مقالات پذیرفته شده در هشتمین کنگره بین المللی زیست پزشکی
Thesis title: Triple Combination Therapy with Immunologic Approaches: Modulating Tumor Microenvironment (TME) and Tumor Growth Inhibition
Thesis title: Triple Combination Therapy with Immunologic Approaches: Modulating Tumor Microenvironment (TME) and Tumor Growth Inhibition
Leila Rostamizadeh,1,*Kobra Rostamizadeh,2Seied Rafi Bahavarnia,3Fatemeh Ramezani,4
1. Department of Molecular Medicine, Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran 2. d Department of Psychiatry and Behavioral Sciences, Department of Pharmacology, School of Medicine, University of Washington, Seattle, WA, USA 3. Screening laboratory, Blood Transfusion Organization, Tabriz, Iran 4. Department of Molecular Medicine, Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran
Introduction: The immunosuppressive tumor microenvironment (iTME) significantly influences the effectiveness of various anticancer therapies, including immunotherapy and chemotherapy. This study aimed to target HIF-1α as a reshaping of the iTME combined with Toll-Like Receptor 7 agonist and chemotherapy in a mouse model of colorectal cancer (CRC).
Methods: A HIF-1α-specific siRNA duplex was formulated based on the ionic gelation of tripolyphosphate (TPP) with cationic chitosan (CH) as a nanoplex and evaluated in terms of size, charge, polydispersity index and gel retardation assay. MTT assay was conducted to assess the cytotoxicity of the specific siRNA duplex against CT26 cells. The hypoxic condition was generated to evaluate the gene and protein expression levels of HIF-1α, respectively. CT26 mouse model was established to assess the synergistic effect of silencing HIF-1α combined with oxaliplatin (OXA) and imiquimod (IMQ) on tumor growth.
Results: The findings showed that the combination of HIF-1α siRNA with OXA and IMQ caused a significant delay in tumor growth, which was associated with high levels of cytokines related to cellular immunity. The CH/siRNA nanoparticles had a mean diameter of 243 ± 6 nm with a size distribution of 0.3 ± 0.04. There were no significant differences observed between the CT26 cells treated with nanoparticles alone and the untreated cells, indicating that these nanoparticles are safe and physiologically biocompatible (p ≥ 0.05). Triple combination therapy involving HIF-1α siRNA, OXA, and IMQ significantly retarded tumor growth and led to elevated levels of cytokines linked to cellular immunity (INF-γ and IL-12) compared with those in the other groups (P<0.05). The positive correlation coefficient (r=0.68) between tumor size and HIF-1α expression levels was statistically significant (P= 0.003). Compared with those in the control group, the expression levels of the anti-inflammatory cytokines IL-10 and IL-4 significantly decreased (P<0.05).
Conclusion: In conclusion, our findings suggest that inhibiting HIF-1α could serve as a rational strategy to enhance the antitumor response in the TME.