to this point, the incorporation of piperazine orits derivatives into the pore walls of the PMO would encourage fu-ture prospects in the pharmaceutical industry. The application ofnew PMO carrier systems to impregnate new kinds of model drugmolecules for controlled delivery is of keen interest.

Herein, we report a new PMO with a long chain functionalgroup that includes the co-existence of ureylene (–NHCO–N–)and a heterocyclic ring (piperazine), synthesized by this lab. Theobtained materials were characterized by several spectroscopictechniques and further tested as a drug carrier for captopril and5-flurouracil at pH 7.4 in SBF (simulated body fluid) solution.

2. Experimental

2.1. Materials

Poly (ethylene oxide)-b-poly (propylene oxide)-b-poly (ethyl-ene oxide) [EO20PO70EO20, Pluronic P123, Mw = 5800], 3-(triethoxy-silyl) propylisocyanate (IPTES, 95%), tetraethyl orthosilicate (TEOS,98%), piperazine (99%), captopril (99%), and 5-fluorouracil (5-Fu,99%) were purchased from Aldrich. All chemicals were used as re-ceived without any further purification. Water used in all synthe-ses was distilled and deionized.

2.2. Preparation of BPDU

Piperazine (0.86 g, 10 mmol) was dissolved in 90 mL of dry ace-tonitrile. To this, 3-(triethoxysilyl) propylisocyanate (4.62 g,20 mmol) in 10 mL of dry acetonitrile was added slowly under anitrogen atmosphere (Scheme 1). The mixture was refluxed for24 h under inert conditions. The progress of the reaction was mon-itored by TLC (thin layer chromatography) analysis. Upon comple-tion, the solvent was evaporated, followed by production of a whiteprecipitate that was then dispersed in dry hexane for 1 h. Theswelled white product was filtered, washed with hexane, and driedin vacuo.

[(EtO)3Si(CH2)3NHCO]2N2C4H8, Yield: 5.08 g, 92%; 1H NMR(300 MHz, CDCl3): d 0.4 (t, 4H, SiCH2), d 1.0 (t, 18H, CH3CH2O), d1.4 (t, 4H, SiCH2CH2), d 3.0 (q, 4H, CH2NH), d 3.2 (t, 8H, NCH2, het-erocyclic) d 3.6 (q, 12H, CH3CH2O), d 4.6 (t, 2H, CH2NH, propyl-amine). 13C NMR (300 MHz, CDCl3): d 0.34 (CH2Si), d 10.6 (CH3), d15.6 (CH2), d 35.3 (NCH2), d 50.7 (CH2O), d 149.8 (C@O). FT-IR(KBr): 3351 cm�1 (mNH), 2980 and 2885 cm�1 (mCH), 1624 cm�1

(mCO), 1546 cm�1 (mNH-amide), 1443 cm�1 (mNC), 1252 cm�1 (mSiC).

2.3. Synthesis of N,N0-diureylenepiperazine-bridged periodic hybridmesoporous organosilicas (PDPMO)

N,N0-diureylenepiperazine-bridged periodic hybrid mesoporousorganosilica materials were prepared according to a previously re-ported synthetic procedure [36]. In a typical synthesis, PluronicP123 (1.0 g, 0.17 mmol) was dissolved in deionized water (33 g,1.83 mol) containing conc. HCl (36 wt.%, 5.0 g, 48.6 mmol) in aclosed polypropylene bottle at room temperature. The resultingsolution was stirred for 3 h, followed by the addition of sodiumchloride (4.68 g, 0.8 mol), and continued to be stirred another3 h. Then, BPDU and TEOS, at different ratios, were added, followedby vigorous stirring for 24 h at 35 �C. The final mixture was trans-ferred to a Teflon-lined autoclave and crystallized for 24 h at100 �C. The obtained white precipitate was separated by filtration,washed thoroughly with deionized water, and dried at room tem-perature overnight. The occluded surfactant was removed by threesuccessive solvent extractions in ethanol solution containing1 wt.% HCl for 12 h. The molar composition of the reactants wasTEOS:BPDU:P123:HCl:H2O = (1� x):x:0.017:4.79:185, where x = 0.1,0.2, and 0.3. The resulted materials were denoted as PDPMO-n,where n = 10, 20, and 30.

