Solid lipid nanoparticles (SLN) templating of macroporous silica beads{

Andreea Pasc,*a Jean-Luc Blin,a Marie-Jose Stebea and Jaafar Ghanbajab

Received 1st September 2011, Accepted 2nd September 2011

DOI: 10.1039/c1ra00659b

We report the first example of solid lipid nanoparticles (SLN)

templating silica. The biocompatible nanoparticles were obtained

from cetylpalmitate and Tween 20 via the solvent injection

method. The macroporous material consists of silica beads of 0.5–

1.5 mm with a hollow morphology, imprinting from the starting

SLN, of 50–400 nm in size.

Porous materials design remains an important scientific and

technological issue due to their wide range of applications in

catalysis,1 sensing,2 sorption or separation3 processes.

Colloidal templating has been widely used to fabricate such

materials4 with different shapes and sizes ranging from several nm

(micro and mesoporous) to several microns (macroporous).

Hierarchical macro–mesostructured silica has been successfully

synthesized by the use of self-assembled templates of colloidal

spheres5 such as polystyrene (PS), poly(methyl methacrylate)

(PMMA) latex spheres, silica spheres,6 and emulsion droplets7 with

a narrow size distribution.

Silica is also known to be safe, not only for the environment, but

also for the human body within a certain range of administrated

dose, approved by US Food and Drug Administration (FDA).8

Therefore, its application field may be extended to biocompatible

materials, such as bone substitutes, cements for bone repair and

reconstruction, enzyme and cell immobilization, biocatalysis or

biosensors9 and, recently, for oral drug delivery.10

In the soft matter field, Solid Lipid Nanoparticles (SLN) appeared

very recently as promising drug carriers especially for their potential

applications in pharmaceutics.11 Therefore, combining inorganic

silica matter with a solid lipid, SLN appears as a straightforward

approach for the development of novel hybrid organic–inorganic

biocompatible materials.

SLN have not only a limited toxicity, but they can be produced in

a cost-effective fashion, by different formulation techniques: high

pressure homogenization, emulsification–sonication, microemulsion,

double emulsion, solvent emulsification–evaporation, solvent diffu-

sion and solvent injection. The last one was chosen for the synthesis

of the SLN reported herein,12 since it presents clear advantages over

the existing methods, such as easy handling and fast production

process without technically sophisticated equipment. The solvent

injection method, similar to solvent diffusion method, is based on

lipid precipitation from a dissolved lipid in solution.

The SLN-templated porous material was prepared{ by adding a

silica source (tetramethoxylsilane, TMOS), at neutral pH, on SLN

dispersion, and the mixture was kept in an autoclave at 70 uC to

allow the hydrolysis/polycondensation of the silica. The inorganic

material was obtained after the removal of the organic nanoparticles

by ethanol/dichloromethane extraction. The designed strategy

synthesis is illustrated in Fig. 1.

aSRSMC UMR 7565, Nancy-Universite, BP 70239, F-54506, Vandoeuvre-les-Nancy, France. E-mail: andreea.pasc@srsmc.uhp-nancy.fr;Fax: (0033)383684322; Tel: (0033)383684344bSCMEM, Nancy-University, BP 239, 54506, Vandoeuvre-les-Nancy,France{ Electronic Supplementary Information (ESI) available: Experimentaldetails, DLS hydrodynamic diameter measurements, BJH adsorptionisotherms, SAXS data of SLN and porous silica. See DOI: 10.1039/c1ra00659b/

Fig. 1 Schematic illustration of SLN formation and templating of

macroporous silica beads.

RSC Advances Dynamic Article Links

Cite this: RSC Advances, 2011, 1, 1204–1206

www.rsc.org/advances COMMUNICATION

1204 | RSC Adv., 2011, 1, 1204–1206 This journal is � The Royal Society of Chemistry 2011

Publ

ishe

d on

28

Sept

embe

r 20

11. D

ownl

oade

d on

29/

10/2

014

02:1

3:28

. View Article Online / Journal Homepage / Table of Contents for this issue

The SLN were prepared{ by mixing under stirring, a solution of

cetylpalmitate (n-hexadecylpalmitate, NHP) in THF to a hot (65 uC)

diluted solution of a biocompatible surfactant, Tween 20. Dynamic

light scattering (DLS) measurements and transmission electron

microscopy (TEM) micrographs (Fig. 2) revealed that the suspension

was composed of spherical (a-form) particles ranging from 50 to

400 nm, centered at 250 nm. The particles were stable for more than

1 month and no gelation was observed, probably due to the absence

of polymorphic transformations of the solid lipid during the

storage.13

Small-angle X-ray scattering (SAXS) investigations (Fig. S1) show

that the cetylpalmitate powder is polymorphic whereas the lipid of

the SLN is arranged in a lamellar lattice structure, since the X-ray

diffractogram exhibits the 100 and 300 peak reflections, the 200 being

very low. The corresponding interlayer spacing is 3.9 nm (compared

to 4.1 nm found in the literature14) and remains constant in

the hybrid organic–inorganic material. The lamellar structure of the

SLN was confirmed by TEM analysis (Fig. S3). At 1.5%, the

concentration used to prepare the SLN, Tween 20 forms micelles

(cmc = 8 6 1025 M) of around 10 nm in diameter (Fig. S2).

