Critical Considerations in the Biomedical Use of Mesoporous Silica

Perspective pubs.acs.org/JPCL

Critical Considerations in the Biomedical Use of Mesoporous Silica Nanoparticles Yu-Shen Lin,† Katie R. Hurley,† and Christy L. Haynes* Department of Chemistry, University of Minnesota, 207 Pleasant Street Southeast, Minneapolis, Minnesota 55455, United States ABSTRACT: Since the first report of mesoporous silica nanoparticles in 2001, many efforts have been made to develop them for biomedical applications. With the emergence of new designs and increasingly complex synthetic schemes, mesoporous silica nanoparticles have never been more promising. For this promise to be fulfilled, however, practical considerations for biomedical use must be carefully addressed. Many current mesoporous silica reports, even those reporting in vivo work, neglect the observation of nanoparticle size, pore structure, aggregation state, and biodegradability under biological conditions before administration. These critical considerations, beginning at synthetic stages, must be taken into account to make effective and safe mesoporous silica nanoparticles for biomedical use and timely application in clinical trials. Herein, we present a comprehensive review of mesoporous silica nanoparticle synthetic strategies, pointing out nanoparticle behavior under biological conditions and how it may affect in vitro and in vivo results.

N

large pore volume, uniform and tunable pore size, and facile functionalization.4 The surfactant-templated synthesis of MS materials (Mobil Composition of Matter No. 41, MCM-41) was first discovered at Mobil in 1992,5 but MCM-41 was not investigated in biomedical studies until 2001 when it was first demonstrated as a support for drug delivery systems.6 Fowler et al.7 and Cai et al.8 both developed syntheses for MS NPs in 2001, reporting materials small enough to be considered for drug delivery. Since these initial reports, extensive studies have been performed involving improved MS NP synthesis, incorporation of multifunctionality, and in vitro/in vivo studies. Herein, a timeline scheme (Figure 1) is used to illustrate the development of MS NPs for biomedical applications. In 2003, Lai et al. demonstrated the first modified MS NP to facilitate stimuli-responsive controlled release of neurotransmitters and drugs via chemically removable NPs as caps.9 Since then, researchers have investigated the addition of various components to achieve a multitude of diagnostic or therapeutic effects, including controlled drug release,9−19 cell labeling,20−22 and targeting.23−28 Subsequent cytotoxicity studies are often performed, examining the new effects of these components.29,30 In 2006, multifunctional MS NPs with imaging capabilities were synthesized and reported separately by two groups.21,31 To date, scientists have designed different routes to incorporate imaging agents, such as fluorophores (for fluorescence imaging),20 superparamagnetic NPs,21,31−34 or gadolinium ions22 (for magnetic resonance imaging, MRI), into single MS NPs. These multifunctional MS NPs facilitate uptake and accumulation studies in cells or animals. In 2008, researchers began investigating the in vivo behavior of MS NPs including biodistribution,34−39

anotherapeutics, drug-delivery vehicles with sizes on the nanometer scale, have gained much attention over the last few decades due to their potential for efficient drug delivery and reduced systemic side effects. In contrast to traditional therapies, which involve either untargeted treatment or invasive access to the site of interest, nanoparticles (NPs) may be designed such that, once in the bloodstream, they target sites of disease, such as tumors, and deliver their cargo selectively. Researchers also envision vehicles that incorporate imaging capabilities, overcome drug resistance, operate with zero-order release profiles (i.e., sustained release at relevant concentrations), and degrade safely over time. To date, various types of NPs, such as polymeric, metal, metal oxide, and semiconductor NPs, have been synthesized and used as platforms to integrate therapeutic and diagnostic functions in a single NP, called multifunctional NPs or nanotheranostics.1−3 One system that can accommodate such extensive multifunctionality is mesoporous silica (MS) NPs based on their high surface area,

The critical requirements for in vivo nanotherapeutics are discrete size, small hydrodynamic diameter, and excellent dispersity in physiological aqueous conditions. However, to date, there are only a few syntheses that match these requirements.