2.4. Drug adsorption and release

Captopril (Cp)/5-Fu were dissolved in water (10 mg/mL) and0.1 g of the carrier material added into 12 mL of the above solution.The amounts of loaded drugs are list in Table 1. The mixture wasthen shaken for 24 h at room temperature, which was demon-strated to be long enough to reach the adsorption equilibrium.The porous material incorporated with Cp/5-Fu was collected bycentrifugation, washed with water, and then dried in an oven at35 �C. The amount of drug loaded into the pores of the carrierwas characterized quantitatively using a thermogravimetric ana-lyzer (TGA). In vitro drug release experiments were carried outby placing 50 mg of the drug-loaded PMO material into a dialysismembrane bag (molecular weight cutoff 5000 kDa), followed byimmersion into 40 mL of phosphate buffer solution (PBS). Through-out this drug release study, simulated body fluid (SBF, pH 7.4) buf-fer solution was used as the release medium, at 37 �C. The releaseconcentration as a function of time was analyzed by UV–visiblespectroscopy at 210/259 nm in SBF solution.

2.5. Characterization

Small-angle X-ray scattering (SAXS) measurements were per-formed using a synchrotron X-ray source of the Pohang AcceleratorLaboratory (PAL, Pohang, Korea): Co Ka (k = 1.608 Å) radiation withan energy range of 4–16 keV (energy resolution DE/E = 5.0 � 10�4,photo flux = 1010–1011 ph/s, beam size <1 mm2). Transmissionelectron microscopy (TEM) images were obtained with a JEOL2010

Table 1Physico-chemical properties from N2-sorption analysis and the amounts of loaded drugs of diureylene bridged mesoporous organosilicas.

Material Specific surface area (m2 g�1) Pore diameter (Å) Pore volume (cm3 g�1) 5-FU (wt.%) Captopril (wt.%)

PDPMO-10 663 77 1.26 16.34 19.26PDPMO-20 430 62 0.84 21.88 25.12PDPMO-30 316 54 0.66 – –

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electron microscope with an acceleration voltage of 200 kV. Scan-ning electron microscopy (SEM) images were recorded with a JEOL6400 microscope operating at 20 kV. Fourier-transformed infra-red(FT-IR) spectra were carried out using a Perkin Elmer FT-IR spec-trometer. Nitrogen adsorption isotherms were obtained with aQuantachrome’s Quadrasorb SI analyzer at �196 �C. The adsorp-tion/desorption isotherms of nitrogen at �196 �C were measuredusing a Nova 4000e surface area and pore size analyzer. Beforethe measurement, the samples were degassed at 120 �C for 2 h invacuo. The pore size distribution curve was obtained from analysisof the adsorption branch, using the Barrett–Joyner–Halenda (BJH)method. All 13C cross polarization (CP) and 29Si MAS NMR spectrawere obtained with a Bruker DSX400 spectrometer with a 4 mmzirconia rotor spinning at 6 kHz (resonance frequencies of 79.5and 100.6 MHz for 29Si and 13C CPMAS NMR, respectively; 90�pulse width of 5 ls, contact time 2 ms, recycle delay 3 s for both29Si MAS and 13C CPMAS NMR). Thermogravimetric analysis(TGA) was performed with a Perkin–Elmer Pyris Diamond TGinstrument at a heating rate of 10 �C min�1 in air. To study the sur-face elements of the materials in their existing state, X-ray photo-electron spectroscopy (XPS) measurements were carried out with aPHI-1600ESCA System XPS spectrometer (Perkin–Elmer, City,State, USA) using non-monochromatic Mg Ka radiation, operatedat 15 kV, under 10�7 Pa pressure, and with photoelectron energyset at 1254 eV (Korea Basic Science Institute Daegu Center, Korea).

Fig. 1. Small angle X-ray scattering patterns of (a) PDPMO-10, (b) PDPMO-20 and(c) PDPMO-30; inset: the higher angle reflections of (a) PDPMO-10, (b) PDPMO-20and (c) PDPMO-30.

