Identification of Pretreatment Agents to Enhance Adenovirus Infection of Bladder Epithelium

Adenovirus has been used widely as a gene transfer vector in the laboratory and clinic for the purpose of gene therapy. Conditionally replication-competent oncolytic adenoviruses are capable of multiplying up to a thousand old in target cells, a property that might prove to be of tremendous potential in the area of cancer therapy. Intravesicular therapy of refractory superficial bladder cancer employing an oncolytic adenovirus would allow for local administration and efficient delivery of virus to bladder tumor. The glycosaminoglycan layer on the surface of the bladder urothelium acts as a nonspecific antiadherence barrier and may be a significant roadblock to efficient infection of the urothelium by adenoviruses. Several laboratories have investigated the potential utility of bladder pretreatment with chemical agents to enhance the adenovirus infection of bladder urothelium but with limited success. A class of compounds has been identified that is effective for pretreatment of urothelium, permitting efficient adenoviral infection. In a murine model, pretreatment of the bladder with 0.1% dodecyl-β-d-maltoside (DDM) or sodium dodecyl sulfate (SDS) for 5 min resulted in >90% transduction of the urothelial layer within 15 min after exposure to a replication-defective adenovirus compared to ≤5% transduction in untreated bladders. DDM could be coformulated with adenovirus, and complete transduction of the urothelium was achieved following retention of the admixture in the bladder for 45 min. A similar enhancement of adenoviral infection following pretreatment of bladder with DDM and SDS was observed in a rat model. The use of these compounds may facilitate the development of adenovirus-based therapy for bladder cancer. [Copyright &y& Elsevier]