Potentiation of the therapeutic effect of intravesical BCG through synthetic and biogenic selenium nanoparticles in a nitrosamine-induced bladder cancer mouse model

Abstract

Introduction

Intravesical Mycobacterium Bovis bacillus Calmette-Guérin (BCG) therapy for non-muscle invasive bladder cancer has been successfully applied to prevent metastasis and disease progression. However, some studies have reported a percentage of treatment failure and recurrence along with possible side effects. Therefore, this study has evaluated the effect of administration of synthetic (SSeNPs) and biogenic selenium nanoparticles (BSeNPs) as an adjuvant drug in combination with intravesical BCG for the treatment of mice-bearing bladder tumors.

Methods

Orthotopic bladder cancer model mice were established by 12 weeks of N-butyl-N-(4-hydroxybutyl) nitrosamine oral gavage. Mice-bearing bladder cancer was treated by sequential intravesical treatments with SSeNPs, BCG, BCG/SSeNPs, and BCG/SSeNPs. After immunotherapy, the status of the immune system was evaluated by quantitatively measuring mRNA expression of cytokines by Real-time qRT-PCR in the spleen samples and measuring cytokines protein level by enzyme-linked immunosorbent assay in the serum samples. As well, in the tumor microenvironment, the mRNA expression level of autophagic molecules (Beclin-1, ATG2B, and ATG5), apoptotic molecule (Caspase-3), iNOS, HMGB1, and PD-L1 were evaluated in all groups.

Results

Immunotherapy with BCG/SSeNPs and BCG/BSeNPs elicited a considerable immune response by increasing the expression of IFN-γ, IL-12, and IL-6 and inhibiting the expression of IL-10 and TGF-β cytokines. As well, BCG/SSeNPs and BCG/BSeNPs could increase Caspase-3 expression and decrease autophagic genes as well as PD-L1.

Conclusion

Our results showed that synthetic and biogenic SeNPs as an effective adjuvant could enhance intravesical BCG's efficacy and therapeutic effect for bladder cancer treatment with almost the same function.