title: Selective in vivo targeting of human liver tumors by optimized AAV3 vectors in a murine xenograft model.
abstract: Current challenges for recombinant adeno-associated virus (rAAV) vector-based cancer treatment include the low efficiency and the lack of specificity in vivo. rAAV serotype 3 (rAAV3) vectors have previously been shown to be ineffective in normal mouse tissues following systemic administration. In the present study, we report that rAAV3 vectors can efficiently target and transduce various human liver cancer cells in vivo. Elimination of specific surface-exposed serine and threonine residues on rAAV3 capsids results in further augmentation in the transduction efficiency of these vectors, without any change in the viral tropism and cellular receptor interactions. In addition, we have identified a potential chemotherapy drug, shikonin, as a multifunctional compound to inhibit liver tumor growth as well as to significantly enhance the efficacy of rAAV vector-based gene therapy in vivo. Furthermore, we also document that suppression of tumorigenesis in a human liver cancer xenograft model can be achieved through systemic administration of the optimized rAAV3 vectors carrying a therapeutic gene, and shikonin at a dose that does not lead to liver damage. Our research provides a novel means to achieve not only targeted delivery but also the potential for gene therapy of human liver cancer.
authors.affiliation: 1 Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine , Gainesville, FL 32611.
authors.forename: Chen
authors.initials: C
authors.lastname: Ling
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Yuanhui
authors.initials: Y
authors.lastname: Zhang
authors.forename: Anila
authors.initials: A
authors.lastname: Ejjigani
authors.forename: Zifei
authors.initials: Z
authors.lastname: Yin
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lu
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Zhongbo
authors.initials: Z
authors.lastname: Hu
authors.forename: George V
authors.initials: GV
authors.lastname: Aslanidi
authors.forename: Li
authors.initials: L
authors.lastname: Zhong
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.forename: Arun
authors.initials: A
authors.lastname: Srivastava
authors.forename: Changquan
authors.initials: C
authors.lastname: Ling
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D022781:Hepatocytes / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D023041:Xenograft Model Antitumor Assays