bio sphere
Finding cancer cells with quantum dots L
ike spies that infiltrate terrorist groups and betray their locations, new quantum dots can target cancer cells in living mice and reveal the whereabouts of those cells (Nat. Biotechnol. 2004, 8, 969–976). “Previously, people had managed to target without imaging or image without targeting,” says Shuming Nie, who developed the quantum dots with Leland Chung and their colleagues at Emory University, the Georgia Institute of Technology, and Cambridge Research & Instrumentation. Quantum dots are semiconductor nanocrystals that fluoresce brightly in response to a beam of light. Those used by Chung and Nie contain cadmium selenide and zinc sulfide, are 10–15 nm in diameter, and blink red light. Earlier research led some experts to conclude that quantum dots, as originally designed, were unsuitable for use in living systems. Based on his work at the Burnham Institute and the University of California, San Diego, Erkki Ruoslahti says, “They are very stable in test tubes, and they could be targeted with exquisite specificity in mice, but they didn’t seem to be stable enough in the cell and tissue environment to give the kind of signal intensity that one expects. The new work now seems to have solved this problem.” After two years of trial and error, Nie and colleagues devised a new surface chemistry that protects quantum dots from bodily fluids and targets them to cancer cells. The researchers first coated quantum dots with tri-n-octylphosphine oxide (TOPO). When a triblock polymer was added, it bonded to the TOPO layer through strong hydrophobic interactions, cocooning and dispersing the quantum dots. The resulting shell kept out salts and water. It also resisted enzymes and strong acids. © 2004 AMERICAN CHEMICAL SOCIETY
Tumors
Injection site
Quantum dots modified with antibodies to human prostate-specific membrane antigen light up murine tumors that developed from human prostate cells. (Adapted with permission. Copyright 2004 Macmillan Publishers, Ltd.)
Because the triblock polymer has many functional groups, it can also serve as a pegboard for adding smaller molecules to enhance quantum dot function. Nie and Chung attached polyethylene glycol, a drug-delivery agent, which caused the dots to accumulate passively in tumor cells. The scientists actively targeted the quantum dots to human prostate cells by attaching to the shell a monoclonal antibody specific to human prostate-specific membrane antigen. Despite all the modifications, the quantum dots retained their optical properties. To observe quantum dots in living animals, Xiaohu Gao in Nie’s group injected them into mice that had tumors derived from human prostate cells. The researchers observed a bright red signal from the tumors that was distinguishable from autofluorescence. Warren Chan at the University of Toronto believes this is a great innovation. “In most previous studies [using quantum dots], you had to excise a tumor to image it,” he says.
The collaborators compared the efficacy of quantum dots with that of fluorescent labels by injecting 1000 prostate cancer cells loaded with quantum dots into one side of a mouse and 1000 cells transfected with green fluorescent protein into the other side. Only the signal from the quantum dots was detectable by microscopy. Before quantum dots can be used in the clinic to find cancer cells in humans, several problems must be solved. For example, Ruoslahti says the targeting system used by Nie’s group may not be practical for clinical use. The antibody cleanly targeted the tumors in the mice because the tumors contained human antigens. Those antigens are not as specific for tumors in patients. Another challenge is that quantum dots contain cadmium, which is toxic and might cause damage if the dots remain in the body; it is not yet known whether the kidneys can eliminate them. Nie agrees that more studies are needed to determine toxicity. “But so far, all the experimental data indicate that quantum dots are safe in the short term and are much less toxic than organic dyes,” says Nie. He adds that cadmium selenide is not toxic if cadmium ions are not released. Finally, a red signal, though visible from a mouse, is unlikely to escape the human body, which contains a greater mass of tissue that absorbs red light. “So we will improve the instrumentation and improve the quantum dot probes by going into the near infrared part of the spectrum,” Nie says. Chan estimates that 5–6 years of fundamental studies will be necessary before clinical trials can begin. “But this is a big step in the direction of developing a new kind of contrast agent for cancer detection,” he says. a —Linda Sage
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