Immunomodulatory and tumor-targeting palladium nanoparticles functionalized with resveratrol <i>via</i> green nanotechnology: synthesis, mechanisms, and <i>in vivo</i> therapeutic evaluation

This paper reports an innovative green nanotechnology approach utilizing electron-rich resveratrol, abundantly available in grape skin, to transform the palladium salt into biocompatible and tumor-specific resveratrol functionalized palladium nanoparticles (Res-PdNPs). This 'zero carbon emission' process affords four types of nanoparticles: Res-PdNPs 1-4, wherein the phytochemical serves dual roles of a reductant as well as a nanoparticle stabilizer through the creation of a phytochemical corona. Complete characterization has allowed selection of Res-PdNP-4 (zeta potential: -40 ± 3 mV; TEM core size: 24 ± 3 nm), with excellent <i>in vitro</i> stability, as the best candidate for further cancer therapeutic applications as elucidated through detailed <i>in vivo</i> investigations. Immunomodulatory features of Res-PdNPs suggest that they target and modulate the primary signaling pathway NF-κB, thus opening new precision medicine therapeutic opportunities for using functionalized PdNPs in treating cancer and various other inflammatory diseases. The innate relationship between NF-κB signaling and macrophage activation has been probed by investigating the ability of Res-PdNPs to target the pro-tumor M2 macrophage with concomitant re-education to the anti-tumor M1 phenotype using RAW 264.7 macrophages derived from murine cells. The immunomodulatory characteristics of this nanoceutical have been corroborated through excellent therapeutic efficacy data in prostate tumor bearing SCID mice administered with Res-PdNPs at various doses. It is highly significant that Res-PdNPs showed selective toxicity to tumor cells and minimal/no toxicity to normal cells. This is in sharp contrast to the FDA approved cancer therapy drugs cisplatin and etoposide, which showed indiscriminate severe toxicity to both normal and tumor cells. The vital role of green nanotechnology in oncology is described through compelling experimental results.