3. Results and discussion

Fig. 1 depicts the SAXS patterns of the surfactant-extracted PMOsamples prepared with different proportions of BPDU in the silicasource. All patterns showed three scattering peaks that could be in-dexed as the 100, 110, and 200 reflections of the hexagonal sym-metry lattice of the SBA-15 type material. The 100 scatteringpeak was well-resolved in all the PMO, indicating persistence ofthe integrity of the two-dimensional (2D) hexagonal mesostruc-ture, even though the intensities of the 110 and 200 scatteringpeaks declined as the ratio of BPDU to TEOS in the silica source in-creased. These results indicate the presence of a periodic arrange-ment of the channels in a hexagonal geometry. The 110 and 200peaks of PDPMO-30 were not as obvious as that of the PDPMO-10 and PDPMO-20. Moreover, when the concentration of BPDU in-creased in the synthetic raw materials, the first peak of the result-ing PMO gradually shifted to a higher-angle region, implying acontraction of the unit cells [36,37]. Further increasing the contentof BPDU to 40% and 50% (x = 0.4 and 0.5, SAXS patterns not given)yielded no obvious scattering, suggesting that the presence of theexcessive complex organic building blocks inside the pore wallswould decrease the macroscopic order of the PMO and lead tothe collapse of the mesoporous structures.

Representative TEM images shown in Fig. 2 provide excellentevidence for the periodic hexagonal arrangement of the hybridmaterials. It is noteworthy to mention that the ordered alignmentof the mesopores in a p6mm symmetry can also be clearly observedin the TEM image of PDPMO-30, confirming an ordered 2D hexag-onal mesostructure [38].

Fig. 3 provides a comparison of nitrogen adsorption isothermsof solvent-extracted hybrid PDPMO materials; the corresponding

pore size distributions are given in Fig. 4. All isotherms displayedtype IV patterns with steep capillary condensation/evaporationsteps and obvious H1 hysteresis loops, characteristic of mesopor-ous materials according to the IUPAC classification. Table 1 liststhe BET specific surface area, mesopore diameter, and volume ofthe fine pores of the hybrid PDPMO. As seen from Figs. 3 and 4,the sorption isotherm and corresponding pore size distributionchanged gradually for the PDPMO samples from PDPMO-10 toPDPMO-30. The capillary condensation step shifted to lower P/P0

values upon increasing the concentration of BPDU in the initialsol mixture, suggesting a gradual decrease in the pore diameterfrom PDPMO-10 to PDPMO-30, with a relative pressure range ofP/P0 = 0.43–0.56. This is expected because of the geometrical con-strictions to accommodate a large number of lengthy BPDU bridg-ing groups in the mesopore walls of the PDPMO. The specificsurface areas of PDPMO-10, PDPMO-20, and PDPMO-30 were cal-culated to be 663, 430, and 316 m2 g�1, respectively. The specificsurface area of the PDPMOs decreased from 663 to 316 m2 g�1,with an enlargement of diureylenepiperazine moiety content inthe frameworks. It is worthy to mention that all PDPMO materialssynthesized with different fractions of BPDU have an orderedmesostructure with uniform pore size distributions. The pore diameterand pore volume of PDPMO-10, PDPMO-20, and PDPMO-30 were77, 62, and 54 Å and 1.26, 0.84, and 0.66 cm3 g�1, respectively,decreasing with the fraction of BPDU (Table 1). BPDU has a largemolecular size and the bulk organic groups which can occupy moreof the mesopore wall space when a large amount of the guest

Fig. 2. Transmission electron microscopic images of PDPMO-30.

Fig. 3. N2 adsorption–desorption isotherms of (a) PDPMO-10, (b) PDPMO-20 and (c)PDPMO-30.

Fig. 4. Pore size distribution of (a) PDPMO-10, (b) PDPMO-20 and (c) PDPMO-30.

Fig. 5. FT-IR spectra of (a) As-synthesized PDPMO-30, (b) PDPMO-10, (c) PDPMO-20 and (d) PDPMO-30; (b–d after solvent extraction).

S. Parambadath et al. / Microporous and Mesoporous Materials 141 (2011) 94–101 97

molecules are incorporated into the framework, no doubt resultingin a large reduction of the pore diameter and volume [1,39,40]. Byincreasing the BPDU fraction, more organic groups were incorpo-rated into the silica matrix, leading to a PDPMO-30 with a broadendistribution of the pore size and a slightly distorted hexagonalmesostructure. The results are well consistent with the XRD andTEM results.

