Photochemistry offers precise spatiotemporal control over chemical reactivity, enabling selective transformations using light as an external stimulus rather than conventional chemical reagents. In principle, such control could enable targeted drug activation, real-time imaging, and localized release of bioactive molecules while minimizing off-target effects. However, photo-medical methods are currently limited to mostly topical and subcutaneous applications due to the fundamental challenge of delivering light through UV-Visible opaque environments^1,2. This seminar will present three complementary research projects that utilize light to control reactivity across synthetic, materials, and biomedical contexts. 

The expanding role of macrocycles in medicinal chemistry has led to an increased demand for efficient synthetic methods that enable rapid access to structurally diverse macrocycles. However, the design and synthesis of functionalized macrocycles remains a challenge, as conventional macrocyclization strategies often rely on costly hygroscopic catalysts and require highly dilute conditions to minimize unwanted dimerization and oligomerization side-products3. In an effort to overcome these limitations, a photo-induced strain-promoted azide-alkyne cycloaddition (photo-SPAAC) platform was developed for the preparation of macrocycles. Despite their stability to organic/ inorganic azides and endogenous nucleophiles, cyclopropenones subjected to mild UVA irradiation are quantitatively converted into reactive cyclooctynes. In this approach, the spatiotemporal control afforded by photo-SPAAC is leveraged for the efficient, concentration-independent synthesis of macrocycles.

To navigate the fundamental challenge of light delivery in biological or other UV-Visible opaque environments, a strategy employing upconversion nanoparticles (UCNPs) and photoactive cyclopropenones was explored. Near-Infrared UCNPs can act as transducers, absorbing two or more low

energy photons and subsequently emitting a higher energy photon through a process called resonance-enhanced multi-photon excitation4. This NIR triggerable platform enables spatially confined high-resolution protein labeling, providing a platform capable of deep-tissue imaging and visualization.

Lastly, a complementary strategy to overcome depth limitation of conventional light-based therapies utilizing x-ray induced photochemistry is being explored. To this end, a strategy employing x-ray precharged optically stimulated luminescent nanoparticles (OSLNPs) and a photoactive carbon monoxide releasing molecule (photo-CORM) was developed. Upon various forms of external stimulation, stored energy is released as local luminescence triggering photochemical CO release, demonstrating a potential strategy for remotely activated cancer therapeutic platforms.

Citations

1. Wolf, P.; De Gruijl, FR. Photomedicine. Front. Med. 2019, (6) 161.

2. Hashim, P. K.; Shaji, A.T.; Amrutha, A.S.; Ahmed, S. RSC Med. Chem. 2025, (16), 2360-2372.

3. Kim, T.; Baek, E.; Kim, J. Pharmaceuticals (Basel). 2025, 18(5), 617.

4. Xin, N.; Wei, D.; Zhu, Y.; Yang, M.; Ramakrishna, S.; Lee, O.; Luo, H.; Fan, H. Master. Today. Chem. 2020, 17, 100329.