Barbiturate Derivative JL1 Encapsulated with a Hafnium-Based MOF in Poly(<i>N</i>-isopropylacrylamide) for Non-Small Cell Lung Cancer Therapy

Nonsmall cell lung cancer (NSCLC), which accounts for the majority of cancer-related deaths globally, remains refractory to available therapies despite advancements in treatment modalities. Hence, there is a pressing need for the development of safer and more efficacious combination therapeutic strategies. Barbiturate derivatives have emerged as promising candidates for cancer chemotherapy. In this study, we introduced JL1-MOF/PNIPAM (JMP), a nanomedicine platform that encapsulates JL1, a barbituric acid derivative, within poly(N-isopropylacrylamide) (PNIPAM) and hafnium-based metal–organic frameworks (Hf-MOF), conferring pH- and temperature-responsive properties. When combined with radiotherapy, JMP demonstrated remarkable antitumor efficacy and extended survival in mice bearing NSCLC xenografts. The mechanisms underlying the antitumor action of JMP encompass several key aspects: (1) suppression of cellular activity, leading to the inhibition of migratory and proliferative capacities of NSCLC cells; (2) induction of apoptosis through the reduction of mitochondrial membrane potential (MMP), disrupting the balance between cell survival and death; and (3) augmentation of reactive oxygen species (ROS) levels, thereby eliciting oxidative stress within NSCLC cells and promoting cellular damage. Notably, JMP exhibited superior efficacy against lung squamous cell carcinoma, a subtype of NSCLC. This study presents a strategy for the synergistic treatment of NSCLC through the use of a nanomedicine formulated from barbiturate derivatives. By optimizing drug bioavailability and elucidating the synergistic mechanisms underlying the enhancement of NSCLC sensitivity through the combination of radiotherapy and chemotherapy, this strategy facilitates the encapsulation and delivery of antineoplastic agents, thereby opening up avenues for the therapeutic intervention of this fatal malignancy.