Biomedical Engineering Reference
In-Depth Information
d.
Monitoring cell migration
: Monitoring the trafi cking and fate of labeled cells in vivo
has a wide range of applications in DDD. Tumor cells have been transfected to express
l uorescent or bioluminescent proteins for the noninvasive assessment of tumor growth
or metastasis load in murine tumor models. Inl ammatory processes have been studied
using MRI by monitoring the ini ltration of monocytes and lymphocytes labeled with
superparamagnetic iron oxide nanoparticles into inl amed tissue. Cell therapy is becom-
ing an increasingly important therapeutic strategy requiring tools to visualize the loca-
tion, migration, and viability of stem or progenitor cells. The fate of such cells has been
monitored using either MRI and bioluminescence imaging in models of cerebral and
cardiac ischemia or in brain tumor models. While phagocytotic cells such as monocytes
can be efi ciently labeled in situ, other cell types have to be harvested and labeled in vitro.
Alternatively, genetically engineered cells expressing a reporter gene have been applied.
While for most molecular imaging approaches the use of MRI is limited by its low intrin-
sic sensitivity, cells tolerated relatively high amounts of superparamagnetic iron oxide;
therefore low amount of cells, in favorable cases even single cells, can be detected with
unsurpassed spatial resolution.
7.3
SELECTED IMAGING APPLICATIONS IN DDD
7.3.1 D1: T
ARGET
V
ALIDATION
We will illustrate the role of imaging for target validation with several examples from oncology.
Peptide receptors are frequently over-expressed in tumors and therefore constitute attractive tar-
gets both for therapeutic interventions and for diagnostic imaging. Extensively studied examples are
the membrane-bound somatostatin receptors (SSTRs) that are highly expressed in neuroendocrine
tumors. A number of imaging probes based on octreotide, a metabolically stabilized analogue of the
endogenous ligand somatostatin (SST-14 or SST28), have been developed, using either radionuclides
or l uorescent groups as reporters. Feasibility of visualizing SSTR expression has been demonstrated
b o t h i n p a t i e n t s s u f fe r i n g f r o m n e u r o e n d o c r i n e t u m o r s a n d i n a n i m a l m o d e l s o f t h e h u m a n d i s e a s e . T h e
imaging probes specii cally accumulated at the tumor site(s). One of the ligands (
111
In-pentetreotide,
Octreoscan
®
) has been approved for clinical use as diagnostic SPECT probe. There are several other
radiopeptides that are currently being evaluated as tumor-specii c imaging agents such as bombesin
or cholecystokinin, for example, for detection of prostate cancer. Alternatively l uorescent probes
have been developed for experimental studies in animals (Figure 7.4).
Overexpression of the Her-2/neu tyrosine kinase receptor is observed in approximately 25% of
human breast cancers and is associated with poor prognosis. Inhibition of Her-2/neu signaling, for
example, using a specii c antibody (trastumazab) therefore constitutes a therapeutic strategy in these
cancer patients. Correspondingly, an imaging probe suited for demonstrating Her-2/neu overexpres-
sion would be essential for the selection of patients amenable to therapy. A PET imaging probe
based on Her-2 antibody fragments has been used in murine tumor models to study the effects of
inhibition of heat shock protein 90, a molecular chaperon, on Her-2/neu levels. A signii cant reduc-
tion of Her-2/neu levels could be observed noninvasively within hours after therapy onset, which
later translated into reduced tumor growth.
A third example relates to tumor angiogenesis, a critical step in the formation of a neoplastic
lesion. A high degree of neovascularization is commonly associated with rapid tumor proliferation
and thus malignancy. Inhibition of angiogenesis is considered an attractive strategy in tumor ther-
apy, in particular in combination with other therapeutic strategies. Critical proangiogenic factors
induced are vascular endothelial growth factor (VEGF) and its receptor (VEGF-R). When selecting
patients for treatment with VEGF-R inhibitors, the demonstration of high levels of the receptor in
tumor tissue would be relevant; this has prompted the development of target-specii c assays suitable
for in vivo imaging. As VEGF-R is expressed at the endoluminal side of the endothelial cell layer it
