Gold nanoparticles (GNPs) are being extensively used in cancer therapeutic applications due to their ability to act both as an anticancer drug carrier in chemotherapy and as a dose enhancer in radiotherapy. The therapeutic response can be further enhanced if nanoparticles (NPs) can be effectively targeted into the nucleus. Here, we present an uptake and removal of GNPs functionalized with three peptides. The first peptide (RGD peptide) enhanced the uptake, the second peptide (NLS peptide) facilitated the nuclear delivery, while the third one (pentapeptide) covered the rest of the surface and protected it from the binding of serum proteins onto the NP surface. The pentapeptide also stabilized the conjugated GNP complex. The peptide-capped GNPs showed a five-fold increase in NP uptake followed by effective nuclear localization. The fraction of NPs exocytosed was less for peptide-capped NPs as compared to citrate-capped ones. Enhanced uptake and prolonged intracellular retention of peptide-capped GNPs could allow NPs to perform their desired applications more efficiently in cells. These studies will provide guidelines for developing NPs for therapeutic applications, which will require "controlling" of the NP accumulation rate while maintaining low toxicity.

To enhance PEG uptake for radiation therapy, a peptide containing an integrin binding domain (RGD) was conjugated to PEG. Nanoparticles functionalized with both the RGD peptide and PEG had a higher uptake than NPs functionalized with PEG alone.

Optimizing the interface between nanoparticles (NPs) and the biological environment at various levels should be considered for improving delivery of NPs to the target tumor area. For NPs to be successfully delivered to cancer cells, NPs needs to be functionalized for circulation through the blood vessels. In this study, accumulation of Polyethylene Glycol (PEG) functionalized gold nanoparticles (GNPs) was first tested using in vitro monolayer cells and multilayer cell models prior to in vivo models. A diameter of 10 nm sized GNP was selected for this study for sufficient penetration through tumor tissue. The surfaces of the GNPs were modified with PEG molecules, to improve circulation time by reducing non-specific uptake by the reticuloendothelial system (RES) in animal models, and with a peptide containing integrin binding domain, RGD (arginyl-glycyl-aspartic acid), to improve internalization at the cellular level. A 10–12% accumulation of the injected GNP dose within the tumor was observed in vivo and the GNPs remained within the tumor tissue up to 72 h. This study suggests an in vitro platform for optimizing the accumulation of NP complexes in cells and tissue structures before testing them in animal models. Higher accumulation within the tumor in vivo upon surface modification is a promising outcome for future applications where GNPs can be used for drug delivery and radiation therapy.

Combined use of chemotherapy and radiation therapy is commonly used in cancer treatment, but the toxic effects on normal tissue are a major limitation. This study assesses the potential to improve radiation therapy when combining gold nanoparticle (GNP) mediated radiation sensitization with chemoradiation compared to chemoradiation alone. Incorporation of GNPs with 2 Gy, 6 MV (megavoltage) radiation resulted in a 19 ± 6% decrease in survival of MDA-MB-231 cells. Monte-Carlo simulations were performed to assess dosimetric differences in the presence of GNPs in radiation. The results show that physics dosimetry represents a small fraction of the observed effect. The survival fraction of the cells exposed to GNPs, cisplatin, and radiation was 0.16 ± 0.007, while cells treated with cisplatin and radiation only was 0.23 ± 0.011. The presence of GNPs resulted in a 30 ± 6% decrease in the survival, having an additive effect. The concentration of the GNPs and free drug used for this study was 0.3 and 435 nM, respectively. These concentrations are relatively lower and achievable in an in vivo setting. Hence, the results of our study would accelerate the incorporation of GNP-mediated chemoradiation into current cancer therapeutic protocols in the near future.