Multifaceted peptide assisted one-pot synthesis of gold nanoparticles for plectin-1 targeted gemcitabine delivery in pancreatic cancer

Abstract

An astute modification of the plectin-1-targeting peptide KTLLPTP by introducing a C-terminal cysteine preceded by a tyrosine residue imparted a reducing property to the peptide. This novel property is then exploited to fabricate gold nanoparticles (GNP) via an in situ reduction of gold (III) chloride in a one-pot, green synthesis. The modified peptide KTLLPTPYC also acts as a template to generate highly monodispersed, spherical GNPs with a narrow size distribution and improved stability. Plectin-1 is known to be aberrantly expressed in the surface of pancreatic ductal adenocarcinoma (PDAC) cells while showing cytoplasmic expression in normal cells. The synthesized GNPs are thus in situ surface modified with the peptides via the cysteine residue leaving the N-terminal KTLLPTP sequence free for targeting plectin 1. The visual molecular dynamics based simulations support the experimental observations like particle size, gemcitabine conjugation and architecture of the peptide-grafted nanoassembly. Additionally, GNPs conjugated to gemcitabine demonstrate significantly higher cytotoxicity in vitro in two established PDAC cell lines (AsPC-1 and PANC-1) and an admirable in vivo antitumor efficacy in a PANC-1 orthotopic xenograft model through selective uptake in PDAC tumor tissues. Altogether, this strategy represents a unique method for the fabrication of a GNP based targeted drug delivery platform using a multifaceted peptide that acts as reducing agent, template for GNP synthesis and targeting agent to display remarkable selectivity towards PDAC.

Active targeting of gold nanoparticles as cancer therapeutics

“…These AuNPs were further functionalised with the chemotherapeutic drug gemcitabine (Gem), which adsorbs to the AuNP core through hydrophobic interactions, as well as forming a reversible Au-N bond. 97 These AuNPs show higher cytotoxicity towards PDAC cell lines than Gem alone and display excellent selectivity for PDAC cells over healthy tissue in mouse models. 97 This use of the YC dipeptide to simultaneously nucleate and cap AuNPs has also been used to form AuNPs for use as radiosensitisers.…”

“…97 These AuNPs show higher cytotoxicity towards PDAC cell lines than Gem alone and display excellent selectivity for PDAC cells over healthy tissue in mouse models. 97 This use of the YC dipeptide to simultaneously nucleate and cap AuNPs has also been used to form AuNPs for use as radiosensitisers. These AuNPs are targeted towards a v b 3 integrin expressing cells through the cyclic peptide c(RGD) (Fig.…”

Advances in Gold Nanoparticle-Based Combined Cancer Therapy

“…This is explained by showing that GNPs inhibited epithelial to mesenchymal transition and reduced cancer cell stemness-possible causes of anticancer drug resistance [168]. Furthermore, Pal et al showed in Figure 9 that gemcitabine-conjugated GNPs that specifically target pancreatic cancer cells with a plectin-1 peptide have improved efficacy in situ compared to the free drug alone [169]. The use of gemcitabine with radiotherapy has also been shown to be more effective than the drug alone through clinical trials [170].…”

“…(B) KI67, a marker for proliferation, also showed reduced proliferative cells when treated with the GNP complex compared to the free drug alone, signifying improved efficacy. Reproduced with permission from[169]. Copyright 2017 Royal Society of Chemistry.…”

DNA–SWCNT Biosensors Allow Real-Time Monitoring of Therapeutic Responses in Pancreatic Ductal Adenocarcinoma

“…PANC1 (item number CRL-1469 and batch number 62278038; ATCC) was cultured following a standard method, as described previously (36). Briefly, PANC1 was grown in DMEM supplemented with 10% FBS and 1% penicillin--streptomycin.…”