Nanoparticle-Mediated Gene Silencing for Sensitization of Lung Cancer to Cisplatin Therapy

Abstract

Platinum-based chemotherapy remains a mainstay treatment for the management of advanced non-small cell lung cancer. A key cellular factor that contributes to sensitivity to platinums is the 5′-3′ structure-specific endonuclease excision repair cross-complementation group 1 (ERCC1)/ xeroderma pigmentosum group F (XPF). ERCC1/XPF is critical for the repair of platinum-induced DNA damage and has been the subject of intense research efforts to identify small molecule inhibitors of its nuclease activity for the purpose of enhancing patient response to platinum-based chemotherapy. As an alternative to small molecule inhibitors, small interfering RNA (siRNA) has often been described to be more efficient in interrupting protein–protein interactions. The goal of this study was therefore to determine whether biocompatible nanoparticles consisting of an amphiphilic triblock copolymer (polyethylenimine-polycaprolactone-polyethylene glycol (PEI-PCL-PEG)) and carrying siRNA targeted to ERCC1 and XPF made by microfluidic assembly are capable of efficient gene silencing and able to sensitize lung cancer cells to cisplatin. First, we show that our PEI-PCL-PEG micelleplexes carrying ERCC1 and XPF siRNA efficiently knocked down ERCC1/XPF protein expression to the same extent as the standard siRNA transfection reagent, Lipofectamine. Second, we show that our siRNA-carrying nanoparticles enhanced platinum sensitivity in a p53 wildtype model of non-small cell lung cancer in vitro. Our results suggest that nanoparticle-mediated targeting of ERCC1/XPF is feasible and could represent a novel therapeutic strategy for targeting ERCC1/XPF in vivo.

Association of the Epithelial–Mesenchymal Transition (EMT) with Cisplatin Resistance

“…CP is a key member of platinum compounds with excellent anti-tumor activity against different cancers such as breast cancer, prostate cancer, bladder cancer, lung cancer, brain tumors, and so on [21][22][23]. The rational reasons for selection of CP are as follows: (1) its anti-tumor activity has been extensively examined, particularly in clinical trials [24][25][26], and (2) the molecular mechanisms and pathways involved in CP resistance/sensitivity have been explored [27][28][29]. Consequently, it has been possible to implicate the process of EMT in drug resistance and directing further studies towards targeting EMT in suppressing resistance developed against CP treatment.…”

Meta-analysis of P53 expression and sensitivity to platinum-based chemotherapy in patients with non-small cell lung cancer

“…In vitro experiments, sensitivity of lung cancer cells to platinum-based chemotherapy is closely related to expression of P53. Feldmann et al [ 37 ] proved that nanoparticles-carrying siRNA enhances sensitivity of platinum in the model of p53 wild-type NSCLC. P53 would also make chemically resistant non-small cell lung cancer sensitive by increasing the reactive oxygen species and inhibiting EGFR/PI3K/AKT signal.…”

A new microfluidic platform for the highly reproducible preparation of non-viral gene delivery complexes

“…18,19,40 Given the great potential of microfluidics for the preparation of non-viral gene delivery (nano)carriers, the number of publications related to this topic has been steadily increasing. [42][43][44][45][51][52][53][54] Nevertheless, to the best of our knowledge, no one has tackled the daunting quest for the simultaneous generation of gene delivery complexes over a range of N/Ps. As this is the very first practical problem that scientists have to face to gauge the performance of transfection reagents [6], we decided to address this issue.…”