MFP-FePt-GO Nanocomposites Promote Radiosensitivity of Non-Small Cell Lung Cancer Via Activating Mitochondrial-Mediated Apoptosis and Impairing DNA Damage Repair

Abstract

Background: Recent advances in nanomedicine provided promising alternatives for tumor treatment to improve the survival and life quality of cancer patients. This study was designed to explore the insight mechanisms of the anti-tumor effects of the novel nanocomposites (NCs) MFP-FePt-GO with non-small cell lung cancer (NSCLC). Methods: A chemical co-reduction method was applied to the synthesis process of MFP-FePt-GO NCs. The chemical synthesis efficiency and morphology of the NCs were measured with spectroscope and transmission electron microscope. Colony formation assay and cell apoptosis were conducted to assess the radiosensitivity effect of NCs with radiation. Then, we detected cell mitochondrial membrane potential and reactive oxygen species (ROS) level by flow cytometry to further explore the cause of cell death. Immunofluorescence staining and Confocal were carried out to determine the DNA damage repair. A Lewis lung carcinoma animal model was used to measure safety and anti-tumor efficiency in vivo. Results: The novel NCs MFP-FePt-GO designed on a lamellar-structure magnetic graphene oxide and polyethylene glycol drug delivery system was synthesized and functionalized for co-delivery of metronidazole and 5-fluorouracil. While no severe allergies, liver and kidney damage, or drug-related deaths were observed, MFP-FePt-GO NCs promoted radiosensitivity of NSCLC cells both in vivo and in vitro. It improved the effects of radiation via activating intrinsic mitochondrial-mediated apoptosis and impairing DNA damage repair. This NCs also induced a ROS burst, which suppressed the antioxidant protein expression and induced cell apoptosis. Furthermore, MFP-FePt-GO NCs prevented NSCLC cell migration and invasion. Conclusion: MFP-FePt-GO NCs showed a synergistic anti-tumor effect with radiation to eliminate tumors. With good safety and efficacy, this novel NCs could be a potential radiosensitive agent for NSCLC patients.

Genetic Variants in Double-Strand Break Repair Pathway Genes to Predict Platinum-Based Chemotherapy Prognosis in Patients With Lung Cancer

“…Platinum agents are typically used in combination with other antitumor drugs, but efficacy is limited due to resistance ( Garufi et al, 2020 ; Yu et al, 2020 ). The DNA repair system contributes to platinum resistance, which influences the curative effects of chemotherapy and negatively impacts the clinical outcomes ( Simon et al, 2007 ; Sullivan et al, 2014 ; Jiang et al, 2019 ; Peng et al, 2020 ). Polymorphism research has shown that gene polymorphisms affect prognosis, the folate metabolism pathway, drug transporters, and metabolic enzymes.…”

DNA damage and cell apoptosis induced by fungicide difenoconazole in mouse mononuclear macrophage RAW264.7

“…MMP collapse is considered a sign of early cell apoptosis and one of the key factors in inducing cell apoptosis 25 . The change of MMP is determined by the mitochondrial retention of fluorescent dye Rhodamine123 (Rho‐123) 26 .…”

Respiratory Toxicology of Graphene-Based Nanomaterials: A Review

“…Although GBNs induced DNA strand breaks in A549 and HLF cells in a dose-dependent manner, acid polyethylene glycol (LA-PEG) and PEG-modified GO induced only mild DNA damage and reduced the genotoxicity of GO on HLF cells [ 9 , 30 ]. However, other functionalized GBNs (MFP-FePt-GO NCs) can upregulate the DNA breakage protein γ-H2AX and downregulate the DNA repair proteins such as p-53, RAD-51, and GADD45 in non-small-cell lung cancer cells (NSCLC cells), thereby enhancing DNA breakage, which in turn promotes the anticancer effects of drugs [ 83 ]. It is suggested that the potential genotoxicity of GBNs may be attributed to their impact on nucleotide excision repair and nonhomologous end-joining repair mechanisms [ 58 ].…”