Nano Today
ReviewNonporous silica nanoparticles for nanomedicine application
Introduction
Nanomedicine, the use of nanotechnology for medical applications, has undergone rapid development in the last several decade [1], [2], [3], [4], [5], [6], [7], [8]. The goal of nanomedicine is to design and synthesize drug delivery vehicles that can carry sufficient drug loads, efficiently cross physiological barriers to reach target sites, and safely and sustainably cure diseases. Numerous organic nanomedicines, including liposomes, drug–polymer conjugates, dendrimers, polymeric micelles and nanoparticles (NPs), have been extensively studied as drug delivery systems (Fig. 1). Each delivery platform has its advantage and disadvantage. For example, high drug loadings have been achieved in liposomes [9], but the intrinsic structural stability of liposomes is undesirably low, especially under fluid shear stress during circulation. Inorganic drug delivery systems, such as gold NPs, quantum dots (QDs), silica NPs, iron oxide NPs, carbon nanotubes and other inorganic NPs with hollow or porous structures, have emerged as promising alternatives to organic systems for a wide range of biomedical applications (Fig. 2). Among these NPs, silica NPs have attracted significant interest because of their unique properties amenable for in vivo applications [10], [11], such as hydrophilic surface favoring protracted circulation, versatile silane chemistry for surface functionalization, excellent biocompatibility, ease of large-scale synthesis, and low cost of NP production. In 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 [12], [13], highlighting the great potential and the most recent progress of clinical translation of silica NP drug delivery platform.
Silica NPs used for biomedical applications can be categorized as mesoporous or nonporous (solid) NPs, both of which bear amorphous silica structure. Mesoporous silica NPs characterized by the meso-pores (2–50 nm pore size) are widely used for delivery of active payloads based on physical or chemical adsorption (Fig. 3a) [10], [14]. In contrast, nonporous silica NPs deliver cargos through encapsulation or conjugation (Fig. 3b and c). Payload release from mesoporous silica NPs can be controlled by using the “gatekeeper” strategy or modifying the inner surface of the pores to control the binding affinity with drugs (Fig. 3a) [10], whereas the release profile of payloads delivered by nonporous silica NPs are controlled by means of chemical linkers or the degradation of silica matrix (Fig. 3b and c). The size and shape of nonporous silica NPs can be excellently controlled, and the pore size and structure of mesoporous silica NPs can be controlled by tuning the composition and concentration of surfactants during synthesis. The nanomedicine applications of mesoporous silica NPs have been extensively reviewed elsewhere [10], [14], [15], [16], [17] and are not discussed here. We also do not discuss the use of silica as a host material for other types of functional NPs (e.g., gold NPs, QDs and iron oxide NPs) to form hybrid NPs. This important class of silica-based hybrid nanomedicines has been thoroughly reviewed by Piao et al. [18]. Here, we focus on nonporous silica NPs and their biomedical applications for disease diagnosis and therapy. We will first discuss the synthesis of various nonporous silica NPs, including the methods developed to control the size, shape and surface properties of silica NPs. Their biomedical applications for both therapy and diagnosis will then be discussed. These applications are categorized based on the different active cargoes delivered by silica NPs: drug delivery for small molecule drugs, proteins, or photosensitizers, gene delivery, molecular imaging by incorporating different contrast agents. Finally, the safety and toxicity of silica NPs both in vitro and in vivo will be discussed, which is important for their potential clinical translation.
Section snippets
Synthesis and control of the properties of silica NPs
Many efforts have been made to prepare silica NPs with precisely controlled physicochemical properties. The excellent control over syntheses is the prerequisite for the biomedical application of silica NPs.
Silica NPs for drug delivery
The use of silica materials for delivery and controlled release of drug payloads was reported as early as 1983 [76]. Since then, silica NPs have been extensively used as drug carriers, owing to their biocompatibility and easy formulation with drugs. Initially, silica was used mainly in the form of xerogels loaded with bioactive agents [77]. For example, silica xerogels have been used as implantable carrier for controlled drug release [78], [79]. Silica NPs emerged as a popular drug delivery
Silica NPs for gene delivery
Gene delivery is another major application of silica NPs besides the delivery of small molecules and proteins. The use of silica NPs for gene delivery has been extensively explored because their surfaces can be easily modified with cationic molecules, which allow for the stable condensation with nucleotides that are highly negatively charged and the protection of them from nuclease in physiological condition. Additionally, silica is bio-inert and less toxic than some cationic polymers employed
Silica NPs for imaging and diagnosis
Nanotechnology offers unprecedented opportunities for addressing current challenges in cancer diagnosis. NPs carrying diagnostic probes can provide structural and metabolic information from disease sites. NP-based imaging techniques can markedly improve the detection and staging of cancers and their metastases. Besides the application for delivery of therapeutic agents, silica NPs are also actively employed as the platform for incorporating contrast reagents for molecular imaging. Owing to
Safety and toxicity of silica NPs
The applications of silica NPs for therapy and diagnosis have already been demonstrated in many preclinical studies. To facilitate the potential clinical translation of these silica NPs, it is important to fully evaluate the safety and potential toxicity of these silica based nanomedicines. The toxicity and safety of various forms of silica was comprehensively reviewed by Napierska et al. [203] and Fruijtier-Polloth [204]. Until recently, toxicological research of silica particles focused
Conclusions and future perspectives
Silica NPs offer a promising alternative to organic drug delivery systems and exhibit many unique properties, such as highly controllable size and shape. Nonporous silica NPs have found numerous biomedical applications for the delivery of drugs, proteins, and genes and for molecular imaging. However, before silica NPs can be used routinely in clinic, some major challenges must be overcome, including the need for improved drug loading (high drug loading and high incorporation efficiency),
Acknowledgements
J.C. acknowledges supports from the NIH (Director's New Innovator Award program 1DP2OD007246-01 and 1R21CA152627). L.T. was funded at University of Illinois at Urbana – Champaign from NIH National Cancer Institute Alliance for Nanotechnology in Cancer ‘Midwest Cancer Nanotechnology Training Centre’ Grant R25 CA154015A. We thank Ms. Catherine Yao for her help on drawing the 3D images.
Li Tang received his BS degree in chemistry from Peking University in China in 2007. He then moved to US to pursue his PhD under the supervision of Professor Jianjun Cheng at the University of Illinois at Urbana – Champaign (UIUC). He received his PhD in materials science and engineering at University of Illinois at Urbana−Champaign in 2012. During his PhD study, he focused on the development of precisely size-controlled drug–silica nanoconjugates for cancer diagnosis and therapy. He is the
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Li Tang received his BS degree in chemistry from Peking University in China in 2007. He then moved to US to pursue his PhD under the supervision of Professor Jianjun Cheng at the University of Illinois at Urbana – Champaign (UIUC). He received his PhD in materials science and engineering at University of Illinois at Urbana−Champaign in 2012. During his PhD study, he focused on the development of precisely size-controlled drug–silica nanoconjugates for cancer diagnosis and therapy. He is the trainee of NIH National Cancer Institute Alliance for Nanotechnology in Cancer ‘Midwest Cancer Nanotechnology Training Center (M-CNTC)’ (2011–2012) and the recipient of Racheff-Intel Award (2012). He is now a postdoctoral associate at Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology.
Jianjun Cheng is an associate professor of materials science and engineering and a Willett faculty scholar at the University of Illinois at Urbana−Champaign. His research is focused on design, synthesis and application of polymeric- and nano-biomaterials in drug and gene delivery. He received a National Science Foundation Career Award in 2008 and a NIH Director's New Innovator Award in 2010.