Abstract
BackgroundThe concept of personalized therapy has been proven to be a promising approach. A popular technique 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. Both drug and nanocarrier designs play important roles in the treatment efficacy. In our study, we standardized the nanosystem regarding NPs type, size, surface ligands and coverage percentage leaving only the drugs mode of action as the confounding variable. We propose that similarly constructed nanoparticles (NPs) can selectively leverage different conjugated drugs irrelevant to their original mode of action. If proven, AuNPs may have a secondary role beyond bypassing cancer cell membrane and delivering their loaded drugs.MethodsWe 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.ResultsFlow 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. In our in vivo model, 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.ConclusionsOur data indicates that the cellular biological events do not predict the outcome seen in our in vivo model. Furthermore, our results suggest that AuNSs selectively enhance the therapeutic effect of small molecule inhibitors such as FGFR1i than potent anticancer drugs. Future studies are required to better understand the underlying mechanism.
Highlights
The concept of personalized therapy has been proven to be a promising approach
5Fu and CPT free forms resulted in same fluorescent signal values, upon calculating the mean percentage of CPT-Gold nanospheres (AuNSs) and 5Fu-AuNSs nuclear localization, we discovered a significant increased fluorescent signalling for CPT-AuNSs as shown in (Fig. 2j) compared to 5Fu-AuNSs
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
Summary
The concept of personalized therapy has been proven to be a promising approach. A popular technique 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. Nanoparticles actively target oral cancer cell receptors such as surface integrins αvβ by peptides such as Arginyl-glycylaspartic acid (RGD) [7] Both drug and nanocarrier designs play important roles in the treatment efficacy. We synthesized average size (~ 30 nm) gold nanospheres (AuNSs) and sequentially coated their surface with ligands such PEG, RGD peptide, cytotoxic drugs 5Fu and CPT, or fibroblastic growth factor receptor 1 inhibitor (FGFR1i). This was performed using the same surface coverage ratio and chemical linker. We used the free forms of 5Fu, CPT and FGFR1i molecules as controls since their impact on cellular functions is well reported [11,12,13,14]
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