The Viability of Mesoporous Silica Nanoparticles for Drug Delivery

Keywords:

• controlled release
• intracellular transportation • mesoporous silica
• nanocarriers
• targeting

Encapsulation of potent drugs within nanocarriers that selectively target diseased cells raises high hopes to increase the efficacy of conventional drug delivery and decrease side effects. Mesoporous silica nanoparticles (MSNs), whose characteristic properties include uniform mesopores, facile and flexible surface functionalization and appreciable biocompatibility have gained much recent attention for facilitating biomedical applications.

The characteristic mesoscopically ordered topology provides MSNs with four distinct domains that can be independently functionalized: the silica framework, the nanoparticle's outermost surface, the nanochannels/pores, and the nanoparticle's inner space in the case of hollow void formation inside the particles. Among these domains, the former two can be employed for attaching surface functional groups which play several roles in the interactions between the nanocarriers and drug, as well as the interactions between nanocarriers and the physiological environment. The latter two domains, in turn, can be utilized for encapsulating guest molecules. Consequently, MSNs are especially well-suited for the task of incorporating the essential capabilities of a theranostic drug delivery platform, with separate domains for the contrast agent for follow-up of the drug delivery process by a suitable imaging technique, the drug payload for therapeutic intervention, the gating mechanism for regulating the transit of cargo molecules in and out of these reservoirs and the biomolecular ligands for enhanced affinity toward target cells/tissue and reduced recognition and clearance by the immune system [1].

In the case of using modified MSNs for drug delivery, the pore compartments and large surface area provide a natural platform for high drug payload (up to 50 wt%) and sophisticated release mechanism designs through robust surface modifications [2]. Additionally, the inorganic MSNs with a nonswellable silica network can effectively protect loaded cargo molecules against enzymatic degradation or denaturation induced by the external environmental and/or harsh physiological conditions such as those prevailing in the GI tract [3], which is especially critical for the delivery of biomolecular cargo [4]. Because an MSN's structural integrity is kept intact in organic solvents, MSNs are especially suitable for loading of hydrophobic drugs from nonaqueous media. Thus, for the drug loading process, the solvent can be chosen at will depending on the drug characteristics; which may be difficult with many other types of carrier particles [5]. For more hydrophilic drugs, charge-matching-based adsorption in aqueous solvent can be utilized to reach higher drug loading degrees than possible from organic media. In these delivery systems, the drug release process is diffusion controlled, and the open pore entrance could be a significant problem if a temporally or spatially controlled drug release is aimed for. Another possibility for drug incorporation into MSNs is to covalently link the drug to functional groups present on the pore wall. However, the prerequisite to retain the drug activity after decoupling from the pore wall makes the drug delivery design complicated and formulation specific. Moreover, it excludes the possibility of delivering drugs without linkable groups in their molecular structure.

Novel delivery systems based on hybrid MSNs focus on stimuli-responsive controlled release of drugs using removable nanogates or sheddable coatings to cap the pores, whereby the caps can be removed via redox reactions, pH changes or photo-activated release. The biggest challenge in current development is the design and synthesis of controlled biocompatible nanogates or capping systems on MSNs to realize ‘zero premature release’ and targeted delivery of drugs in a controlled fashion. Considering that the pore closing via nanogates needs to be accomplished on the outer surface of MSNs after drug loading, it is of great advantage to utilize a facile capping/gating technique which does not induce any influence to the drug molecules encapsulated in the mesopores. Supramolecular nanogates or mechanically interlocked molecules on the basis of molecular recognition and self-assembly, that operate in aqueous solution or biologically relevant conditions, are being utilized to gain the feasibility as well as biocompatibility required for drug delivery. Typical systems include nanogates based on macrocyclic receptors, protein–protein interactions, strand recognition of nucleic acids, carbohydrate–protein interactions and so forth [6].

Since MSNs can simultaneously carry several drugs with different physicochemical properties at high loading degrees, the delivery of a cocktail of drugs will be its special advantage [7]. Cooperative delivery of a hydrophobic drug plus a hydrophilic drug has proven to be a successful strategy to date, considering the feasibility of easy drug loading and fine-tuning of the drug ratio. An important problem encountered in chemotherapy toward cancer cells is MDR, which remains the main cause of chemotherapy failure as more than 90% of tumor patients die from certain extents of MDR. Further functionality can be built into MSNs for overcoming MDR in this case. Co-delivery strategies that utilize Pgp or Bcl-2 siRNAs to suppress, respectively, the drug efflux (pump resistance) or activation of cellular anti-apoptotic defense (nonpump resistance) together with an anticancer drug, have been developed for overcoming MDR in cancer cells.

The intracellular drug delivery efficacy can be affected by the intracellular transport routes of the drug-loaded MSNs. It is interesting to note that for particles that enter cells through clathrin-mediated endocytosis, 50–100 nm nanoparticles appear to be the most efficient size for various materials [8]. In order to avoid the retention of the MSN within the endosome, which could diminish the efficacy of the entrapped drugs, endosomal escape mechanisms can be built into the MSN design. Typical methods include: immobilizing a proton sponge or photosensitizer on the nanoparticle such that osmotic influx upon protonation of the sponge base or photodynamic process can break the endosome, anchoring a membrane penetrating peptide. It is noteworthy, however, that depending on the stability of the cargo molecules, the delivery system itself do not necessarily need to escape from the endo/lysosomes in case the drug can be released in the endosome and subsequently escape while still retaining its activity. After completing its task, the MSN would then ideally be degraded into harmless degradation products or be exocytosed by the cells to ultimately degrade in the extracellular environment, where prospectively more body fluids (water) are available for dissolution.

For further pharmaceutical considerations, the in vivo behavior of MSNs has to be exhaustively examined. This includes biocompatibility, biodegradation, toxicity, pharmacokinetics, biodistribution and clearance, to name a few. Amorphous silica biodegrades to monomeric and oligomeric silicic acids which, in the best case scenario, could even be utilized as nutrients by the cells [9]. Indeed, silica has been classified as a GRAS material by the US FDA, but the biocompatibility will ultimately depend on the final formulation design. Presently, some conflicting data related to toxicity have been reported, which may be caused by a multitude of variables such as different synthesis routes, size, shape, surface functionalizations, dosage, and administration route, among others. The same variables largely determine the fate of the MSNs in vivo, which currently is poorly understood and also here, conflicting data exists [10]. This calls for a standard protocol for particle evaluation and toxicity investigation, which is a current matter for the whole nanomedicine community. In addition, targeting the MSNs to specific cells, as well as tissue accumulation and elimination mechanisms, although very complicated, merit more efforts to understand these critical processes. Changing the design for each paper for yet another proof-of-concept study will not add significantly to this body of knowledge, but more systematic and mechanistic studies on MSN behavior in conjunction to biological systems toward deeper in vitro–in vivo correlation understanding are necessitated. Adding to this body of literature will facilitate timely translation of MSNs from bench to bedside.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.