Development of NIR-I/II Nanoparticle Contrast Agents for Photoacoustic Imaging

Abstract

Cancer is a leading cause of death worldwide and poses a significant burden on society through loss of life, increased healthcare costs, and lost earnings. While targeted cancer therapies are improving rapidly, imaging modalities are slower to advance and are not yet effective in diagnosing many early-stage cancers. One novel hybrid optical-ultrasound based technology, photoacoustic (PA) imaging, has recently received attention for rapid structural, functional, and molecular imaging. PA imaging combines high spatial resolution, non-ionizing radiation, non-invasive techniques, and deeper tissue penetration than traditional optical methods, to create functionalized images. Unfortunately, multiplexed PA imaging is limited by the availability of spectrally distinct exogenous contrast agents. The development of new PA contrast agents can therefore vastly improve methods to diagnose and treat cancer. The following report discusses the production of stable Near Infrared I (600-900nm) and Near Infrared II (900-1350nm) (NIR-I/II) active nanoparticles (NPs) engineered through Flash NanoPrecipitation (FNP). FNP is a copolymer controlled self-assembly methodology that encapsulates hydrophobic compounds into water-dispersible NPs coated with biocompatible polyethylene glycol (PEG) polymers. NIR-I and NIR-II contrast agents are formed by encapsulating absorbers with distinct absorbance spectra into NPs through FNP. NPs with tunable sizes ranging from 16nm-282nm in diameter can be formed and exhibit significant NIR-II absorption activity optimal for PA imaging. The co-encapsulation of Vitamin E (VitE) and polystyrene (PS) in the NP core with organic contrast agents validates the capability of simultaneously imaging and delivering multiple therapeutic compounds. Particle size, absorbance profiles, and storage stability were varied by tuning FNP compositions, and optimized formulations were sent to collaborators at VisualSonics and the University of Toronto for PA activity assessment. Results demonstrated strong PA activity with potential for increased imaging depth and sustained drug delivery. These particles represent the first instance of NIR-II PA contrast agents formed by encapsulation of optical absorbers. This work is also the first to demonstrate that stable NP imaging agents as small as 20nm can be formed with FNP. Ultimately, this thesis successfully develops new imaging agents that can assist in meeting the growing need for versatile, next-generation cancer diagnostic tools.