Chiral nanoparticles can be synthesised, tested for biological activity, and screened for drug safety all in the same tiny plastic wells used for high-throughput chemistry. The problem is that nanoparticle-based drugs—promising for vaccines, antibacterial agents, and treatments for cancer and neurodegeneration—are currently discovered and safety-tested using methods that cannot keep pace with the vast number of possible nanoparticle designs. The parameter space is enormous, and existing drug discovery libraries do not exist for these materials. This project combines two breakthroughs: a rapid method to synthesise chiral nanoparticles using amino acids, and a newly observed nonlinear optical effect that lets researchers detect how those nanoparticles bind to proteins in microliter-scale volumes. The team will build optical rigs that measure second- and third-harmonic scattering from nanoparticles in standard microplates, then cross-check the results with nuclear magnetic resonance and mass spectrometry. If successful, the work could turn nanoparticle drug discovery into a data-rich, high-throughput process—similar to how pharmaceutical companies now screen small-molecule drugs. The technology will be built on Renishaw’s commercial inVia Raman microscope platform, making it potentially deployable in existing labs.
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Chiral nanoparticles (NPs) can serve as components of vaccines and antibacterial agents, drug formulations against cancer and neurodegeneration. However, the methods for discovery and safety assessment of NPs as drugs are growing inadequate. Here, we aim to drastically accelerate discovery of NP-based medicines taking advantage of their chirality and of novel nonlinear optical effects that are compatible with data-rich high-throughput chemistry processes. Chirality (i.e. mirror asymmetry) is in most building blocks of life –DNA, proteins, etc. Mimicking proteins, chiral inorganic NPs can strongly interact with biomacromolecules forming sophisticated biological complexes with nanoscale dimensions and high biological activity; e.g. triggering an enhanced immune response [NAK, Nature2022, 601, 366] or killing viruses [NAK, Nat. Catalysis 2022, 5, 694]. The parameter space for such complex NPs is vast and its exploration requires novel high-throughput methods. Current drug discovery protocols rely on libraries of drug candidates but they do not exist for. Instead, we will take advantage of (a) versatile and rapid in-situ synthesis of chiral NPs with amino acids from the US team and (b) breakthrough observations of the UK team who reported the first experimental observation of NPs’ strong chiroptical nonlinearities [VKV, Phys Rev. X 2019, 9, 011024]; these will enable detection of Protein complexes in tiny microliter wells of microplates. NAK and VKV demonstrated a new form of this effect that has a maximum of emission in forward direction, which makes it most suitable for the microplates [NAK & VKV, Nat. Photonics 2022, 16, 126]. Our aims:1) Establish the broad applicability of our methodology to chiral NPs. We will synthesize biocompatible chiral NPs from metals, ceramics, and nanocarbons with broad optical properties (plasmonic, excitonic, dielectric). We will then reveal their nonlinear chiroptical properties. 2) Realize the new chiroptical effects in microwell optical systems. We will build dedicated optical rigs for high-throughput optical systems with robotic microwell positioning. The 2nd and 3rd harmonic scattering from NPs will be measured, revealing a previously unknown chiroptical spectroscopy in data-rich format, informing us about multispectral nonlinearities that are specific to NP interactions with biomolecules. 3) NP binding with proteins: The NPs will be tested with model proteins from bacterial biofilms, viral capsids, and immune cell membranes. The data obtained will be cross-checked in parallel tests with nuclear magnetic resonance, mass spectrometry, etc. providing independent data on formation of NP-protein complexes. The binding sites and constants will be also evaluated computationally using our recently developed models (NAK, 2022 Nature Computational Sci). 4) Apply our new technology, based on Renishaw’s inVia platform: With Renishaw’s active assistance, we will modify our inVia Raman microscope for operation with ultrafast lasers, add polarisation control and a highly sensitive detector, and use the high-throughput microplate scanning hardware and software developed by Renishaw.
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