Chemistry Reference
In-Depth Information
technique is reductive amination. Ketones or aldehydes react with amines to form imines that are further stabilised through
reduction with sodium cyanoborohydride to provide a stable conjugation product. This procedure has been shown to be
effective in aqueous conditions expanding its usefulness for biological systems [5, 6]. Further, amines can react with isothio-
cyanate groups [7-9]. Another common approach utilises thiols, either to form a strong gold-thiol bond [10] or a thiol-
maleimide reaction that results in a thioether bond.
Silanisation is the controlled hydrolysis of siloxane species such as tetraorthosilicate (TEOS) resulting in the formation
of a silica (SiO
2
) coating on the surface of the nanoparticle [11]. This process lends itself to the addition of (3-aminopropyl)
triethoxysilane(APTES), which is frequently used to incorporate an amine on the surface of the silica layer (Scheme 16.2).
Finally, the use of charged polymers such as polylysine can improve the electrostatic adsorption of species on the surface of
a nanoparticle or can be used to modify the surface with polymeric layers.
16.1.2
early Work
Early reports combine multiple modalities on nanoparticle platforms. The combination of ultrasound and MRI was used to
evaluate the effectiveness of targeting groups, stem-cell tracking, visualisation of angiogenesis, and imaging transplant
rejection [12]. The combination of optical, CT, and MRI in the form of paramagnetic silica nanoparticles was proposed to
be useful for preoperative diagnosis and intraoperative surgical resection of brain tumours or other surgical targets [13].
One of the first
in vivo
applications of multimodal nanoparticles was to assist the determination of brain tumour margins
[14]. SPIONs with cross-linked dextran coating were labelled with Cy5.5 and injected into mice bearing GFP-expressing 9 L
glioma tumours. The
T
2
-weighted MRI showed accumulation of the SPIONs in the tumour after 24 hours. Optical imaging
was performed and showed co-localisation of GFP with the Cy5.5 dye. At a cellular level, using CD11b staining, microglia
were found to extend slightly beyond the GFP-defined tumour border. This finding was consistent with the estimation of
tumour area by Cy5.5 fluorescence. The combined optical and magnetic properties of this probe allowed delineation of the
brain tumour both by pre-operative magnetic resonance imaging and by intra-operative optical imaging.
Atherosclerosis is a chronic, progressive inflammatory disease, and there is significant need for diagnostic tools to non-
invasively assess the therapeutic efficacy in the clinic as well as to identify molecular changes for basic research purposes.
Vascular adhesion molecule-1 (VCAM-1) is upregulated in endothelial cells under inflammatory conditions such as those
associated with atherosclerosis. In order to image inflammation, SPIONs were conjugated with a fluorescent dye and a pep-
tide designed to target inflamed tissue [15]. The SPION effectively targeted VCAM-1 and
in vivo
accumulated in the vessel
wall. The SPIONs were detectable for at least 24 hours by both optical and MRI modalities, proving that this nanoparticle
system is an effective amplification strategy to achieve high target-to-background ratios.
16.2
fluoreScence-MrI
Nanoparticles are frequently and widely used for the labelling of cells and targeting of tissues in theranostic medical studies
[16-22]. The main applications for multimodal therapy are to (1) visualise the effectiveness of targeting cancerous tumours
in vivo
, (2) directly observe the effectiveness of therapy, or (3) label cells for
in vivo
tracking. In this section we examine the
recent use of nanoparticles that incorporate a fluorescent dye and a magnetic nanoparticle together.
The combination of MRI and fluorescent imaging can be accomplished in two different ways. One method is to cova-
lently attach an organic fluorescent dye to the surface of a superparamagnetic iron oxide nanoparticle (SPION) [7]. The
second approach is to use a nanoparticle of 'inert' material, such as silicon oxide, as a scaffold and decorate the surface with
both the fluorescent dye and small SPIONs [23, 24].
16.2.1
theranostic applications of fluorescent-MrI bimodal agents
Nanoparticles that carry both imaging capability and therapeutic agents are known as
theranostic agents
. One major concern
is the biodistribution and toxicity of the nanoparticle platforms used to deliver the treatment. One means of addressing this
question is to use nanoparticle systems that attach imaging agents that can be tracked
in vivo
. This approach provides
real-time location monitoring of the treatment and the delivery system.
Harrison and co-workers have developed aPGMA (poly(glycidyl methacrylate)-encapsulated SPION with rhodamine B
(Figure 16.2) for fluorescent imaging [23]. The particles were synthesised according to a previous report [25]. In brief, gly-
cidylmethacrylate was polymerised using azobisisobutyronitrile as an initiator. The dye was incorporated to the polymer by
heating a solution of rhodamine B with PGMA under nitrogen for 18 h. The SPIONs were incorporated by emulsification
with the dye-labelled PGMA.
