Mesoporous silica nanoparticle nanocarriers: biofunctionality and biocompatibility

Abstract

The study of ordered mesoporous silica materials has exploded since their discovery by Mobil researchers 20 years ago. The ability to make uniformly sized, porous, and dispersible nanoparticles using colloidal chemistry and evaporation-induced self-assembly has led to many applications of mesoporous silica nanoparticles (MSNPs) as "nanocarriers" for delivery of drugs and other cargos to cells. The exceptionally high surface area of MSNPs, often exceeding 1000 m²/g, and the ability to independently modify pore size and surface chemistry, enables the loading of diverse cargos and cargo combinations at levels exceeding those of other common drug delivery carriers such as liposomes or polymer conjugates. This is because noncovalent electrostatic, hydrogen-bonding, and van der Waals interactions of the cargo with the MSNP internal surface cause preferential adsorption of cargo to the MSNP, allowing loading capacities to surpass the solubility limit of a solution or that achievable by osmotic gradient loading. The ability to independently modify the MSNP surface and interior makes possible engineered biofunctionality and biocompatibility. In this Account, we detail our recent efforts to develop MSNPs as biocompatible nanocarriers (Figure 1 ) that simultaneously display multiple functions including (1) high visibility/contrast in multiple imaging modalities, (2) dispersibility, (3) binding specificity to a particular target tissue or cell type, (4) ability to load and deliver large concentrations of diverse cargos, and (5) triggered or controlled release of cargo. Toward function 1, we chemically conjugated fluorescent dyes or incorporated magnetic nanoparticles to enable in vivo optical or magnetic resonance imaging. For function 2, we have made MSNPs with polymer coatings, charged groups, or supported lipid bilayers, which decrease aggregation and improve stability in saline solutions. For functions 3 and 4, we have enhanced passive bioaccumulation via the enhanced permeability and retention effect by modifying the MSNP surfaces with positively charged polymers. We have also chemically attached ligands to MSNPs that selectively bind to receptors overexpressed in cancer cells. We have used encapsulation of MSNPs within reconfigurable supported lipid bilayers to develop new classes of responsive nanocarriers that actively interact with the target cell. Toward function 4, we exploit the high surface area and tailorable surface chemistry of MSNPs to retain hydrophobic drugs. Finally, for function 5, we have engineered dynamic behaviors by incorporating molecular machines within or at the entrances of MSNP pores and by using ligands, polymers, or lipid bilayers. These provide a means to seal-in and retain cargo and to direct MSNP interactions with and internalization by target cells. Application of MSNPs as nanocarriers requires biocompatibility and low toxicity. Here the intrinsic porosity of the MSNP surface reduces the extent of hydrogen bonding or electrostatic interactions with cell membranes as does surface coating with polymers or lipid bilayers. Furthermore, the high surface area and low extent of condensation of the MSNP siloxane framework promote a high rate of dissolution into soluble silicic acid species, which are found to be nontoxic. Potential toxicity is further mitigated by the high drug capacity of MSNPs, which greatly reduces needed dosages compared with other nanocarriers. We anticipate that future generations of MSNPs incorporating molecular machines and encapsulated by membrane-like lipid bilayers will achieve a new level of controlled cellular interactions.

FIGURE 1

Schematic of multifunctional mesoporous silica nanoparticle showing possible core/shell design, surface modifications, and multiple types of cargos. cargos

FIGURE 2

Gallery of mesoporous silica nanoparticles. Particles in a, b, c, and d are formed by EISA. Lower panel are solution prepared MSNPs.

FIGURE 3

(a) Schematic showing reaction of surface silanol groups with an alkoxysilane linker to introduce functionality. (b) Various linkers to attach bio-molecules or to change the surface properties.

FIGURE 4

Schematic (a) and cryo-TEM image (b) of protocells.

FIGURE 5

Hyperspectral confocal imaging of targeted delivery of multicomponent cargos in protocells. Alexa Fluor 532-labelled nanoporous silica cores (yellow) were loaded with calcein (green), an Alexa Fluor 647-labelled dsDNA oligonucleotide (magenta), RFP (orange) and CdSe/ZnS quantum dots (teal). Cargos were sealed in the cores by fusion of Texas Red-labeled DOPC liposomes (red). (Adapted from ref. 17).

FIGURE 6

Schematic diagram depicting the successive steps of multivalent binding and internalization of targeted MSNP supported lipid bilayers, followed by endosomal escape and nuclear localization of MSNP-encapsulated cargo. (Adapted from ref. 17).

FIGURE 7

Selective and non-selective binding characteristics of peptide (SP94)-targeted protocells. a) Dissociation constants (K_d) of SP94-targeted protocells and liposomes for the target hepatocarcinoma cell, Hep3B, as a function of the average number of SP94 peptides per particle (average SP94 wt% is in parentheses). b) Dissociation constants (K_d) of SP94-targeted protocells for the target Hep3B and selected non-target control cells. Peptide density is 0.015wt%. All surface-binding experiments were conducted at 4° C to prevent internalization of targeted protocells and liposomes. All error bars in a and b represent 95% confidence intervals (1.96 σ) for n = 5. ^{and supplemental information}

FIGURE 8

Reactive oxygen species generation (MitoSox Red) and % cell death (Propidium Iodide) of MSNP (nanoporous core), neutral, cationic, or anionic (DOTAP or DOPG) protocells, liposomes, and polystyrene beads. The antioxidant, N-acetylcysteine (NAC), was used as a negative control. (C.E. Ashley, unpublished data).