A photonic effect in semiconducting helical particles, discovered through a collaboration between the University of Bath and the University of Michigan, could facilitate the use of robotic chemistry to speed the development and screening of pharmaceutical drugs. The researchers found that twisted semiconductor nanostructures can convert red light into twisted blue light in tiny volumes, which could aid in the development of chiral drugs. The physical quality of chirality can explain whether a drug molecule twists. Similarly, the measurement of chirality, which is a critical analysis to drug discovery and development, can determine which way the molecule twists. At best, a drug molecule with the wrong twist does nothing; at worst, it can cause harm. The photonic effect discovered by the researchers allows chirality to be measured in volumes that are 10,000× smaller than one cubic millimeter (1 mm3). To achieve the effect, researchers at the University of Michigan shaped structures made from the semiconductor cadmium telluride into nanoparticles resembling short segments of twisted ribbon. These structures assembled into semiconducting helices at the nanoscale, mimicking the way proteins assemble. When the semiconductor nanoparticles were illuminated with circularly polarized light in red, third-harmonic Mie scattering light streamed out in blue. “Being illuminated with red light, the small semiconductor helices generate new light that is blue and twisted. The blue light is also emitted in a specific direction, which makes it easy to collect and analyze,” University of Michigan professor Nicholas Kotov said. “The trifecta of unusual optical effects drastically reduces the noise that other nanoscale molecules and particles in biological fluids may cause.” University of Bath professor Ventsislav Valev said that the researchers can determine the direction of twist (or chirality) of the structures by measuring the blue light. The photonic effect observed by the researchers can be applied to the rapid analysis of drug molecules and molecule combinations. “Our latest finding does have the potential to link AI algorithms that analyze chemical reactions and robotic arms that prepare chemical mixtures — a process known as high-throughput screening,” Valev said. Upon illuminating chiral semiconductor nanoparticles with circularly polarized light (red), third-harmonic Mie scattering light streams out (blue). The illustration shows a microplate well in the foreground, while in the background a tested sample receives red laser light and releases twisted blue light. Courtesy of Ventsislav Valev, Kylian Valev, and Lukas Ohnoutek, University of Bath. High-throughput screening is used to analyze vast libraries of drug molecules. It relies on robots to simultaneously operate a large number of syringes, preparing thousands of chemical mixtures for robotic analysis. The results are fed back to AI algorithms, which determine what mixtures to prepare next, until a useful drug is discovered. The nanohelices can be mixed with a drug candidate. When they form a lock-and-key structure with the drug, simulating the drug target, the twist of the nanohelices changes. In high-throughput screening, a tiny sample of each compound fills a well on a microplate. A plate the size of a chocolate bar can contain a thousand wells, each as small as 1 mm3. The more wells a plate holds, the more chemical compounds can be analyzed in a single hit. The photonic effect allows chirality to be measured in volumes that are 10,000× times smaller than 1 mm3, supporting the speed of high-throughput screening. “To meet the requirements of the emerging robotized chemistry, wells are getting really tiny — too small for current analytical methods,” Valev said. “So, fundamentally new methods are needed to analyze would-be drugs.” “The small volumes possible for registration of these effects are the game-changing property that enables the researchers to use very small amounts of expensive drugs and collect thousands times more data,” Kotov said. Valev said that most new drugs entering the market and the majority of old drugs are chiral. “Therefore, it is especially important to be able to measure chirality in tiny volumes of less than 1 mm3, which is about the size of a cube with sides of the thickness of a credit card,” he said. The researchers recorded third-harmonic Mie scattering on illuminated helices with 1065-, 1095-, and 1125-nm laser beams. The intensity was around 10× higher in the forward direction than sideways. The third-harmonic ellipticity was as high as 3°, which the researchers attributed to the interference of chiral and achiral effective, nonlinear susceptibility tensor components. According to the team, its results chart a path for rapid high-throughput chiroptical characterization of tiny sample volumes. “Although the structures that we measured so far are much larger than typical pharmaceuticals, we have proven that the physical effect is real, so in principle, applications to molecules and especially drugs are now only a question of technological development,” Valev said. The University of Michigan has filed for patent protection and is seeking partners to bring the new technology to market. Members of the team said that the generation of the blue light from red could also be helpful in drug development in samples approaching the complexity of biological tissues. The research was published in Nature Photonics (www.doi.org/10.1038/s41566-021-00916-6).