© 2012 American Chemical Society

Received: October 14, 2011 Accepted: January 11, 2012 Published: January 11, 2012 364

dx.doi.org/10.1021/jz2013837 | J. Phys. Chem. Lett. 2012, 3, 364−374

The Journal of Physical Chemistry Letters

Perspective

Figure 1. Schematic representation of MS NP development toward biomedical use.

clearance,36,37 toxicity,36−39 and tumor therapy32,38,39 in an effort to move MS NPs toward clinical applications. Although MS NPs have already undergone extensive study for biomedical applications over the past decade, there are several critical issues that must be considered before clinical use of MS NPs. For example, if MS NPs are administrated by intravenous (iv) injection, the blood circulation time and biodistribution are mainly dependent on their effective diameter and surface properties. It is known that large NPs (>100 nm in diameter) or aggregated NPs are rapidly taken up by the reticuloendothelial system (RES), limiting in vivo efficacy.40 Nonspecific protein adsorption to MS NP exterior surfaces also causes an effective diameter increase and may lead to the same RES uptake.41,42 In addition, the population of adsorbed proteins likely influences the MS NP cellular uptake and fate. Therefore, significant effort must be focused on controlling the size and stability of MS NPs under relevant biological conditions (37 °C, highly salted or serum-containing media) before administration to animals. Another critical concern is the unintentional toxicity of MS NPs. Any possible adverse effects caused by MS NPs should be carefully examined to ensure the safety of MS NPs for in vivo use. Small hydrodynamic size, high stability, and minimal unintentional toxicity are basic requirements and desired properties for stealth drug delivery systems, especially iv-injectable NPs. Several recent review articles have focused on controlled release, in vitro drug delivery, and general toxicity of MS NPs.43−47 In contrast, this Perspective will highlight synthetic developments and progress in the field, drawing attention to critical synthetic considerations that must be addressed before the practical use of MS NPs. We present a review of reported MS NP synthesis methods, strategies to improve MS NP stability, and a discussion of MS NP biodegradability. In addition, we provide specific examples of both multifunctional MS NP systems and in vivo studies in which these considerations should be applied. Summary of Syntheses: Controlling Size, Hydrodynamic Diameter, and Pore Structure. According to the critical considerations mentioned above, the first essential requirement of MS NPs for in vivo therapeutic applications is small size. MS NP size is mainly determined by the preparation method used. In the early development of MS NPs, scientists focused on improving the synthesis of MS NPs, making efforts to control the size, pore structure, and stability of MS NPs to broaden their use. A comprehensive summary of published MS NP syntheses is presented in Table 1. Typical transmission electron microscopy (TEM) images of MS NPs prepared from different research groups are shown in Figure 2. A general synthetic scheme is as follows: a silica precursor such as tetraethyl orthosilicate (TEOS) is added to a surfactant solution; next, a mineralizer

such as NH4OH or NaOH is added, which allows the TEOS to hydrolyze around the spherical surfactant micelles; and then, the silicate micelles self-assemble into cylinders around which silica continues to condense to form the final hard structure. Surfactants must then be removed by calcination, solvent extraction, or dialysis. MS NPs with diameters small enough for biomedical consideration were first synthesized in 2001. Fowler et al. demonstrated the use of excess water followed by neutralization to quench particle growth.7 The size and pore structure were controlled by altering the time between the water addition and pH neutralization steps. Cai et al. used an extremely low surfactant (cetyltrimethylammonium bromide, CTAB) concentration to synthesize MS NPs with a diameter of around 110 nm (Figure 2a).8 In the following years, many research groups adopted these dilute conditions accompanied by other strategies, such as the addition of a cosolvent or a second surfactant as a particle growth suppressant, to prepare size-controlled MS NPs.7−9,42,48−59 For example, Nooney et al. varied the MS particle size from 65 to 750 nm by adjusting the TEOS/CTAB ratio in dilute conditions and using ethanol as a cosolvent.48 Yano et al. simply used tetramethyl orthosilicate as a silica precursor and changed the methanol cosolvent amount to obtain spherical, monodisperse MS NPs (controlled diameters ranged from 150 to 860 nm).51 Suzuki et al. employed the double surfactant method, using a triblock copolymer, Pluronic F127, as a second template to suppress particle growth.50 MS NPs having well-ordered pore structure and diameters less than 50 nm were successfully obtained using this double surfactant system; however, these small MS NPs showed severe aggregation in TEM images (Figure 2b). Pore architecture may also be influenced by changes in the surfactant system. Han et al. employed novel fluorocarbon surfactants as a particle size quencher and nonionic block copolymers as pore-structuredirecting agents to synthesize MS NPs with 3D cubic pore structure (Figure 2c) rather than the more typical hexagonal pore structure.52 Before 2007, all MS NP preparation work only confirmed the particle size by TEM or scanning electron microscopy (SEM) images. In 2007, however, Moller et al. developed a method that utilized triethanolamine (TEA) as a base to synthesize stable colloidal suspensions of size-controlled MS NPs.53 In this study, dynamic light scattering (DLS) was first used to examine the hydrodynamic diameter of as-prepared MS NPs. Since then, DLS has been considered an essential characterization method for MS NP synthesis work, especially for the use of MS NPs in biological applications. It can be used to determine not only MS NP size but also aggregation state as a correlative technique to TEM. It should be noted, however, that the Stokes−Einstein 365


