title: Dual-function nanosystem for synergetic cancer chemo-/radiotherapy through ROS-mediated signaling pathways.
abstract: Radioresistance and limitation of irradiative dosage usually lead to failure in depletion of hypoxic tumors. Herein we developed multifunctional mesoporous silica nanoparticles (MSNs) as a carrier of a novel anticancer selenoamino acid (selenocystine, SeC), to achieve synergistic chemo-/radiotherapy. This multifunctional nanosystem effectively sensitizes cancer cells to X-ray radiotherapy. Conjugation of TAT cell penetrating peptide and transferrin to the surface of MSNs significantly enhances its internalization in cancer cells through receptor-mediated endocytosis. SeC@MSNs-Tf/TAT significantly enhanced X-ray-induced growth inhibition in cervical cancer cells by induction of apoptosis, mainly through death receptor-mediated extrinsic apoptotic pathway. Upon radiation, SeC@MSNs-Tf/TAT promoted intracellular ROS overproduction, which induced apoptotic cell death by affecting p53, AKT and MAPKs pathways. Furthermore, SeC@MSNs-Tf/TAT also significantly inhibited HeLa tumor growth in nude mice model through suppression of cell proliferation and induction of apoptosis. In vivo toxicity of the SeC@MSNs-Tf/TAT nanoparticles was investigated using the mouse model. The results of histological analysis revealed that, the nanoparticles did not show any obvious damage to these major organs under the experimental conditions, including heart, liver, spleen, lung and kidney. Taken together, this study demonstrates an effective and safe strategy for cancer-targeted chemo-/radiotherapy of human cancers.
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Lizhen
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Haoqiang
authors.initials: H
authors.lastname: Lai
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China. Electronic address: tchentf@jnu.edu.cn.
authors.forename: Tianfeng
authors.initials: T
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003553:Cystine / Q000031:analogs & derivatives / Q000737:chemistry; D004249:DNA Damage; D016503:Drug Delivery Systems; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000532:radiotherapy*; D009584:Nitrogen / Q000737:chemistry; D016566:Organoselenium Compounds / Q000737:chemistry; D056951:Photoelectron Spectroscopy; D016062:Porosity; D011859:Radiography; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D012822:Silicon Dioxide / Q000737:chemistry; D014168:Transferrin / Q000378:metabolism; D014965:X-Rays; D023041:Xenograft Model Antitumor Assays; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; D014168:Transferrin; D054322:tat Gene Products, Human Immunodeficiency Virus; C009226:selenocystine; D003553:Cystine; D012822:Silicon Dioxide; D009584:Nitrogen
keywords: Apoptosis; Mesoporous silica nanoparticles; Radiotherapy; Targeted nanodrug delivery