Nonporous Silica Nanoparticles for Nanomedicine Application

Nano Today (2013) 8, 290—312 Available online at www.sciencedirect.com journal homepage: www.elsevier.com/locate/nanotoday REVIEW Nonporous silica nanoparticles for nanomedicine application Li Tang, Jianjun Cheng ∗ Department of Materials Science and Engineering, University of Illinois at Urbana — Champaign, Urbana, IL 61801, USA Received 31 January 2013; received in revised form 17 April 2013; accepted 29 April 2013 Available online 5 June 2013 KEYWORDS Summary Nanomedicine, the use of nanotechnology for biomedical applications, has poten- Nanomedicine; tial to change the landscape of the diagnosis and therapy of many diseases. In the past several Nonporous silica decades, the advancement in nanotechnology and material science has resulted in a large nanoparticles; number of organic and inorganic nanomedicine platforms. Silica nanoparticles (NPs), which Drug delivery; exhibit many unique properties, offer a promising drug delivery platform to realize the poten- Gene delivery; tial of nanomedicine. Mesoporous silica NPs have been extensively reviewed previously. Here Molecular imaging; we review the current state of the development and application of nonporous silica NPs for Nanotoxicity drug delivery and molecular imaging. © 2013 Elsevier Ltd. All rights reserved. Introduction structural stability of liposomes is undesirably low, espe- cially under fluid shear stress during circulation. Inorganic Nanomedicine, the use of nanotechnology for medical appli- drug delivery systems, such as gold NPs, quantum dots cations, has undergone rapid development in the last several (QDs), silica NPs, iron oxide NPs, carbon nanotubes and decade [1—8]. The goal of nanomedicine is to design and syn- other inorganic NPs with hollow or porous structures, have thesize drug delivery vehicles that can carry sufficient drug emerged as promising alternatives to organic systems for loads, efficiently cross physiological barriers to reach target a wide range of biomedical applications (Fig. 2). Among sites, and safely and sustainably cure diseases. Numerous these NPs, silica NPs have attracted significant interest organic nanomedicines, including liposomes, drug—polymer because of their unique properties amenable for in vivo conjugates, dendrimers, polymeric micelles and nanoparti- applications [10,11], such as hydrophilic surface favoring cles (NPs), have been extensively studied as drug delivery protracted circulation, versatile silane chemistry for sur- systems (Fig. 1). Each delivery platform has its advan- face functionalization, excellent biocompatibility, ease of tage and disadvantage. For example, high drug loadings large-scale synthesis, and low cost of NP production. In have been achieved in liposomes [9], but the intrinsic 2011, an Investigational New Drug Application for exploring an ultrasmall nonporous silica NP for targeted molecular imaging of cancer was approved by the US Food and Drug Administration (FDA) for a first-in-human clinical trial ∗ Corresponding author. Tel.: +1 217 244 3924; [12,13], highlighting the great potential and the most recent fax: +1 217 333 2736. progress of clinical translation of silica NP drug delivery E-mail address: [email protected] (J. Cheng). platform. 1748-0132/$ — see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.nantod.2013.04.007 Nanoparticles for nanomedicine application 291 Figure 1 Examples of organic nanomedicines for cancer diagnosis and therapy. Figure 2 Examples of inorganic nanomedicines for cancer diagnosis and therapy. 292 L. Tang, J. Cheng Silica NPs used for biomedical applications can be catego- The particle formation (or particle nucleation) proceeds rized as mesoporous or nonporous (solid) NPs, both of which through an aggregation process of siloxane substructures bear amorphous silica structure. Mesoporous silica NPs char- that is influenced strongly by the surface potential of the sil- acterized by the meso-pores (2—50 nm pore size) are widely ica particles and the ionic strength of the reaction medium. used for delivery of active payloads based on physical or Thus, the stability behavior of the silica NPs in alcohol, chemical adsorption (Fig. 3a) [10,14]. In contrast, nonporous water, and ammonia mixtures and the dependence of the silica NPs deliver cargos through encapsulation or conjuga- rate constants of hydrolysis and condensation as a func- tion (Fig. 3b and c). Payload release from mesoporous silica tion of the reaction mixture play the most important role NPs can be controlled by using the ‘‘gatekeeper’’ strategy or in determining the final silica NP sizes [21]. modifying the inner surface of the pores to control the bind- A seeded regrowth strategy was explored to improve the ing affinity with drugs (Fig. 3a) [10], whereas the release