TEOS

TMOS

TEOS

TEOS

TEOS

TEOS

C16TAC

CnTAC (n = 14, 16, 18)

Pluronic F127, P65, P123, F108 C16TAC

Pluronic P123

C16TAB

366

a

ordered 3D cubic ordered 2D hexagonal

ordered 2D hexagonal ordered 2D hexagonal disordered disordered

ordered 2D hexagonal ordered 2D hexagonal ordered 2D hexagonal ordered 3D cubic wormlike

ordered 2D hexagonal ordered 2D hexagonal ordered 2D hexagonal disordered

pore structure

42

100−220

100−300 100 nm) in size. To address the problem of large size, Lu et al. simply adjusted the concentration of ammonium hydroxide (pH value) to synthesize MS NPs with sizes around 30 nm (based on TEM analysis).55 Unfortunately, the DLS data showed that MS NPs with this small size formed irreversible aggregates after the surfactant removal step. This paper pointed out that surfactant template removal is an important step to obtain well-dispersed and discrete MS NPs in addition to minimizing MS NP size. Removal of the surfactant is generally performed by calcination (high-temperature decomposition) or solvent extraction. During calcination, MS NP drying and high-temperature treatment cause interparticle condensation, resulting in irreversible aggregation and very poor dispersity in aqueous solutions. Another commonly used method is solvent extraction. Although this method greatly improves the dispersity of MS NPs after surfactant removal compared to calcination, small MS NPs (80%). On the basis of quantitative analysis of Si content in organs (measured by inductively coupled plasma optical emission spectrometry, ICP-OES), the authors found that spherical and short-rod MS NPs mainly accumulated in the liver. The long-rod MS NPs were mainly distributed in the spleen. In addition, after PEGylation, both spherical and rodshaped MS NPs had increased accumulation levels in the lungs. The authors further found that the clearance of MS NPs is shape-dependent. Spherical and short-rod MS NPs have faster excretion rates than long-rod MS NPs by both renal and hepatobiliary excretion routes. The high biocompatibility of the spherical and rod-shaped MS NPs was confirmed by hematological, serological, and histopathology results, which are consistent with previous reports studying spherical MS NPs.36,38 On the basis of the currently published in vivo studies mentioned above, various types of MS NPs including unmodified, positively charged, PEGylated, or different shaped MS NPs preferentially accumulate in RES. In addition, MS NPs are highly biocompatible, degradable, and excreted by urine and feces. The first example of preferential accumulation of Fe3O4coated fluorescent MS NPs with PEG postmodification (hydrodynamic size ∼ 100 nm in PBS) in a tumor site via the enhanced permeability and retention (EPR) effect was reported by Kim et al. in 2008.32 In addition to the tumor, strong fluorescence was measured from other organs, including the liver and spleen, indicating that many of the injected particles were trapped by the RES. In very recent work reported by Nel and co-workers,39 the authors clearly show the effect of the hydrodynamic size on biodistribution and consider the passive targeting efficiency of MS NPs. Three types of

PEI: poly(ethylene imine); NHS-PEG-Mal: N-hydroxysuccinimide-polyethylene glycol-maleimide.

phospholipid-PEG-amine for folate attachment multiple steps to modify amine groups with disulfide bonds for collagen conjugation epoxy-silane for transferrin attachment; mercapto-silane for RGD conjugation

Figure 5. (a) Biodistribution images of fluorescent MS NPs in an anesthetized rat before and after iv injection. (b) Photographic image and (c) corresponding fluorescent images of dissected organs from a rat 3 h after iv injection. All figures are modified and reproduced with permission from ref 35. Copyright 2009, Wiley Publishing Company.

a

MDA-MB-231 (breast cancer cell) BT-474 (breast cancer cell) amino-silane for mannose attachment NHS-PEG-Mal for anti-herceptin attachment

mannose monoclonal antibody, Herceptin folic acid lactobionic acid in collagen transferrin (Tf) and cyclic-RGD

100 ∼100

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Ferris, 201128

Liong, 200823 Rosenholm, 200924 Brevet, 200925 Tsai, 200926 100−200 400 PANC-1 (pancreatic cancer cell) HeLa (cervical cancer cell) amino-silane for folate attachment PEI layer for folate attachment folic acid folic acid

modification methoda targeting ligand

Table 3. Summary of Reported Targeted MS NPs

targeted cell

particle size (TEM or SEM, nm)

hydrodynamic diameter (DLS, nm)

reference


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use in Figure 7. These simple requirements, including size characterization (primary and hydrodynamic size), particle

near-infrared fluorophore-labeled MS NPs, (1) phosphonatecoated MS NPs (primary size: 100 nm; hydrodynamic size in PBS: 520 nm, denoted as NP1), (2) PEGylated MS NPs (primary size: 50 nm; hydrodynamic size in PBS: 597 nm, denoted as NP2), and (3) PEI−PEG-coated MS NPs (primary size: 50 nm; hydrodynamic size in PBS: 110 nm, denoted as NP3) were injected into mice with xenografted tumors for consideration of biodistribution. As shown in Figure 6, NP1 was mainly trapped