However, herein the surfactant is essentially stabilizing the SLN

dispersions, and no micelles were observed neither by DLS nor by

SAXS measurements.

SAXS data of SLN-free silica material (data not shown) exhibit a

broad low angle reflection in the region 4–7 nm, which suggests the

existence of unorganized mesopores.

Evidence of the mesoporosity can also be reached from the

nitrogen adsorption isotherms (Fig. S4). According to the IUPAC

classification, the sample exhibits a type II isotherm, characteristic of

macroporous material. The pore size distribution obtained by the

BJH method applied to the adsorption branch of the isotherm

evidences mesopore sizes of 7 nm. However, the low volume of

dV/dD indicates that the proportion of mesopores in the sample is

rather weak. The BET specific surface area and the mesopore

volume are 50 m2 g21 and 53 mm3 g21, respectively. The macro-

porous network can be observed by SEM analysis. As a matter of

fact, silica beads containing spherical macropores of 0.5–1.5 mm in

diameter are clearly shown in Fig. 3. The pores are not well ordered

and range between 50 and 150 nm. Also, large hollow silica beads

were observed and the cavity diameter is around 500 nm. These

macropore diameters are of the same order of magnitude as the

starting SLN. Deeper insights on the morphology of the material

were reached by TEM. The thickest silica external shell was 80 nm

and the thinnest silica internal wall was 4 nm (Fig. 4c).

Clear evidence of the macroporosity can be reached from mercury

intrusion porosimetry measurements§(Fig. 5). The specific surface

area of the sample (27.1 m2 g21) is smaller than the BET surface area

but the porous volume is more than 10 times higher (864 mm3 g21).

As indicated in Table 1, the pores smaller than 438 nm are

responsible for the surface area of the sample, whereas they represent

only 39% of the relative pore volume. The material exhibits a

multimodal size distribution: three broad peaks centered at 9, 68 and

450 nm in diameter. The peak at 9 nm could be attributed to

Fig. 2 TEM micrograph of prepared SLN (insert: hydrodynamic diameter

of SLN as determined by DLS).

Fig. 3 SEM micrographs of SLN-templating porous silica beads.

Fig. 4 TEM micrographs of SLN-templating porous silica.

This journal is � The Royal Society of Chemistry 2011 RSC Adv., 2011, 1, 1204–1206 | 1205

Publ

ishe

d on

28

Sept

embe

r 20

11. D

ownl

oade

d on

29/

10/2

014

02:1

3:28

. View Article Online

mesopores. The increase in the Hg adsorption isotherm above 3 mm

could be attributed to inter-particular distances between hollow silica

beads. Finally, the peak at 450 nm could correspond to the hollow

silica whereas the one at 68 nm corresponds to the secondary, multi

cavity structure of some silica beads. Thus, one can conclude that

these pores are the imprint of the starting morphology of the

nanoparticles and appear as spherical cavities, as it was visualized by

scanning and transmission electron microscopy (Fig. 3 and 4).

In conclusion, we report the synthesis of macroporous silica via

SLN template-directed hydrolysis–polycondensation reactions of

TMOS. To the best of our knowledge, this templating route is the

first example reported in the literature. Work is underway to tune the

size of the SLN in order to control the porosity of the resulting silica

and to further organize the inorganic matter at the mesoporous–

macroporous scale. SLN-silica matter could be tailored afterwards as

drug carriers with a potential application in cosmetics and

pharmaceutics, such as oral drug delivery.

The authors would like to thank Amelie Clement (masters student)

for her contribution to this work, Melanie Emo for performing the

X-ray measurements, Jonathan Jacoby and Anna May for the

nitrogen adsorption–desorption isotherms and Lionel Richaudeau

for the mercury intrusion porosimetry analysis.

References

{ General procedure of SLN preparation: A cold solution of NHP (10%) inTHF was added to a 10 mL dispersion of Tween 20 (1.5%) maintained at70 uC under magnetic stirring, at a flow rate of 10 mL min21. The milkysuspension spontaneously formed was kept under stirring until the solventwas completely evaporated and the room temperature was reached. Generalprocedure of the material preparation: To a 5 mL dispersion of SLNcontaining 10% solid lipid and 1.5% Tween 20 was added 150 mg of TMOS atneutral pH and kept at 70 uC for 24 h. Then, the resulting mixture waswashed with dichloromethane and ethanol until the solid lipid and thesurfactant were completely removed (as verified by FT-IR by following thedisappearance of the CLO band at 1732 cm21).§ Mercury intrusion porosimetry measurements (MIP) were performed onPascal 140/240 Instrument (Thermo Scientific).

