Targeted Phototriggered and pH-Responsive Micellar Cancer Drug Delivery System with Real-Time Monitoring through the NSET Mechanism

A phototriggered and pH-responsive cancer drug delivery system based on polymeric micelles was formulated, utilizing easily available and cost-effective materials such as an amphiphilic diblock copolymer (mPEG-PLA) and a Spiropyran derivative. It addressed the major challenges in drug delivery systems, i.e., monitoring real-time drug release, targeted, and on-demand drug delivery. To monitor real-time drug release, the fluorescence quenching of the cancer drug, doxorubicin (DOX), by <i>in situ</i> synthesized gold nanoparticles (AuNPs) through the Nanomaterial Surface Energy Transfer (NSET) mechanism was explored. Photoisomerization and size switching were characterized using UV-vis spectroscopy and dynamic light scattering (DLS) techniques. The NSET process during <i>in situ</i> synthesis of AuNPs and drug release from nanocarrier after 365 nm UV light exposure was demonstrated by steady-state and time-resolved fluorescence of DOX. The mPEG-PLA-Spiropyran-DOX (3:1:1) formulation exhibited ∼ 73.16% encapsulation efficiency and ∼ 6.45% DOX-loading with proven kinetic stability. Sustained DOX release over 50 h was validated through <i>in vitro</i> studies at pH 5.5, 6.5, and 7.4, showing enhanced DOX release at acidic pH 5.5, representative of cancer cell organelles with prolonged UV exposure. Cell internalization, intracellular phototriggered drug release, and fluorescence cell imaging in mouse breast adenocarcinoma cells (4T1) were investigated. The results demonstrated that the micellar nanocarrier, after 365 nm UV light exposure, was highly efficient in inducing apoptosis, significant cytotoxicity, and mitochondrial membrane depolarization. Furthermore, <i>in vivo</i> studies were conducted in both oral and breast cancer-bearing mice to assess tumor growth inhibition, changes in body weight, tumor weight, and immunohistochemical analysis. Notably, the therapeutic response was more pronounced in oral cancer, allowing for enhanced UV penetration and efficient activation of the micellar system. Overall, this study highlighted the potential of the dual-responsive micellar drug delivery system for targeted, on-demand cancer therapy with real-time monitoring. The enhanced efficacy in treating superficial malignancies underscores its promise for future clinical applications.