Figure 7. Diagram of considerations in design of MS NPs for the biomedical applications.

stability and degradation behavior in biological media at physiological conditions, and in vitro toxicity, are critical and would be best addressed during the experimental design of new MS NPs for in vivo use, not in the midst of development as a problemsolving maneuver. As new components are introduced, no matter their function, we have shown that these fundamental MS NP characteristics must be well-studied before the new system is considered for in vitro or in vivo analysis. We look forward to new MS NPs that will satisfy these requirements, pushing them closer to application in clinical trials.

Figure 6. Biodistribution of NIR fluorophore-labeled MS NPs with different surface modifications to the KB31-luc tumor xenograft model in nude mice at different time points after NP injection. The figure is reproduced with permission from ref 39. Copyright 2011, American Chemical Society.

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AUTHOR INFORMATION

Corresponding Author

in the liver and spleen within 24 h, and both NP2 and NP3 show less RES uptake along with longer circulation times. NP3 further showed prominent uptake in the tumor site by the EPR effect at 24 h. The accumulated mass percentages of the total mass of the injected particle (quantified by inductively coupled plasma optical emission spectrometry, ICP-OES) of NP1, NP2, and NP3 in the tumor were ∼1, ∼3, and ∼12%, respectively. These results clearly show that the particle size and dispersity play a key role in MS NP passive tumor targeting. In addition, this work further demonstrates that passive targeting by MS NPs greatly reduces the systemic side effects of chemotherapy, making progress into clinical trials more likely. Future Perspective. Over the last 10 years, there has been extensive progress toward developing size-controlled, multifunctional MS NPs for biomedical applications. Encouraging results have been presented, demonstrating not only drug delivery but effective cell-specific targeting, enhanced contrast imaging, and stimuli-controlled drug release. Several recent reviews have highlighted the growth edges in this field. Experts contend that MS NPs will become even more sophisticated, incorporating imaging, targeting, and controlled release capabilities into one platform. Multiple reviews have highlighted the need for in vitro studies examining intracellular localization of MS NPs and their eventual biodegradation in the cell. In addition, in vivo studies such as those reviewed herein should be expanded to investigate long-term biodistribution, excretion, and therapeutic efficacy of different MS NP types.43−47 As these research directions are addressed, we emphasize that studies will provide the most accurate results if the MS NPs demonstrate small size, high colloidal stability in biological environments, controlled biodegradation, and high biocompatibility. We simply summarize our Perspective on the essential considerations to design ideal MS NPs for in vivo biomedical

*E-mail: [email protected]. Web: http://www.chem.umn.edu/ groups/haynes/. Fax: +1 612-626-7541. Tel: +1 612-626-1096. Author Contributions †

These authors contributed equally to this work.

Biographies Yu-Shen Lin is currently a Ph.D. candidate in chemistry with Christy L. Haynes at the University of Minnesota. He received his B.S. (2002) and M.S. (2004) in chemistry from National Chung Cheng University and National Taiwan University, respectively. His research interests include synthesizing novel nanotheranostics and assessing their cytotoxicity. Katie R. Hurley is currently a graduate student in chemistry studying under Christy L. Haynes at the University of Minnesota. She received her B.A. (2010) in chemistry from Carthage College, Kenosha, WI. Working as a NSF graduate research fellow, her research interests include the design and synthesis of multifunctional mesoporous silica nanoparticles for combined chemo- and photothermal therapy applications. Christy L. Haynes is an associate professor at the University of Minnesota. During her time at the University of Minnesota, Christy has been recognized with multiple prestigious awards including designation as a Searle Scholar, a NIH New Innovator, a Dreyfus Teacher−Scholar, and a Sloan Fellow. Beyond her interest in nanotheranostics, her research group explores a myriad of bioanalytical research questions, mostly focused on the topics of cell−cell immune response, nanoparticle toxicology, and novel sensing platforms for biomolecules in complex environments. Website: http://www.chem.umn.edu/groups/haynes/.

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ACKNOWLEDGMENTS This work was funded by the National Science Foundation (NSF, CHE-0645041). Y.-S.L. and K.R.H. acknowledge financial support from a University of Minnesota Doctoral 372



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Dissertation Fellowship and NSF Graduate Research Fellowship, respectively.

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Critical Considerations in the Biomedical Use of Mesoporous Silica

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