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

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 in multiple cycles of intravenons 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 LA-5-RIP-TK/CGV 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-RJP-TK was assessed using C57/B6J mice challenged with adenovirus or liposome adenovirus complex. Results. The minimal residual tumor burden (3.2 +/- 0.6 mm(3)) 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 RJP-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 hate substantial mortality after the 4th cycle. Liposome-encapsulated adenovirics 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. (Surgery 2011;149:484-95.)