Biodegradable Ultrasmall-in-Nano Architectures Loaded with Cisplatin Prodrug in Combination with Ionizing Radiation Induces DNA Damage and Apoptosis in Pancreatic Ductal Adenocarcinoma.

Abstract

Simple SummaryThe occurrence of severe normal tissue side effects and acquired drug resistance of the malignancy are the most important limitations that are associated with currently given systemic treatment in pancreatic cancer. The aim of this study was to assess the therapeutic efficacy of encapsulated cisplatin prodrug and gold nanoparticles combined with radiation to improve the toxicity profile of cisplatin and develop new multimodality treatments. Here, we demonstrated the therapeutic effect of NAs-cisPt as a platform to encourage nanomedicine in the context for future applications in multimodality treatments.Considering the dismal survival rate, novel therapeutic strategies are warranted to improve the outcome of pancreatic ductal adenocarcinoma (PDAC). Combining nanotechnology for delivery of chemotherapeutics—preferably radiosensitizing agents—is a promising approach to enhance the therapeutic efficacy of chemoradiation. We assessed the effect of biodegradable ultrasmall-in-nano architectures (NAs) containing gold ultra-small nanoparticles (USNPs) enclosed in silica shells loaded with cisplatin prodrug (NAs-cisPt) combined with ionizing radiation (IR). The cytotoxic effects and DNA damage induction were evaluated in PDAC cell lines (MIA PaCa2, SUIT2-028) and primary culture (PDAC3) in vitro and in the chorioallantoic membrane (CAM) in ovo model. Unlike NAs, NAs-cisPt affected the cell viability in MIA PaCa2 and SUIT2-028 cells. Furthermore, NAs-cisPt showed increased γH2AX expression up to 24 h post-IR and reduced β-globin amplifications resulting in apoptosis induction at DNA and protein levels. Similarly, combined treatment of NAs-cisPt + IR in PDAC3 and SUIT2-028 CAM models showed enhanced DNA damage and apoptosis leading to tumor growth delay. Our results demonstrate an increased cytotoxic effect of NAs-cisPt, particularly through its release of the cisplatin prodrug. As cisplatin is a well-known radiosensitizer, administration of cisplatin prodrug in a controlled fashion through encapsulation is a promising new treatment approach which merits further investigation in combination with other radiosensitizing agents.