Image-Guided Nanodelivery of Pt(IV) Prodrugs to GRP-Receptor Positive Tumors.

Over the last decades, gold nanoparticles (AuNPs) have proven to be remarkable tools for drug delivery and theranostic applications in cancer treatment. On the other hand, Pt(IV) prodrugs have been employed as an interesting alternative to the more common Pt(II) complexes, such as cisplatin, for cancer chemotherapy. Searching to design an image-guided nanocarrier to deliver selectively Pt(IV) prodrugs to tumors expressing the gastrin releasing peptide receptor (GRPR), we have synthesized small core AuNPs carrying a thiolated DOTA derivative, a GRPR-targeting bombesin analog (BBN[7-14]) and a Pt(IV) prodrug attached to the AuNPs without () or with a PEGylated linker ( and ). In the GRPR+ prostate cancer PC3 cell line, the cytotoxic activity of the designed nanoparticles is strongly influenced by the presence of the PEGylated linker. Thus, displayed the lowest IC value (9.3 ± 2.3 µM of Pt), which is comparable to that exhibited by cisplatin in the same cell line. In contrast, showed an IC value of 97 ± 18 µM of Pt in the non-tumoral RWPE-1 prostate cells with a much higher selective index (SI) towards PC3 cells (SI = 10) when compared with cisplatin (SI = 1.3). The AuNPs were also successfully labeled with Ga and the resulting were used to assess their cellular uptake in PC3 cells, with also displaying the highest cellular internalization. Finally, intratumoral administration of in a PC3 tumor-bearing mice showed a prolonged retention of the nanoparticle compared to that of cisplatin, with optimal stability and 20% of the injected platinum remaining in the tumor after 72 h post-injection. Furthermore, microSPECT imaging studies confirmed the uptake and considerable retention of the Ga-labeled AuNPs in the tumors. Overall, these results show the potential of these targeted AuNPs loaded with Pt(IV) prodrugs for prostate cancer theranostics.