Two-Photon Activable Excited-State Proton Transfer-Induced Photoresponsive Nanocarriers for <i>In Vitro</i> Image-Guided Delivery of Bioactive Molecules

The excited-state proton transfer (ESPT) process, along with a high two-photon absorption cross-section, unlocks a pathway in the field of photocages. So far, only a limited number of photocages have been reported that combine the advantages of excited-state proton transfer (ESPT) and a high two-photon absorption cross-section, enabling the direct photorelease of alcohols without relying on carbonate or carbamate linkages. Henceforth, we strategically modified a “push–pull” based 6-hydroxy-substituted 1,8-naphthalimide (NID) chromophore as an ESPT-induced two-photon responsive photocage NID (5a–d, 6) for the direct release of alcohols. Our developed photocages exhibited a large Stokes shift due to the ESPT process and also demonstrated a change in fluorescence from yellow-orange to blue upon exposure to light, enabling their suitability for image-guided delivery of bioactive molecules. Inspired by these interesting properties, we formulated our photocage as nanoparticles (nano-NID-ES) with enhanced cell penetration ability to release the bioactive molecule estrone (ES). An in vitro study demonstrated that our photoresponsive nanocarrier (nano-NID-ES) exhibited better cellular internalization and real-time monitoring ability in the MCF-7 breast cancer cell line. MTT assay further revealed that nano-NID-ES exhibited an enhanced cytotoxic effect only after exposure to light. This development establishes an emerging pathway for the design of photocages and the advancement of photoresponsive drug delivery systems.