Resveratrol-loaded gold nanoparticles enhance caspase-mediated apoptosis in PANC-1 pancreatic cells via mitochondrial intrinsic apoptotic pathway

Abstract

Background Pancreatic ductal adenocarcinoma (PDAC) remains one of the most fatal malignancies. Several chemotherapies employing fluorouracil (5-FU) and gemcitabine were attempted, but the survival rate was extremely low. Resveratrol (RVT), known as a polyphenol compound and phytoalexin, was demonstrated to induce intrinsic apoptosis in cancer cells. However, its low delivery performance and efficiency at tumor sites remain an obstacle to exploit RVT as a drug. To address these problems, we bio-conjugated resveratrol with gold nanoparticles (GNPs) via polyvinylpyrrolidone as a cross-linker (RVT@PVP-GNPs) and investigated whether the fabrications could enhance the delivery performance and anti-tumor efficacy of RVT. Results The fabrication of gold nanoparticles (GNPs) and bio-conjugated with resveratrol (RVT@PVP-GNPs) was conducted firstly. TEM image, spectrophotometry and zeta-potential revealed that the GNPs and RVT@PVP-GNPs having a size of approximately 40 nm were successfully synthesized and exhibited moderate stability. GNPs alone represented no damage in PANC-1 cells and moreover diminished the cytotoxicity of RVT in Raw264.7 murine macrophage cells, demonstrating the superiority of gold nanoparticles as a drug carrier. Evaluation using dialysis showed a burst release rate of RVT within 96 h at pH 5.0, demonstrating the possibility of enhanced efficiency of RVT delivery through blood vessels to the tumor. The RVT@PVP-GNPs induced increased rates of S-phase cell cycle arrest and apoptosis compared with free RVT. Notably, RVT@PVP-GNPs diminished the proportion of necrotic cells, whereas free RVT increased it. We also demonstrated that the RVT@PVP-GNPs may induce an apoptosis via intrinsic mitochondria with higher degree compared with free RVT, indicating the possibility of enhanced anti-tumor agents. In animal studies, RVT@PVP-GNPs conjugated with AS1411 aptamer induced efficient tumor volume suppression without accumulation in or damage to the kidneys in vivo. Conclusions The results demonstrate that RVT@PVP-GNPs enhance the anti-tumor efficacy of free RVT by activating the intrinsic apoptotic pathway and could be considered as potential anti-tumor drug candidates against pancreatic cancer cells.

Recent Developments in Nanoparticle Formulations for Resveratrol Encapsulation as an Anticancer Agent

“…RSV-PVP-GNPs trigger more aggressive apoptosis via intrinsic mitochondria compared to free RSV. In preclinical trials, RSV-PVP-GNPs conjugated with AS1411 aptamer effectively suppressed tumor volume without renal toxicity [ 182 ].…”

Enhancing the Bioavailability of Resveratrol: Combine It, Derivatize It, or Encapsulate It?

“…The delivery performance and anticancer efficacy of RSV were enhanced when RSV was conjugated with gold nanoparticles (Au SNPs) using polyvinylpyrrolidone as a cross-linker. Compared with free RSV, these RSV-loaded NPs reduced the proportion of necrotic cells by activating the mitochondrial intrinsic apoptotic pathway in human pancreatic cancer cells [ 195 ]. Other studies on the encapsulation of RSV in AuNPs have shown that RSV induces cell cycle arrest in MCF-7 cancer cell lines [ 196 ] and has better anti-invasive effects on human breast cancer cells than RSV alone [ 197 ].…”

Recent progress in nanotechnology-based drug carriers for resveratrol delivery

“…GNPs exhibit good stability, high thermal, optical, and electrical activity, high surface area, and multifunctionality (Amina and Guo, 2020 ), RES was biocoupled with GNPs via the cross-linking agent polyvinylpyrrolidone (RES@PVP-GNPs) to enhance the delivery performance and anti-tumor efficacy of RES (Lee et al., 2022 ). However, GNPs are usually synthesized by physical or chemical methods that may be toxic to humans.…”