Fig. 5 displays the FTIR spectra of as-synthesized and solventextracted PDPMO-n samples. In all the materials, the vibrationbands at 2984, 2928, and 2875 cm�1 were assigned to the CHstretching vibrations of propyl and piperazine moieties [1,4,5].These bands were intensified in the case of the FTIR spectra ofthe as-synthesized samples, due to the presence of surfactant mol-ecules inside the mesopore. A sharp and intense band at 1660 cm�1

was attributed to the C@O stretching vibration of the urea group[41–44]. The peaks at 1495 cm�1, together with 692 cm�1, resultedfrom the presence of the bending vibration of N–H, while the bandat 1442 cm�1 was characteristic of an N–C functional moiety insidethe material [45]. The peak from 1100 to 1000 cm�1 can be attrib-

uted to Si–O–Si stretching vibrations, while the peak at 670 cm�1

should be related to the bending vibration of the O–Si–O bond[20]. These results indicate the hydrolysis and co-condensation of

Fig. 7. (a) 29Si MAS and (b) 13C CP-MAS NMR spectra of PDPMO-30.

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the Si–OCH2CH3 groups. Moreover, the intensity of the 1660–1456 cm�1 band increased gradually from the PDPMO-10 to thePDPMO-30 sample, which signifies increased concentration of ureagroups in the resultant materials. A weak and small peak of1250 cm�1 in all the samples for the vibration of Si–C indicatedthat the Si–C bond was not broken during the synthesis process[46–48]. The weak signals at 1348 and 1377 cm�1 originated fromthe P123 surfactant residues, and their weak intensity indicated re-moval of most of the surfactants by solvent extraction.

XPS spectra of BPDU molecule and N,N0-diureylenepiperazinebridged PDPMO-30 are illustrated in Fig. 6. The analysis disclosedthe binding states of the major elements present in the material.The representative intensity and area of the peaks in the XPS spec-trum of BPDU can offer insight into the abundance of the variouselements within the material. For N 1s, a binding energy of399.9 eV was measured for PDPMO-30, which is in excellent agree-ment with the value for the parent BPDU (399.9 eV). The severalpeaks at ca. 99.1, 282.69, and 529.5 eV were a result of Si 2p, C1s, and O 1s, respectively [19].

The solid-state 29Si MAS NMR spectrum (Fig. 7a) of the surfac-tant-extracted PDPMO-30 material confirms successful incorpora-tion of the covalently anchored organic groups in the framework.Two groups of signals can be distinguished in the spectrum: (a)three Q signals from silicon atoms without organic substitution;(b) two T signals related to organo-substituted silicon. The Q sig-nals at �86, �94, and �101 ppm were assigned to Q2, Q3, and Q4

structures, respectively. The Q3 signal, corresponding to SiO3OH,was clearly dominating, while the Q4 signal was caused by theSiO4 groups generated from fully condensed silanol groups. TheQ2 signal, related to partially condensed SiO2(OH)2, contributedof a less percentage [49–51]. The signals originating from the sili-con, bridged by the organic group, can be found in the range of �45to �90 ppm, thus confirming the incorporation of organic groupsinside the framework [52]. The signals at �59 and �65 ppm canbe assigned to the silicon resonances of partially condensed T2

[(SiO)2(OH)SiC] and fully condensed T3 [(SiO)3SiC] sites, respec-tively, indicating both the presence of organic moieties inside theframework and the high degree condensation of the silanol groups.

Fig. 7b exhibits the 13C CP-MAS NMR spectrum of the PDPMO-30 sample after solvent extraction. Three signals (0–50 ppm) areobserved, due possibly to the Si–CH2CH2CH2– groups, demonstrat-ing the presence of the Si–C bond. The resonance at 9.6 ppm isattributed to a –CH2 (C1 carbon), which is directly bonded to a Siatom. The resonance at 22 ppm represents a –CH2 (C2 carbon),

Fig. 6. X-ray photoelectron spectra of (a) BPDU and (b) PDPMO-30.

30 ppm for a –CH2 (C4 carbon atom of the piperazine ring), and42 ppm (C3 carbon of the alkyl chain bonded to –NH group) canbe assigned to a –CH2, respectively. The clear resolution of the fourcarbons can be attributed to the homogeneous conformation of theorganic groups in the pore walls [53]. Furthermore, the resonanceof C@O at 161 ppm can also be observed with a weak intensity inPDPMOs.

The TG profile of PDPMO-30 is depicted in Fig. 8. Upon heatingin air, the material undergoes a total weight loss of 36%. The initialweight loss, until 393 K, was attributed to thermodesorption ofwater and corresponds to 7%. No significant weight loss (only ca.2%) was observed in the corresponding thermal decompositionrange of the surfactant (393–506 K), indicating a major removal

Fig. 8. TGA curve of PDPMO-30.

Fig. 10. (A) Captopril release profiles from (a) PDPMO-10 and (b) PDPMO-20. (B) 5-Fluorouracil release profiles from (a) PDPMO-10 and (b) PDPMO-20.

