Mechanized silica nanoparticles: a new frontier in theranostic nanomedicine

Abstract

Medicine can benefit significantly from advances in nanotechnology because nanoscale assemblies promise to improve on previously established therapeutic and diagnostic regimes. Over the past decade, the use of delivery platforms has attracted attention as researchers shift their focus toward new ways to deliver therapeutic and/or diagnostic agents and away from the development of new drug candidates. Metaphorically, the use of delivery platforms in medicine can be viewed as the "bow-and-arrow" approach, where the drugs are the arrows and the delivery vehicles are the bows. Even if one possesses the best arrows that money can buy, they will not be useful if one does not have the appropriate bow to deliver the arrows to their intended location. Currently, many strategies exist for the delivery of bioactive agents within living tissue. Polymers, dendrimers, micelles, vesicles, and nanoparticles have all been investigated for their use as possible delivery vehicles. With the growth of nanomedicine, one can envisage the possibility of fabricating a theranostic vector that could release powerful therapeutics and diagnostic markers simultaneously and selectively to diseased tissue. In our design of more robust theranostic delivery systems, we have focused our attention on using mesoporous silica nanoparticles (SNPs). The payload "cargo" molecules can be stored within this robust domain, which is stable to a wide range of chemical conditions. This stability allows SNPs to be functionalized with stimulus-responsive mechanically interlocked molecules (MIMs) in the shape of bistable rotaxanes and psuedorotaxanes to yield mechanized silica nanoparticles (MSNPs). In this Account, we chronicle the evolution of various MSNPs, which came about as a result of our decade-long collaboration, and discuss advances in the synthesis of novel hybrid SNPs and the various MIMs which have been attached to their surfaces. These MIMs can be designed in such a way that they either change shape or shed off some of their parts in response to a specific stimulus, such as changes in redox potential, alterations in pH, irradiation with light, or the application of an oscillating magnetic field, allowing a theranostic payload to be released from the nanopores to a precise location at the appropiate time. We have also shown that these integrated systems can operate not only within cells, but also in live animals in response to pre-existing biological triggers. Recognizing that the theranostics of the future could offer a fresh approach to the treatment of degenerative diseases including cancer, we aim to start moving out of the chemical domain and into the biological one. Some MSNPs are already being tested in biological systems.

Figure 1

Timeline showing the evolution of MSNPs, where each circle represents a landmark MSNP with the solid support and stimulus used to release the cargo, and which studies the MSNPs were subjected to. The research began in 2001 with the demonstration that supramolecular machines operate on and within glass in a manner similar to that in solution, and progressed to incorporating a variety of machines both on and in SNPs. Several kinds of stimuli have been used to release cargo molecules from MSNPs, including redox-activation (2004), increasing the basicity (2006), irradiating (2007), and increasing the acidity (2009). All MSNPs have been subjected to release experiments in solution to confirm their operation, and some have progressed to in vitro (2008) and in vivo (2010) testing.

Figure 2

(A) SEM image of MCM-41 SNPs. (B) TEM image of MCM-41 SNPs. (C) TEM image of hollow SNPs. (D) TEM image of magnetic-core SNPs (MCSNPs).

Figure 3

(A) A monolayer of rotaxanes covering the surface of an SNP. (B) Schematic representation of cargo being released from the nanopores of an MSNP using rotaxanes (top) or psuedorotaxanes (bottom) as the external machinery.

Figure 4

Diagram of the different methods employed for controlled release of cargos in vitro. Cargo can be released in response to external stimuli – such as light or a magnetic field – or by taking advantage of the natural biochemistry inside cells by using redox, enzymes, or a pH change in the cellular compartments to release the cargo. Redox and enzymatic activation has yet to be tested in vitro.

Figure 5

MSNPs with azobenzene-based nanoimpellers attached to the inner surface of the nanopores. When the MSNPs are uptaken into PANC-1 cells, apoptosis is induced by releasing CPT after irradiating for 1 minute (a) 3 minutes (b) 5 minutes (c) or 10 minutes (d).

Figure 6

MSNPs in which stalks containing benzimidazoles are attached to the surfaces of SNPs. They are encircled by β-CD rings, and upon the addition of acid, the benzimidazoles are protonated, causing the β-CD rings to dissociate from the stalks, releasing the cargo – either Hoechst 33342 for cell imaging or doxorubicin for inducing apoptosis. KB-31 cancer cells endocytosed the doxorubicin-loaded fluorescein-labeled MSNPs within 3 h. This action is followed by doxorubicin release to the nucleus, induction of cytotoxicity and the appearance of apoptotic bodies after 60 h (indicated by arrows), followed by nuclear fragmentation after 80 h.

Figure 7

MCSNPs which generate heat upon exposure to an oscillating magnetic field, causing the CB[6] rings to slip off the stalks, thus releasing a cargo of either rhodamine B or doxorubicin. No cell death is observed prior to applying a magnetic field (left panel), while 16% of the cells were killed upon the application of an oscillating magnetic field to MCSNPs without doxorubicin loaded in the pores (center panel). When MCSNPs are loaded with doxorubicin and exposed to an oscillating magnetic field, 37% of the cells are killed, with apoptotic bodies indicated by arrows (right panel).

Figure 8

Diagram showing how MSNPs, when injected into an organism with a tumor, are capable of localizing in and around diseased tissue and display a signal (diagnosis), and release therapeutics to eliminate diseased cells (treatment), yielding a true theranostic device.