Inhibition of ataxia-telangiectasia mutated by antisense oligonucleotide nanoparticles induces radiosensitization of head and neck squamous-cell carcinoma in mice.
Ataxia-telangiectasia-mutated (ATM) is a radiosensitization gene. In the present study, we investigated the efficacy of poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles containing ATM antisense oligonucleotides (ASOs) for the radiosensitization of head and neck squamous-cell carcinoma in mice, using the SCCVII cell line. Nanoparticles containing ATM ASOs were prepared with PLGA by using a double-emulsion solvent evaporation method. The results showed that the nanoparticles were suitable for intracellular uptake, and ATM ASOs inhibited ATM expression when delivered by using nanoparticles or lipofectin, but not in their free form. Meanwhile, we found that ATM reduction sensitized SCCVII cells in vitro and tumors in vivo to irradiation. In conclusion, biodegradable PLGA nanoparticles, used as a delivery carrier, enhanced intracellular uptake of ATM ASOs into SCCVII cells and the inhibitory effect of ATM ASOs. These results demonstrated that antisense ATM therapy, using PLGA nanoparticles, might provide a therapeutic benefit to patients undergoing radiation therapy for head and neck squamous-cell carcinoma.
Department of Otolaryngology, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
Jian
J
Zou
Xiaoming
X
Qiao
Huiping
H
Ye
Yi
Y
Zhang
Junming
J
Xian
Houyu
H
Zhao
Shixi
S
Liu
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000532:radiotherapy*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D016296:Mutagenesis / Q000187:drug effects*; D053758:Nanoparticles / Q000737:chemistry*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D010316:Particle Size; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014965:X-Rays; D023041:Xenograft Model Antitumor Assays
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016376:Oligonucleotides, Antisense; D011838:Radiation-Sensitizing Agents; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases