Palladium nanoparticles encapsulated with resveratrol-derived phenols and polyphenols for targeted prostate cancer therapy

Abstract

The main goal of this dissertation was to explore the development of a new generation of green nanoformulations through the production of biocompatible palladium nanoparticles using resveratrol to treat, image and evaluate the efficacy of the formulations in prostate cancer cells with minimal toxicity to surrounding normal tissues. This dissertation is classified into three parts with three main objectives of the producing and characterizing resveratrol-derived phenols and polyphenols encapsulated palladium nanoparticles (Res-PdNPs) for the imaging and treatment of prostate cancer. Rigorous studies were performed for the optimization of the synthesis to achieve increased resveratrol-derived phenols and polyphenols corona loading on the palladium nanoparticle surface capable of providing adjuvant therapeutic benefits through delivering potent doses of both resveratrol phenols and nanoparticles directly to prostate cancer cells. A total of four formulations were produced Res-PdNP-1 (resveratrol-palladium nanoparticles), Res-PdNP-2 (increased resveratrol corona loaded palladium nanoparticles), Res-PdNP-3 (resveratrol-gum arabic stabilized palladium nanoparticles) and Res-PdNP-4 (increased resveratrol corona loaded and compacted with gum arabic stabilized palladium nanoparticles), respectively. Electron microscopic (TEM) results revealed that role of gum arabic was not limited to the stability of the nanoparticles but also facilitated the crystallization of the produced palladium nanoparticles (Res-PdNP-3 and Res-PdNP-4) and subsequently provided a supportive matrix for increased resveratrol phenols loading capacity. In vitro evaluation of the Res-PdNPs showed that Res-PdNP-1 and Res-PdNP-2, were not stable in serum while Res-PdNP-3 and Res-PdNP-4 maintained superior stability, thus ruling out further analysis using Res-PdNP-1 and Res-PdNP-2. The LC-MS/MRM results confirmed increased resveratrol phenols loading in Res-PdNP-4 when compared to Res-PdNP-3; consequently Res-PdNP-4 nanoparticles were confirmed as the ideal nanoformulation to improve the bioavailability, biodistribution and emblematize as an adjuvant therapy to induce selective and specific tumor-cell-death. The prostate tumor selective and specific affinity of Res-PdNP-4 nanoparticles through numerous cellular internalization studies undoubtedly revealed that Res-PdNP-4 nanoparticles can be internalized into prostate cancer cells via laminin receptor-mediated endocytosis which are receptors overexpressed on prostate cancer cells compared to normal cells. The Res-PdNP-4 nanoparticles were evaluated to investigate in vitro cellular toxicity against both prostate cancer (PC-3) cells and normal human aortic endothelial cells (HAEC). Results indicated that Res-PdNP-4 exhibited comparable anticancer efficacy against prostate cancer cells as chemotherapeutic drugs (cisplatin and etoposide). However, the results showed that cisplatin and etoposide treatments were highly toxic to normal cells while Res-PdNP-4 nanoparticles presented no toxicity further corroborating laminin receptor-mediated delivery, making Res-PdNP-4 nanoparticles selective and specific to prostate cancer cells. Res-PdNP-4 nanoparticles were investigated in vivo using a human prostate tumor-bearing severely combined immunodeficient (SCID) male mice as the animal model to evaluate Res-PdNP-4 nanoparticles ability to control or reduce prostate tumor size. The in vivo results of Res-PdNP-4 showed a good dose response which was well tolerated by the animals, as no animal health problems and discomfort was observed as evidenced by body weight/eating habits of animals. Although further studies are required to determine a better dose to see increased efficacy. This study was performed through intravenous (IV) administration of the Res-PdNP-4, intraperitoneal (IP) delivery and direct injection into the tumor may show a better response as has been the case with many different types of nanoparticles. In conclusion, the therapeutic efficacy results showed that Res-PdNP-4 have significant therapeutic effect and are able to control the tumor size in comparison to the saline control and free resveratrol treated groups. This was due to the high corona of resveratrol-derived phenols and polyphenols on the PdNPs facilitating effectively enhanced delivery of resveratrol with high bioavailability, giving an advantage in tumor therapy.

Upgrading gold to green nanoparticles: applications in prostate cancer

“…For example, EGCG, which is used in the green synthesis of NPs, has specificity for the laminin receptor (Lam 67R), over expressed on PC cells [136,137]. Similarly, PC Lam 67R specificity is granted to palladium NPs after their encapsulation with resveratrol (Res-PdNP-4 NPs) [138]. Another ligand named bombesin, a peptide isolated from the skin of the European fire-bellied toad, possesses targeting specificity for the gastrin-releasing peptide (GRP) receptor overexpressed in breast, prostate, non-small cell lung cancers, and a host of mammalian tumours [139].…”

“…In addition, only a few g-AuNPs rely on green coats for acquired specificity towards various cancers, with no single form specific to PC (figure 2(A)). This also applies for g-AuNPs specificity to GRC (acquired from bombesin) [139] and Lam67R (acquired from Resveratrol [138] or EGCG [136,137]). Interestingly, g-AuNPs still possess an intrinsic high affinity for biomolecules like antibodies [141].…”