RESUMEN
Intrinsic or acquired resistance to chemical drugs severely limits their therapeutic efficacy in cancer treatment. Various intracellular antioxidant molecules, particularly glutathione (GSH), play a crucial role in maintaining intracellular redox homeostasis by mitigating the overproduced reactive oxygen species (ROS) due to rapid cell proliferation. Notably, these antioxidants also eliminate chemical-drug-induced ROS, eventually diminishing their cytotoxicity and rendering them less effective. In this study, we combined erastin, a GSH biosynthesis inhibitor, with 2'-deoxy-5-fluorouridine 5'-monophosphate sodium salt (FdUMP), an ROS-based drug, to effectively disrupt intracellular redox homeostasis and reverse chemotherapy resistance. Therefore, efficient ferroptosis and apoptosis were simultaneously induced for enhanced antitumor effects. Additionally, we employed small interfering RNA targeting PD-L1 (siPD-L1) as a third agent to block immune-checkpoint recognition by CD8+ T cells. The highly immunogenic cell peroxidates or damage-associated molecular patterns (DAMPs) induced by erastin acted synergistically with downregulated PD-L1 to enhance the antitumor effects. To codeliver these three drugs simultaneously and efficiently, we designed GE11 peptide-modified lipid nanoparticles (LNPs) containing calcium phosphate cores to achieve high encapsulation efficiencies. In vitro studies verified its enhanced cytotoxicity, efficient intracellular ROS induction and GSH/GPX4 downregulation, substantial lipid peroxidation product accumulation, and mitochondrial depolarization. In vivo, this formulation effectively accumulated at tumor sites and achieved significant tumor inhibition in subcutaneous colon cancer (CRC) mouse models with a maximum tumor inhibition rate of 83.89% at a relatively low dose. Overall, a strategy to overcome clinical drug resistance was verified in this study by depleting GSH and activating adaptive immunity.
Asunto(s)
Antineoplásicos , Apoptosis , Antígeno B7-H1 , Regulación hacia Abajo , Ferroptosis , Nanopartículas , Ferroptosis/efectos de los fármacos , Animales , Humanos , Ratones , Nanopartículas/química , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Regulación hacia Abajo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Lípidos/química , Proliferación Celular/efectos de los fármacos , Femenino , Ensayos de Selección de Medicamentos Antitumorales , Línea Celular Tumoral , LiposomasRESUMEN
Soil cadmium (Cd) pollution poses severe threats to food security and human health. Previous studies have reported that both nanoparticles (NPs) and biochar have potential for soil Cd remediation. In this study, a composite material (BN) was synthesized using low-dose TiO2 NPs and silkworm excrement-based biochar, and the mechanism of its effect on the Cd-contaminated soil-pak choi system was investigated. The application of 0.5 % BN to the soil effectively reduced 24.8 % of diethylenetriaminepentaacetic acid (DTPA) Cd in the soil and promoted the conversion of Cd from leaching and HOAc-extractive to reducible forms. BN could improve the adsorption capacity of soil for Cd by promoting the formation of humic acid (HA) and increasing the cation exchange capacity (CEC), as well as activating the oxygen-containing functional groups such as CO and CO. BN also increased soil urease and catalase activities and improved the synergistic network among soil bacterial communities to promote soil microbial carbon (C) and nitrogen (N) cycling, thus enhancing Cd passivation. Moreover, BN increased soil biological activity-associated metabolites like T-2 Triol and altered lipid metabolism-related fatty acids, especially hexadecanoic acid and dodecanoic acid, crucial for bacterial Cd tolerance. In addition, BN inhibited Cd uptake and root-to-shoot translocation in pak choi, which ultimately decreased Cd accumulation in shoots by 51.0 %. BN significantly increased the phosphorus (P) uptake in shoots by 59.4 % by improving the soil microbial P cycling. This may serve as a beneficial strategy for pak choi to counteract Cd toxicity. These findings provide new insights into nanomaterial-doped biochar for remediation of heavy metal contamination in soil-plant systems.