Smart drug delivery – releasing medications only at the site of tumor or infection – has presented an ongoing puzzle in disease treatment. Scientists have tried to solve the problem with photosensitive caged compounds, but activating these treatments often requires ultraviolet light, a method harmful to living tissue and, therefore, suitable for in vitro applications only. Now researchers in the laboratory of Younan Xia at Washington University have developed a drug-delivery device that has the potential to become an effective in vivo treatment method. It is triggered by near-infrared light, which can penetrate deeply into soft tissues and does not harm live cells. The innovation, based on their 2002 invention – the “nanocage” – is a 50-nm hollow gold cube with eight lopped-off porous corners. In the new demonstration, the investigators covered the nanocage with the smart polymer poly(N-isopropylacrylamide). What is smart about the polymer is that, up to a critical temperature of about 39 °C, for example, it seals the chemicals that were loaded into the hollow nanoparticles. The polymer chains have a bushy, water-loving configuration that blocks the porous corners of the nanocages (see figure). The cube (top center) represents a nanocage, a hollow gold nanoparticle with eight lopped-off porous corners. The drawing at bottom left shows the smart polymer-covered device in its resting state, filled with a disease-treating substance. At right, the smart polymer on the laser-activated nanocage has shrunk, exposing the corners, where medicine is released. However, when infrared laser light is directed toward these minuscule devices, the gold nanocage absorbs the irradiation, heating the polymer above its critical temperature so that it undergoes a phase change and contracts, exposing the nanocages’ tiny holes and releasing the drug. When the laser is turned off, the polymer returns to its previous state, resealing the contents. Xia said that gold was used to make the original nanocage because of its biocompatibility and its excellent optical properties, including its tunable surface plasmon resonance – that is, collective oscillation of its free-floating electrons. Whereas solid gold nanoparticles absorb light in the visible spectrum only, the hollow quality of the nanocages allows them to be tuned to absorb and/or scatter light in the visible and near-infrared regions. The research team achieved this by adjusting the ratio of the wall thickness to its overall dimensions. This near-infrared spectral window is suitable for human medical applications because its 750- to 900-nm range lies between the wavelengths absorbed by blood and water, respectively. Xia’s team already can alter the composition of the smart polymer such that it is sensitive to the temperature range between 37 and 42 °C – higher than normal body temperature but not hot enough to kill cells. As for the future of the technology, Xia wants to provide evidence of the smart capsules in action, treating diseases such as cancer. “The researchers would like to demonstrate controlled release with good spatial and temporal resolution by manipulating the position of an individual nanocage relative to a cell, for example, and at the same time move into some in vivo applications related to early detection and treatment of cancer.” The research was published online Nov. 1, 2009, in Nature Materials.