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of the template after solvent extraction. Decomposition of the or-ganic components of the material occurred between 506 and973 K, leading to a total weight loss of 26%. Presumably, the ratherextended temperature range was caused by several chemical reac-tions (urea decomposition, oxidation reactions, ‘‘channel metamor-phosis’’ via proton transfer from silanols to methylene groups)[49,54].

Fig. 9 presents SEM images of the PDPMO-10, PDPMO-20, andPDPMO-30 samples. As evident in Fig. 9a, PDPMO-10 consistsmainly of polyhedral bipyramidal crystals with relatively uniformparticle size distributions of approximately 1.5 lm (mean sizes).While increasing the amount of BPDU in PDPMO-20, the particlemorphology changed to a cylindrical bipyramidal structure witha mean particle size of 3.2 lm. A further increase of BPDU inPDPMO-30 fully changed the spherical morphology with a meanparticle size of 0.58 lm. Many factors, such as pH value, surfac-tant/silica ratio, hydrolysis or condensation rate of the silica pre-cursor, and hydrophilicity/hydrophobicity of the organosilanescan affect the morphology of the mesoporous silica. According toliteratures [55–57], the shapes of the mesoporous products dependstrongly on the silica source, the self-assembly of the silica and sur-factant at the two-phase interface, and the reaction conditions em-ployed. Our SEM images suggest that the organic groupsincorporated provide the pivotal factor to affect the particle mor-phologies. We may assume that various types of interactions, suchas electrostatic attraction/repulsion, hydrogen bonding, and hydro-phobic interactions, between the organosilane and surfactant mol-ecules at the micelle–water interface could be critical in producingthe various particle shapes and sizes. The formation of variousmesoporous organosilica particles begins with the nucleation,which involves silica–surfactant interactions that facilitate theassembly of organosilane micelles. This silica–surfactant interac-tion depends on the nature of both the silica source and the surfac-tant micelles. As a result, mesoporous organosilica particles can beformed in the various particle morphologies. More detailed discus-sion on the influence of different organosilanes on the morphologyformation is described elsewhere [38] with referring to literatures[55–57]. In this study, the trend of a gradual formation of thespherical morphology is due to the geometrical constrictions toaccommodate a large number of bulky BPDU bridging moleculesin the mesopore wall, generated from the tendency of tight packingand driven by the intermolecular hydrogen bonding between N,N0-bissilylated diureylene molecules. Thus, the amount of the hydro-philic precursor introduced into the synthesis may be enough todisturb the side-on growth mechanism [17] to generate a cylindri-cal morphology. The BPDU precursor used herein has a hydrophilicurea group, thus, the synthesis follows the above mechanism togive small spherical nanoparticles.

Fig. 10 shows the in vitro release profile of captopril and 5-flu-orouracil at 37 �C from the samples PDPMO-10 and PDPMO-20 into

Fig. 9. Scanning electron microscopic images of (a)

the simulated body fluid (SBF) at pH 7.4. Captopril/5-fluorouracilhas been introduced into both materials (PDPMO-10 andPDPMO-20) in order to study the influence of organosilica loading,pore size, and particle morphology in drug release. The captopril/

PDPMO-10, (b) PDPMO-20 and (c) PDPMO-30.

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5-fluorouracil loading capacity was directly related to the contentof the ureylene moiety in the PMO materials. When increasing thecontent of the functional groups, the captopril/5-fluorouracil loadingcapacity was greatly enhanced.

All the release profiles were similar and exhibited sustainedproperties for both PDPMO-10 and PDPMO-20. The release profilesof PDPMO-30 may be assumed to have similar release profiles asthose of the two PDPMO’s, though the data are not shown here.A relationship between the drug release rate and the particles sizeof the PMO is observed. Because the pore size (7.7 and 6.2 nm) andsurface properties of the two samples only had a slight difference,the variation in drug release rate may be reasonably ascribed tothese properties of the carriers. The particle size for the samplesPDPMO-10 and PDPMO-20 exhibited a dramatic increase from�1.5 and 3.25 lm. Although there was a 15 Å difference in poresize of when comparing PDPMO-10 and PDPMO-20 materials inthis study, it was generally observed that decreasing the pore sizeof the host material lead to a slower drug release rate. The longmesoporous channel for the sample PDPMO-20 was also a favor-able factor for slower release of captopril/5-fluorouracil. The aboveresults show that the composition and morphology of the carrierswere important factors in influencing drug delivery performance[34,58,59].

