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Abstract
In a previous report, 3-aminopropyl functionalized magnesium phyllosilicate (aminoclay) improved adenovirus transduction efficiency by shielding the negative surface charges of adenovirus particles. The present study analyzed the physicochemical characterization of the electrostatic complex of adenoviruses with aminoclay and explored whether it could be utilized for enhancing tumor suppressive activity in the bladder. As a result of aminoclay-adenovirus nanobiohybridization, its transduction was enhanced in a dose-dependent manner, increasing transgene expression in bladder cancer cells and in in vivo animal models. Physicochemical studies demonstrated that positively charged aminoclay led to the neutralization of negative surface charges of adenoviruses, protection of adenoviruses from neutralizing antibodies and lowered transepithelial electrical resistance (TEER). As expected from the physicochemical properties, the aminoclay enabled tumor-targeting adenoviruses to be more potent in killing bladder cancer cells and suppressing tumor growth in orthotopic bladder tumors, suggesting that aminoclay would be an efficient, versatile and biocompatible delivery carrier for intravesical instillation of adenoviruses.
Highlights
As the second most common cause of genitourinary cancerrelated death (Siegel et al, 2013), urothelial carcinoma is the ninth most common cancer in the world
70–80% of patients with urothelial carcinoma of the bladder are diagnosed with non-muscle invasive bladder cancer (NMIBC), and its standard treatment is transurethral resection (TUR) with or without intravesical therapy in order to decrease the risk of recurrence and progression to muscle invasive disease after TUR
We further characterized the nanobiohybrid complex composed of aminoclay and adenoviruses, and evaluated whether it could be utilized for the development of bladder cancer therapy
Summary
As the second most common cause of genitourinary cancerrelated death (Siegel et al, 2013), urothelial carcinoma is the ninth most common cancer in the world. 70–80% of patients with urothelial carcinoma of the bladder are diagnosed with non-muscle invasive bladder cancer (NMIBC), and its standard treatment is transurethral resection (TUR) with or without intravesical therapy in order to decrease the risk of recurrence and progression to muscle invasive disease after TUR. The adenovirus comes in direct contact with the bladder cancer and, as a result, demonstrates potent anti-tumor activities (successful adenovirus-mediated wild-type p53 gene transfer) in patients with bladder cancer by intravesical vector instillation (Kuball et al, 2002; Benedict et al, 2004). With respect to efficient delivery, bladder cancer cells and tumors, especially those at an advanced state and of high grade, frequently lose CAR expression, which limits the use of adenoviruses to treat bladder cancer (Douglas et al, 2001). We further characterized the nanobiohybrid complex composed of aminoclay and adenoviruses, and evaluated whether it could be utilized for the development of bladder cancer therapy
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