Heavy Atom Integration in 2-Hydroxymethylquinoline: A Rational Strategy for Enhanced Two-Photon Absorption-Mediated Tumor and Nuclear-Targeted Drug Delivery in Triple-Negative Breast Cancer

Two-photon absorption (TPA) technology has emerged as a promising approach for precise drug delivery due to its deep tissue penetration and high spatial selectivity. This study introduces a rational design approach to enhance TPA-mediated drug delivery by incorporating an increasing number of heavy bromine atoms into the hydroxymethylquinoline (HMQ) framework. The resulting molecules exhibit significantly improved TPA properties (TPA cross section of up to 130 GM), enabling efficient tumor and nuclear targeting in triple-negative breast cancer (TNBC) models. Structural modifications incorporating heavy Br atoms optimized electronic transitions, enhancing TPA cross sections and photostability. Biological evaluations revealed selective accumulation in TNBC cells, efficient nuclear localization, and enhanced therapeutic efficacy (∼75% cell killing) with minimal off-target effects. This strategy highlights the synergy between molecular design and photophysics for advancing theranostic applications. The study provides a blueprint for developing multifunctional TPA-based drug delivery systems, offering new avenues for the treatment of aggressive cancers, such as TNBC.