The drug release process can be presumed to be mainly diffu-sion controlled. On the one hand, the release medium penetratesinto the drug-matrix phase through pores; on the other hand, thedrug dissolves into the release medium and diffuses from the sys-tem, along with the solvent filled pore channels. This processwould be practically supported by the hydrophilic nature of the sil-ica surface and the diureylene bridge molecule in the pore walls ofthe PMOs. Additionally, a large difference in the initial drug releaserate for both PMOs is observed. For instance, the captopril releaseoccurred at 43% within 4 h, while only 36% of 5-fluorouracil mole-cules were released from the sample PDPMO-10. After the initialrelease, a slower desorption was observed for captopril, while adrastic release occurred for 5-fluorouracil. This may be due tothe diminished interaction between 5-fluorouracil and diureylenemolecules, than with captopril. It is believed that captopril mole-cule is more hydrophilic than 5-fluorouracil. The drug release fromPDPMO-10 seems to be complete within 48 h, particularly for 5-fluorouracil as no release is observed after 36 h. It may be assumedthat all of drugs adsorbed within pores may be released after long-er immersion time for both drugs, but only under harsh experi-mental conditions such as high temperature, high pressure andlong stirring, and so on.

The drug release profile from the sample PDPMO-20 was strictlyin a controlled manner for both captopril and 5-fluorouracil. Whencomparing the initial desorption behavior of both drugs, captoprilreleased 18%, while 5-fluorouracil approximately 28% within 4 h.After that, a reduced amount of drug release was observed for bothdrugs, which may be due to many favorable factors such as particlesize, pore diameter, a greater amount of organosilane loading, andlonger channels of the PDPMO-20 than PDPMO-10. Therefore, itcan be concluded that morphology, amount of organo-bridgedmolecule, and pore diameter play an important role in the drug re-lease behavior from the host material [31].

The nature of the drug molecule and its interaction with thehost matrix also play an important role in controlled release[31,40]. It has been shown elsewhere [60] that the driving forcefor the inclusion of the drug inside the PMO seems to be the hydro-gen bond interactions between the drug molecule and the iminefunctionality or carbonyl functionality in the pore walls. The rea-sons why drugs chosen were in the present study were lie in thatthe first one is highly hydrophilic and the second one is weaklyhydrophilic. Captopril hydrogen binds with the diureylene easierthan 5-fluorouracil, due to the presence of a carboxylic functional-

ity in its molecular structure. Therefore, for the same PMO mate-rial, the release of captopril/5-fluorouracil into the SBF is moredependent on its hydrophilic or hydrophobic nature. Interestingly,the captopril release rate could be well modulated by PDPMO-20than by 5-fluorouracil, which may be a consequence when thehigher hydrophilicity of captopril combines with host propertiessuch as increased amounts of organosilane inside the pore wall,higher particle size, and reduced pore diameter.

4. Conclusions

New symmetrical diureylenepiperazine-bridged mesoporousorganosilicas have been successfully synthesized by a one-stepco-condensation of TEOS and BPDU precursors in the presence ofPluronic P123 as a template. The formation of the uniform and or-dered mesoporous materials was confirmed from the SAXS, N2-iso-therm, and TEM analyses. It was found that the surface area, porediameter, and pore volume decreased, while increasing the organicmoiety inside the PMO materials as a result of the geometricalrestriction of the long bissilylated diureylene molecule to accom-modate the wall structure without any cleavage to the Si–C bond.The maximum amount of organic groups incorporated into thePMO reached 30 mol%, according to the total silane content. SEMimages revealed that the materials exhibited a tendency to becomespherical in morphology, upon increasing the amount of BPDU inthe hybrid material. However, incorporation of a complex organicgroup slightly decreased the macroscopic order. The presence ofthe highly hydrophilic ureylene moieties strongly supported theuse of the materials as an excellent controlled drug delivery systeminto the SBF release medium.

Acknowledgements

This work was supported by the Ministry of Education, Scienceand Technology (MEST) through the National Research Foundationof Korea (NRF) with the Acceleration Research Program (No.20100000790), the Pioneer Research Center Program (2010-0019308/2010-0019482), the Korea–China Joint Research CenterProgram on Mesoporous Thin Films (K20803001459-10B1200-00310), the WCU program, and the Brain Korea 21 Project of theMEST. DYZ thanks the financial supports from NSC of China.

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