Multiple treatment cycles of liposome-encapsulated adenoviral RIP-TK gene therapy effectively ablate human pancreatic cancer cells in SCID mice

Shi He Liu, Nancy Smyth-Templeton, Alan R. Davis, Elizabeth A. Davis, Nikiforos Ballian, Min Li, Hao Liu, William Fisher, F. Charles Brunicardi

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Background: Adenoviral gene therapy has been applied widely for cancer therapy; however, transient gene expression as result of humoral immunoneutralization response to adenovirus limits its effect. The purpose of this study is to determine whether DOTAP:cholesterol liposome could shield adenovirus from neutralizing antibody and permit the use of multiple cycles of intravenous liposome encapsulated serotype 5 adenoviral rat insulin promoter directed thymidine kinase (L-A-5-RIP-TK) with ganciclovir (GCV) to enhance its effect. Methods: The effect of multiple cycles of systemic L-A-5-RIP-TK/GCV therapy was evaluated in grouped PANC-1 SCID mice treated with different numbers of cycles. Humoral immune response to A-5-RIP-TK or L-A-5-RIP-TK was assessed using C57/B6J mice challenged with adenovirus or liposome adenovirus complex. Results: The minimal residual tumor burden (3.2 ± 0.6 mm3) and greatest survival time (153.0 ± 6 days) were obtained in the mice receiving 4 and 3 cycles of therapy, respectively. Toxicity to islet cells associated with RIP-TK/GCV therapy was observed after 4 cycles. DOTAP:chol-encapsulated adenovectors were able to protect adenovectors from the neutralization of high titer of anti-adenoviral antibodies induced by itself. Conclusion: Multiple treatment cycles of L-A-5-RIP-TK/GCV ablate human PANC-1 cells effectively in SCID mice; however, the mice become diabetic and have substantial mortality after the 4th cycle. Liposome-encapsulated adenovirus is functionally resistant to the neutralizing effects of anti-adenoviral antibodies, suggesting feasibility of multiple cycles of therapy. Liposome encapsulation of the adenovirus may be a promising strategy for repeated delivery of systemic adenoviral gene therapy.

Original languageEnglish (US)
Pages (from-to)484-495
Number of pages12
JournalSurgery
Volume149
Issue number4
DOIs
StatePublished - Apr 1 2011
Externally publishedYes

ASJC Scopus subject areas

  • Surgery

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    Liu, S. H., Smyth-Templeton, N., Davis, A. R., Davis, E. A., Ballian, N., Li, M., Liu, H., Fisher, W., & Brunicardi, F. C. (2011). Multiple treatment cycles of liposome-encapsulated adenoviral RIP-TK gene therapy effectively ablate human pancreatic cancer cells in SCID mice. Surgery, 149(4), 484-495. https://doi.org/10.1016/j.surg.2010.11.014