ReviewSmart drug delivery: Capping strategies for mesoporous silica nanoparticles
Graphical abstract
Introduction
Since their emergence in 1970, mesoporous silica nanoparticles (MSNs) have been widely used for biomedical applications, namely controlled drug/gene delivery [[1], [2], [3]], cell tracking [4], tumor targeting [5], and photodynamic therapy [6,7]. MSNs have addressed several issues in regard to other nanomaterials, specifically the possible hydrolysis and enzymatic degradation of conventional polymeric nanovehicles [8], complications in mass transport and inability to form suspensions for bulk mesoporous silica materials [9], and toxicity/carcinogenicity of carbon nanotubes (CNTs) [10]. MSNs offer distinctive properties including meso-nanoscale pores (2–50 nm), adjustable pore size, and versatile morphology (using tunable synthesis techniques). Of note, they are excellent options for smart drug delivery vehicles [11] because of the pores, which can be loaded with the therapeutic agents and then capped with specific gatekeeper molecules. These gatekeepers can be triggered and uncapped by the effect of internal stimuli (pH, ionic strength, reducing agents, and enzyme activity) or by external stimuli (light irradiation, temperature, and magnetic fields). Moreover, through surface modifications or application of magnetic materials to the MSNs core, they can be guided to targeted sites in vivo [12,13]. However, their physical properties like size, shape, composition, and concentration may affect their off-target toxicity [14]. Therefore, biosafety considerations, long-term accumulation in organs [15], nanotoxicity [16], and biodegradability require further investigation [17], as well as, challenges including modification of ultrafine particles (<10 nm) and their biocompatibility, absorption of blood proteins, and in vivo imaging of these particles [[18], [19], [20], [21], [22]].
Targeted MSN-based drug delivery systems (DDSs) have been prepared by conjugating MSNs with specific targeting ligands (aptamers, antibodies, proteins, folate and other bio-inspired and synthetic compounds). The active targeting ligand must have molecular affinity to the receptors expressed on the cells of the specific tissue. Generally, these ligands have a tendency to be sequestered and firmly bound by the target tissue. However, the high affinity of MSNs may lead to low tumor penetration, while their low affinity reduces the efficiency of drug delivery. The density and structural geometry of the active targeting ligands play key roles in defining adequate avidity between the ligands and the receptors. Multivalent ligands, which increase the avidity, can enhance the immunogenicity of the MSNs by causing recognition by the reticuloendothelial system (RES). Functionalization by conjugation of active groups generally does not adversely affect the dispersion of the MSNs, so it is expected that the stability remains at the required level [[23], [24], [25]]. On the other hand, the cellular uptake of MSNs is tunable through changing the physiochemical features such as the surface modification, particle size distribution, and zeta potential. The best case scenario in this regard occurs when the nanoparticles successfully enter the cells and deliver the therapeutic agent(s) to the specific subcellular organelles [[26], [27], [28]]. The present review addresses three important topics concerning MSNs. First, synthesis techniques, common types and properties of MSNs are discussed. Second, we cover biocompatibility issues. Third, smart drug delivery approaches including surface functionalization and capping strategies to avoid off-target cargo release are comprehensively reviewed.
Section snippets
Mesoporous silica nanoparticles: synthesis, types, and properties
In this section, the most common techniques to produce these nanoparticles, and to load the therapeutic agents into the pores are discussed. Furthermore, the widely used types of MSNs are introduced. The structural and physical properties of MSNs, which influence drug delivery, are briefly covered.
Mesoporous silica nanoparticle: Biocompatibility
Given the promising applications of MSNs in drug delivery, their biocompatibility, distribution, retention, and excretion have not yet been extensively investigated. To address these challenges, more systematic in vivo studies are yet required [82]. However, current studies indicate that MSNs are less toxic than other novel nanovehicles including CNTs [83]. In this section, the recent studies on biocompatibility of the MSNs are reviewed.
The enhanced permeability and retention (EPR) effect
Towards smart drug delivery
The concept of smart drug delivery mainly aims to achieve two goals: first, to improve drug-targeting to different specific tissues, and second, to control the release profile and rate. An ideal smart DDS can either reach or be guided to the specific target site in vivo, avoiding interaction with the immune system, and unload the cargo with the required release profile to improve the impact of the therapeutic agent. Fig. 2 illustrates the simplified steps to achieve the smart drug delivery. To
Conclusions
During the past decades, numerous drug delivery systems and strategies have been developed to transport various therapeutic and diagnostic agents to the targeted site at a specific dosage. One of the growing methodologies to overcome the important challenge of combined tracking and controlled delivery is to combine the functions of different agents. It would be ideal to have a multiplex system in which a nanoparticle can deliver the drug of interest in a controlled manner while also having the
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
There is no funding source for this study. Furthermore, the authors would like to thank Ms. Farnaz Fatahi Moghadam for designing the graphical illustrations.
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