size control for larger NPs [20,22]. The smallest NPs that profile of payloads delivered by nonporous silica NPs are can be prepared by the Stöber method without aggrega- controlled by means of chemical linkers or the degrada- tion have diameters of 15—20 nm and are more polydisperse tion of silica matrix (Fig. 3b and c). The size and shape (typically 10—20% standard deviation) than larger NPs (<3% of nonporous silica NPs can be excellently controlled, and standard deviation for NPs larger than 200 nm) [22—24]. the pore size and structure of mesoporous silica NPs can be Recently, in an important breakthrough, Hartlen et al. and controlled by tuning the composition and concentration of Yokoi et al. prepared monodisperse silica NPs with diameters surfactants during synthesis. The nanomedicine applications as small as 12 nm in a heterogeneous reaction with lysine of mesoporous silica NPs have been extensively reviewed or arginine instead of ammonia as a basic catalyst in the elsewhere [10,14—17] and are not discussed here. We also aqueous medium and tetraethoxysilane in the organic layer do not discuss the use of silica as a host material for other [25—27]. In another modification of the Stöber method, sil- types of functional NPs (e.g., gold NPs, QDs and iron oxide ica NPs were prepared in an aqueous microemulsion with NPs) to form hybrid NPs. This important class of silica-based added surfactants [28—31]. For example, the Prasad group hybrid nanomedicines has been thoroughly reviewed by Piao prepared organically modified 30-nm silica-based NPs in an et al. [18]. Here, we focus on nonporous silica NPs and their emulsion system with Aerosol OT surfactant [30,31]; Meng biomedical applications for disease diagnosis and therapy. et al. reported the formulation of 20—300-nm silica NPs in We will first discuss the synthesis of various nonporous silica a water-based emulsion with sodium dodecylbenzene sul- NPs, including the methods developed to control the size, fonate as the surfactant [29]. shape and surface properties of silica NPs. Their biomedi- An alternative method for the production of monodis- cal applications for both therapy and diagnosis will then be perse silica spheres with diameters ranging from tens to discussed. These applications are categorized based on the a few hundreds of nanometers involves the use of reverse different active cargoes delivered by silica NPs: drug deliv- microemulsions, in which particles form in inverse micelles ery for small molecule drugs, proteins, or photosensitizers, compartmentalized by a suitable surfactant in a nonpo- gene delivery, molecular imaging by incorporating different lar organic solvent [32]. This approach works particularly contrast agents. Finally, the safety and toxicity of silica NPs well for monodisperse NPs smaller than 100 nm in diameter both in vitro and in vivo will be discussed, which is important [33—39] and permits easy encapsulation of active molecules for their potential clinical translation. in the reverse micelles during NP formation. For example, Bagwe et al. and Jin et al. reported the synthesis Synthesis and control of the properties of of dye-doped silica NPs with continuously tunable sizes in silica NPs a reverse microemulsion and used them for cellular contrast imaging [40,41]. This method has also been widely used for coating other functional NPs with silica to produce Many efforts have been made to prepare silica NPs with pre- core—shell structures, as summarized in an excellent review cisely controlled physicochemical properties. The excellent by Guerrero-Martinez et al. [42]. control over syntheses is the prerequisite for the biomedical application of silica NPs. Shape control Size control The shape of NPs dramatically affects their blood cir- Synthesis of size-controlled silica NPs was first reported by culation [43] and tumor penetration behavior [44].It Stöber et al. in 1968 [19]. Monodisperse silica spheres with has been reported that worm-like micelles have supe- uniform diameters ranging from 50 nm to 2 ␮m were suc- rior circulation time compared to spheric micelles likely cessfully prepared in a reaction mixture of water, alcoholic due to the enhanced evasion of phagocytosis [43].Itis solvent, ammonia, and tetraalkoxysilane (Stöber method; also noticeable that nanorods penetrate tumor tissues Fig. 4). The effects of various alcoholic solvents and more rapidly than nanospheres likely because of improved tetraalkoxysilanes, as well as the concentration of each transport through tumor vasculature pores [44]. These component, on the reaction rates and particle sizes were results suggest the importance of controlling the shape of systemically studied. The reaction parameters and mecha- nanomedicine for favored circulation or

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