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

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 SLC7A11proteins,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.