Firstly, researchers from Georgia Institute of Technology/Emory University (Atlanta, GA) and the University of Texas Health Science Center (Houston, TX) have come up with a technique for determining the leakiness of tumour blood vessels using a simple digital mammography unit (Radiology 250 398). This leakiness factor correlates closely with the ability of a chemotherapy drug to escape the bloodstream and enter the tumour, and thus can infer a drug's efficacy.
"By simply measuring how much contrast agent reaches the tumour, we can predict how much of a clinically approved chemotherapeutic will reach the tumour, allowing physicians to personalize the dose and predict effectiveness," explained Ravi Bellamkonda, a professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech/Emory University.
Keeping track
Bellamkonda and colleagues designed 100-nm-scale liposomal capsules filled with iodinated contrast agent that would only enter tumours with blood vessels that were growing and therefore leaky. They injected these probes into rats with breast-cancer tumours and recorded digital mammography images of the animals over the next three days. Comparing the pre- and post-injection images revealed the dynamics of contrast accumulation in the tumour.
"During the three-day time course, some tumours exhibited a rapid and significant increase in image brightness, meaning the contrast agent was accumulating in the tumour, whereas other tumours showed a slow and low increase," noted Bellamkonda. No variations were observed in non-tumour areas or in tumours of animals that did not receive contrast.
After the imaging was completed and the leakiness of each cancer vessel quantified, the animals were injected with liposomal doxorubicin, a clinically approved chemotherapy drug. The drug slowed the progress of the tumour, with the measured variability in contrast uptake providing an accurate predictor of the drug's effect on tumour growth rate.
"This study showed that higher uptake of the probe by the tumour related to leakier vasculature and suggested a better therapeutic outcome of liposomal doxorubicin," said Bellamkonda, who - along with colleague Ananth Annapragada - has founded a start-up called Marval Biosciences to commercialize the probes. "Imaging the integrity of the tumour vasculature like this may allow cancer treatment to be more patient-specific and potentially spare patients from chemotherapy if it is not going to be effective."
PET probe
Elsewhere, a team at the University of California, Los Angeles (UCLA) has a different take on the same challenge. Here, researchers are developing a PET-based tool that could one day allow doctors to evaluate an individual tumour's response to a drug before prescribing therapy, enabling them to personalize treatment to a patient's unique biochemistry.
The UCLA team has previously created a PET probe by slightly altering the molecular structure of gemcitabine, one of the most common chemotherapy drugs (see PET sheds light on immune response). The probe, called 18F-FAC, is labelled with positron-emitting particles that allow its movement through the body to be tracked via PET imaging.
In this latest study, the researchers injected the probe into mice with leukaemia and lymphoma tumours, and then imaged the animals an hour later. Gemcitabine is activated intracellularly at a rate controlled by an enzyme called DCK, the activity of which varies significantly among individuals and across different tumour types. The PET scans showed that 18F-FAC accumulated selectively in DCK-positive versus DCK-negative tumours (PNAS doi: 10.1073/pnas.0812890106).
"The PET scan offers a preview for how the tumour will react to a specific therapy," explained first author Rachel Laing, a UCLA graduate researcher in molecular and medical pharmacology. "We believe that the tumour cells that absorb the probe will also take up the drug. If the cells do not absorb the probe, it suggests that the tumour might respond better to another medication."
The team now plans to examine whether the probe can predict cellular response to other widely used chemotherapy drugs. "For the first time, we can watch a chemotherapy drug working inside the living body in real time," said Caius Radu, assistant professor of molecular and medical pharmacology at UCLA's David Geffen School of Medicine.
Radu continued: "The beauty of this approach is that it is completely non-invasive and without side effects. We plan to test this method in healthy volunteers within the year, to determine whether we can replicate our current results in humans." If testing in healthy subjects proves safe and effective, the UCLA researchers plan to begin recruiting volunteers for a larger clinical study of the probe in cancer patients.