1 (a) A. Corma, Chem. Rev., 1997, 97, 2373–2419; (b) J. F. Brown, P. Krajncand N. R. Cameron, Ind. Eng. Chem. Res., 2005, 44, 8565–8572.

2 M. S. Silverstein, H. Tai, A. Sergienko, Y. Lumelsky and S. Pavlovsky,Polymer, 2005, 46, 6682–6694.

3 A. Stein, Adv. Mater., 2003, 15, 763–775.4 (a) G.-R. Yi, J. H. Moon and S.-M. Yang, Chem. Mater., 2001, 13,

2613–2618; (b) P. S. Winkel, W. W. Lukens, P. Yang, D. I. Margolese,J. S. Lettow, Y. J. Ying and G. D. Stucky, Chem. Mater., 2000, 12,686–696.

5 A. N. Khramov and M. M. Collinson, Chem. Commun., 2001, 767.6 H. Zhang and A. I. Cooper, Ind. Eng. Chem. Res., 2005, 44, 8707–8714.7 (a) A. Imhof and D. J. Pine, Nature, 1997, 389, 948–951; (b) T. Sen, G. J.

T. Tiddy, J. L. Casci and M. W. Anderson, Microporous MesoporousMater., 2005, 78, 255–263; (c) J. L. Blin, R. Bleta, J. Ghanbaja and M. J.Stebe Micropor., Microporous Mesoporous Mater., 2006, 94, 74–80.

8 Complementary Medicine Evaluation Committee extracted ratifiedminutes, sixteenth meeting, 1999.

9 (a) T. Reiner, S. Kababya and I. Gotman, J. Mater. Sci.: Mater. Med.,2008, 19, 583–589; (b) J. R. Jones, S. Lin, S. Yue, P. D. Lee, J. V. Hanna,M. E. Smith and R. J. Newport, Proc. Inst. Mech. Eng., Part H, 2010, 224,1373–1387; (c) A. Hertz and I. J. Bruce, Nanomedicine, 2007, 2, 899–918;(d) J. Moura, L. N. Teixeira, C. Ravagnani, O. Peitl, E. D. Zanotto, M. M.Beloti, H. Panzeri, A. L. Rosa and P. T. De Oliveira, J. Biomed. Mater.Res., Part A, 2007, 82, 545–557; (e) G. L. Yuan, M. Y. Yin, T. T. Jiang,M. Y. Huang and Y. Y. Jiang, J. Mol. Catal. A: Chem., 2000, 159, 45–50;(f) D. M. Liu and I. W. Chen, Acta Mater., 1999, 47, 4535–4544.

10 (a) S.-H. Cheng, W.-N. Liao, L.-M. Chen and C.-H. Lee, J. Mater. Chem.,2011, 21, 7130–7137; (b) A. Tan, S. Simovic, A. K. Davey, T. Rades andC. A. Prestidge, J. Controlled Release, 2009, 134, 62–70; (c) M. Manzano,M. Colilla and M. Vallet-Reg, Expert Opin. Drug Delivery, 2009, 6,1383–1400; (d) A. Tan, S. Simovic, A. K. Davey, T. Rades, B. J. Boyd andC. A. Prestidge, Mol. Pharmaceutics, 2010, 7, 522–532; (e) S. Simovic, P.Heard, H. Hui, Y. Song, F. Peddie, A. K. Davey, A. Lewis, T. Rades andC. A. Prestidge, Mol. Pharmaceutics, 2010, 6, 861–872.

11 (a) S. Das and A. Chaudhury, AAPS PharmSciTech, 2011, 12, 62–76; (b)R. H. Muller, K. Mader and S. Gohla, Eur. J. Pharm. Biopharm., 2000, 50,161–177.

12 M. A. Schubert and C. C. Muller-Goymann, Eur. J. Pharm. Biopharm.,2003, 55, 125–131.

13 T. Helgason, T. S. Awad, K. Kristbergsson, D. J. McClements and J.Weiss, J. Am. Oil Chem. Soc., 2008, 85, 501–511.

14 G. Lukowski, J. Kasbohm, P. Pflegel, A. Illing and H. Wulff, Int. J.Pharm., 2000, 196, 201–205.

Fig. 5 Pore size distribution obtained by applying the Washburn equation

to the mercury intrusion curves.

Table 1 Hg intrusion porosimetry results

Pore diameterranges (mm)

Relative volume(mm3 g21)

Relative surface(m2 g21)

10000–0.438 528 (61%) 1.50.438–0.001 336 (39%) 25.6

1206 | RSC Adv., 2011, 1, 1204–1206 This journal is � The Royal Society of Chemistry 2011

Publ

ishe

d on

28

Sept

embe

r 20

11. D

ownl

oade

d on

29/

10/2

014

02:1

3:28

. View Article Online