title: Self-assembly of a virus-mimicking nanostructure system for efficient tumor-targeted gene delivery.
abstract: Molecular therapy, including gene therapy, is a promising strategy for the treatment of human disease. However, delivery of molecular therapeutics efficiently and specifically to the target tissue remains a significant challenge. A human transferrin (Tf)-targeted cationic liposome-DNA complex, Tf-lipoplex, has shown high gene transfer efficiency and efficacy with human head and neck cancer in vitro and in vivo (Xu, L., Pirollo, K.F., Tang, W.H., Rait, A., and Chang, E.H. Hum. Gene Ther. 1999;10:2941-2952). Here we explore the structure, size, formation process, and structure-function relationships of Tf-lipoplex. We have observed Tf-lipoplex to have a highly compact structure, with a relatively uniform size of 50-90 nm. This nanostructure is novel in that it resembles a virus particle with a dense core enveloped by a membrane coated with Tf molecules spiking the surface. More importantly, compared with unliganded lipoplex, Tf-lipoplex shows enhanced stability, improved in vivo gene transfer efficiency, and long-term efficacy for systemic p53 gene therapy of human prostate cancer when used in combination with conventional radiotherapy. On the basis of our observations, we propose a multistep self-assembly process and Tf-facilitated DNA cocondensation model that may provide an explanation for the resultant small size and effectiveness of our nanostructural Tf-lipoplex system.
authors.affiliation: Department of Oncology, Lombardi Cancer Center, Georgetown University Medical Center, Washington, D.C. 20007, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.forename: Peter
authors.initials: P
authors.lastname: Frederik
authors.forename: Kathleen F
authors.initials: KF
authors.lastname: Pirollo
authors.forename: Wen-Hua
authors.initials: WH
authors.lastname: Tang
authors.forename: Antonina
authors.initials: A
authors.lastname: Rait
authors.forename: Lai-Man
authors.initials: LM
authors.lastname: Xiang
authors.forename: Weiqun
authors.initials: W
authors.lastname: Huang
authors.forename: Idalia
authors.initials: I
authors.lastname: Cruz
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Yin
authors.forename: Esther H
authors.initials: EH
authors.lastname: Chang
mesh_terms: D000818:Animals; D004247:DNA / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics; D005260:Female; D018014:Gene Transfer Techniques; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D036103:Nanotechnology; D010316:Particle Size; D014168:Transferrin / Q000737:chemistry*; D019065:Virus Assembly
chemical_list: D008081:Liposomes; D014168:Transferrin; D004247:DNA