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Lighting up elusive cells

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Caren B. Les,

To help improve the effectiveness of cancer surgery, scientists have investigated a more accurate way to differentiate tumor from normal tissue during surgery. In a line of studies, working primarily with immunocompetent mice with tumors, they found that a surgical technique using molecular fluorescence imaging decreased residual cancer and improved animal survival.

The investigation was led by Nobel Prize winner Roger Tsien, who is a researcher at the Howard Hughes Medical Institute and a professor of pharmacology, chemistry and biochemistry at the University of California, San Diego, and at the Moores UCSD Cancer Center. Results were published in two consecutive papers in the March 2, 2010, issue of the Proceedings of the National Academy of Sciences. Emilia Olson, an MD/PhD student in the Tsien lab, and Quyen Nguyen, an assistant professor of head and neck surgery at the University of California, San Diego, School of Medicine, were first authors of the reports, which detail the development of new dual-labeled probes that can be detected via optical imaging and MRI as well as the probes’ application to molecular imaging during surgery.

Roger Tsien and his research team at the University of California, San Diego, developed probes carrying fluorescent and magnetic tags to identify cancerous cells in mice during surgery. They determined that, compared to traditional surgical methods, the technique detected more residual cancer cells. The image shows the tumor that has been removed (large arrow) and the remaining cancer cells (small arrow). Photo courtesy of Quyen Nguyen and Roger Tsien, UCSD.

Positive margins, defined as tumor cells at the cut edge of surgical specimens, have been associated with increased local recurrence of cancer and are a poor prognostic indicator for certain cancers, including breast and colorectal, according to the report by Nguyen et al. Additional “salvage” surgery and treatment are often not effective in treating or curing the disease.

The investigators showed that, compared with standard surgical techniques, using fluorescent probes to adhere to and light up cancerous cells during surgery allows surgeons to see and remove more residual cancer cells in the tissue surrounding a tumor. Traditional surgical lighting and techniques have offered less than optimal conditions for surgeons to view these cells. Standard surgery is defined in the study as surgery with white-light illumination under microscopic visualization to remove the entire ascertainable tumor.

Surgeons have relied more subjectively on feel, sight and experience to remove cancerous tissue. Although marginal tissue can be taken and analyzed during surgery for residual cancer cells, this process requires longer patient time on the operating table.

In their study, the investigators developed synthetic molecules, attaching bio-active molecules called activatable cell-penetrating peptides (ACPPs) to microscopic nanoparticles to develop probes carrying fluorescent and magnetic tags. These tags made tumors visible to MRI and allowed the tumor to “glow” on the operating table. The ACPP-nanoparticle probes enabled surgeons to visualize tumor areas that they wouldn’t ordinarily be able to see.

The scientists investigated whether tumor margins could be visualized more objectively during surgery by using ACPPs. They compared residual tumor cells at the surgical bed and tumor-free survival with and without ACPP guidance and found that the animals whose tumors were resected with the guidance of ACPPs conjugated to dendrimers (ACPPD) had better long-term tumor-free and overall survival rates than animals whose tumors were resected with traditional bright-field illumination only.

They found that the fluorescently labeled probes hit their mark 93 percent of the time, allowing researchers to see leftover tumor tissue. They also discovered that, on average, 90 percent fewer cancer cells remained in mice after surgery using probe-based guidance compared to surgery without it – a tenfold reduction. The polymerase chain reaction technique was used to measure tumor DNA.

“A single injection of ACPPD dually labeled with Cy5 [fluorescent dye] and gadolinium chelates enabled preoperative whole-body tumor detection by MRI, intraoperative guidance by real-time fluorescence, intraoperative histological analysis of margin status by fluorescence, and postoperative MRI tumor quantification,” read the report by Nguyen et al.

Tsien commented that the work was done mainly on mice with syngeneic mouse tumors. He said that these tumors have the advantage that the immune system of the mouse is intact, so that the reaction of the host to the tumor is much more realistic than when human tumors are implanted into immunodeficient mice.

The nanoparticle-based probes may eventually be used to deliver chemotherapy drugs to finish off the remaining cancer, or to stage cancer, especially of the prostate. The visual cues provided by the technology could also be useful in laparoscopic and robotic surgery, where surgeons cannot feel the tumor.

May 2010
ACPPactivatable cell-penetrating peptidesBasic ScienceBiophotonicsBioScancancer surgeryCaren B. LeschemotherapyConsumerCy5dual-labeled probesEmilia Olsonfluorescent dyefluorescent probesHoward Hughes Medical Instituteimagingmagnetic resonance imagingmolecular fluorescence imagingMoores UCSD Cancer CenterMRInanonanoparticlesNewsoptical imagingopticsPNASProceedings of the National Academy of SciencesQuyen Nguyenresidual cancer cellsRoger TsienSan DiegoSchool of MedicinetumorsUniversity of California

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