The progression of molecular imaging technologies for oncological applications is the subject of a Nature review article published earlier this month (Nature 452 580). The authors - Ralph Weissleder and Mikael Pittet from Massachusetts General Hospital (Boston, MA) and Harvard Medical School - cite optical technologies as particularly popular for helping to understand the behaviour of cancers. Fluorescence imaging appears to be the biggest growth area, with variants being adapted for in vivo analysis. Indeed, developments in fluorescent imaging have moved researchers to the verge of addressing some of the big questions in molecular oncology: how best to exploit differences between malignant and normal cells to improve drugs; and which are the key indicators of how a cancer is progressing and whether a therapy is effective?

Optical imaging also offers a wealth of options for use within clinical practise. Take epithelial tumour detection, for example. Here, Weissleder and Pittet highlight a couple of emerging technologies as particularly noteworthy. Near-infrared fluorescence endoscopy, in combination with new imaging agents, has the potential to offer high sensitivity. Fibre-optic confocal laser-scanning micro-endoscopy, meanwhile, can be used to identify cellular and subcellular structures on the basis of reflected light, autofluorescence or exogenous imaging agents. This endoscopic technique could enable diagnosis of colorectal cancer, help target treatment and decrease the number of biopsies required for cancer screening. Fluorescence imaging could also be used intra-operatively - for example, to define tumour margins and identify small metastases to improve surgical accuracy.

The authors point out that the translation of imaging agents and technologies into the clinic has been slower than initially hoped, hindered in part by regulatory hurdles, lower profit margins for imaging agents versus therapeutic drugs and reimbursement issues. Despite this, there are several new technologies poised to enter clinical trials. They conclude that: "Applying the new molecular imaging tools to humans will make a fundamental improvement in how cancer is understood in vivo and should allow earlier detection, stratification of patients for treatment, and objective evaluation of new therapies in a given patient."

Ramped-up Raman
Elsewhere, an alternative optical modality, Raman spectroscopy, is starting to play a bigger role. Once considered too weak an effect for diagnostic applications, Raman is now coming to the fore with the development of ways to boost signal intensity, resulting in a rapid increase in biomedical applications of Raman spectroscopy. As reported in this month's Chemistry World, the potential sensitivity of Raman spectroscopy has been hiked by the development of tailored substrates and tips that enhance the optical signal (Chem. World 5 61). The use of surface-enhanced Raman spectroscopy (SERS), for example, enables signal enhancements of up to 14 orders of magnitude - intense enough to record spectra from individual molecules.

A prime example of the potential of Raman within medical diagnostics is a recent study from Stanford University School of Medicine (Stanford, CA). By exploiting the SERS effect, the Stanford researchers performed non-invasive imaging of nanoparticles within living mice (see Raman lines up for in vivo imaging). They also demonstrated one of Raman's big advantages over fluorescence, namely its ability to multiplex several signals from different entities in a living animal. Subsequent analysis of these spectra enabled the creation of colour-coded, 2D Raman images showing the relative concentrations of four distinct nanoparticles injected into a mouse.

The Stanford team also examined the liver pharmacokinetics of SERS nanoparticles, as well as successfully imaging tagged carbon nanotubes targeted to a mouse-tumour model. Other research teams have demonstrated the ability of Raman spectroscopy to differentiate benign and malignant excised tissue with high sensitivity and specificity. Together with the introduction of Raman fibre-optic probes, these developments should help speed the transfer of Raman to a clinical setting. Indeed, Sanjiv Sam Gambhir, head of the Stanford team, reckons that Raman-based diagnostic imaging may happen sooner rather than later, predicting that in-vivo endoscopic Raman spectroscopy could become feasible in 12 to 18 months' time.