Apoptosis-enhanced ferroptosis therapy of pancreatic carcinoma through PAMAM dendrimer-iron(III) complex-based plasmid delivery

Abstract

The development of promising strategies to improve the treatment efficacy of pancreatic carcinoma still remains to be a challenging task. We report here the development of a new dendrimer-based nanomedicine formulation to tackle pancreatic carcinoma through apoptosis-enhanced ferroptosis therapy. In this article, G5 dendrimers were partially modified with a Fe(III) chelator hydroxyquinoline-2-carboxylic acid (8-HQC) on their periphery, entrapped with gold nanoparticles (Au NPs) within their internal cavities, and chelated with Fe(III). The thus created dendrimer-entrapped Au NPs (Fe-Au DENP-HQC) with an Au core size of 1.9 nm and 20.0 Fe(III) ions complexed per dendrimer are stable, have a pH-dependent Fe(III) release profile, and can generate reactive oxygen species under the tumor microenvironment (TME) and effectively compact plasmid DNA encoding p53 protein to form polyplexes with a hydrodynamic size of 143.9 nm and a surface potential of 33.6 mV. We show that cancer cells treated with the created Fe-Au DENP-HQC/p53 polyplexes can be more significantly inhibited through vector-mediated chemodynamic therapy (CDT) effect via Fe(III)-induced Fenton reaction and the p53 gene delivery-boosted cell apoptosis and oxidative stress in the TME than single-mode CDT and gene therapy. Further investigations using a xenografted tumor model validated the effectiveness of apoptosis-enhanced ferropotosis therapy through the downregulation of GPX-4 and SLC7A11 proteins, upregulation of p53 and PTEN proteins, as well as histological examinations. Meanwhile, the dendrimer nanoplatform enabled tumor fluorescence imaging through gene delivery-mediated enhanced green fluorescent protein expression. The Fe(III)-complexed dendrimer vector system may be developed as a promising theranostic nanoplatform for ferroptosis or ferroptosis-based combination therapy of other cancer types.