title: Ex vivo nonviral gene delivery of μ-opioid receptor to attenuate cancer-induced pain.
abstract: Virus-mediated gene delivery shows promise for the treatment of chronic pain. However, viral vectors have cytotoxicity. To avoid toxicities and limitations of virus-mediated gene delivery, we developed a novel nonviral hybrid vector: HIV-1 Tat peptide sequence modified with histidine and cysteine residues combined with a cationic lipid. The vector has high transfection efficiency with little cytotoxicity in cancer cell lines including HSC-3 (human tongue squamous cell carcinoma) and exhibits differential expression in HSC-3 (∼45-fold) relative to HGF-1 (human gingival fibroblasts) cells. We used the nonviral vector to transfect cancer with OPRM1, the μ-opioid receptor gene, as a novel method for treating cancer-induced pain. After HSC-3 cells were transfected with OPRM1, a cancer mouse model was created by inoculating the transfected HSC-3 cells into the hind paw or tongue of athymic mice to determine the analgesic potential of OPRM1 transfection. Mice with HSC-3 tumors expressing OPRM1 demonstrated significant antinociception compared with control mice. The effect was reversible with local naloxone administration. We quantified β-endorphin secretion from HSC-3 cells and showed that HSC-3 cells transfected with OPRM1 secreted significantly more β-endorphin than control HSC-3 cells. These findings indicate that nonviral delivery of the OPRM1 gene targeted to the cancer microenvironment has an analgesic effect in a preclinical cancer model, and nonviral gene delivery is a potential treatment for cancer pain.
authors.affiliation: Departments of Prosthodontics and.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Yamano
authors.affiliation: Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, NY, USA.|Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY, USA.
authors.forename: Chi T
authors.initials: CT
authors.lastname: Viet
authors.affiliation: Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, NY, USA.|Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY, USA.
authors.forename: Dongmin
authors.initials: D
authors.lastname: Dang
authors.affiliation: Departments of Prosthodontics and.
authors.forename: Jisen
authors.initials: J
authors.lastname: Dai
authors.affiliation: Departments of Prosthodontics and.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Hanatani
authors.affiliation: Departments of Prosthodontics and.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Takayama
authors.affiliation: Departments of Prosthodontics and.
authors.forename: Hironori
authors.initials: H
authors.lastname: Kasai
authors.affiliation: Departments of Prosthodontics and.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Imamura
authors.affiliation: Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, NY, USA.|Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Campbell
authors.affiliation: Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, NY, USA.|Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, NY, USA.|Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Dolan
authors.affiliation: Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, NY, USA.|Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY, USA.
authors.forename: William Myung
authors.initials: WM
authors.lastname: Kwon
authors.affiliation: Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, NY, USA.|Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY, USA.
authors.forename: Stefan D
authors.initials: SD
authors.lastname: Schneider
authors.affiliation: Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, NY, USA.|Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY, USA.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D000072716:Cancer Pain / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002294:Carcinoma, Squamous Cell / Q000150:complications* / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005351:Fibromatosis, Gingival / Q000235:genetics / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*; D014062:Tongue Neoplasms / Q000150:complications* / Q000235:genetics; D014162:Transfection
chemical_list: C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu; D049452:Green Fluorescent Proteins