Following cytotoxic nanoconjugates from injection to halting the cell cycle machinery and its therapeutic implications in oral cancer

Abstract

Background: The concept of personalized therapy has been proven to be a promising approach. A popular approach is to utilize gold nanoparticles (AuNPs) as drug delivery vectors for cytotoxic drugs and small molecule inhibitors to target and eradicate oral cancer cells in vitro and in vivo. While it is currently accepted that the cytotoxic drug’s mode of action remains the key regulator of the therapeutic outcome and toxicity beside nanocarrier design. None of the leading studies have compared multiple chemotherapeutics to their baseline free drugs nor used multiple nanocarriers to calculate drugs impact versus nanocarriers effect. We hypothesized that similarly constructed nanocarriers play a greater role than only acting as cargo-carriers. If proven, AuNPs may have a therapeutic role beyond bypassing cancer cell membrane and delivering their loaded drugs. We propose that similarly constructed AuNPs can flexibly leverage different conjugated drugs irrelevant to their mode of action enhancing the therapeutic outcome.Methods: We conjugated 5- fluorouracil (5Fu), camptothecin (CPT), and a fibroblast growth factor receptor1-inhibitor (FGFR1i) to gold nanospheres (AuNSs). We followed their trajectories in Syrian hamsters with chemically induced buccal carcinomas.Results: Flow cytometry and cell cycle data shows that 5Fu- and CPT- induced a similar ratio of S-phase cell cycle arrest as nanoconjugates and in their free forms. On the other hand, FGFR1i-AuNSs induced significant sub-G1 cell population compared with its free form. Despite cell cycle dynamics variability, there was no significant difference in tumor cells’ proliferation rate between CPT-, 5Fu- and FGFR1i- AuNSs treated groups. Clinically, FGFR1i-AuNSs induced the highest tumor reduction rates followed by 5Fu- AuNSs. CPT-AuNSs induced significantly lower tumor reduction rates compared with the 5Fu- and FGFR1i- AuNSs despite showing similar proliferative rates in tumor cells.Conclusions: Our data indicates that the cellular biological events do not predict the clinical outcome. Furthermore, our results suggest that AuNSs selectively enhances the therapeutic effect of small molecule inhibitors such as FGFR1i than potent anticancer drugs. Future studies are required to better understand the underlying mechanism.