Nanotechnology-Based Cisplatin Intracellular Delivery to Enhance Chemo-Sensitivity of Ovarian Cancer

Int J Nanomedicine. 2020 Jul 7:15:4793-4810. doi: 10.2147/IJN.S247114. eCollection 2020.

Abstract

Background: Platinum resistance is a major challenge in the management of ovarian cancer. Even low levels of acquired resistance at the cellular level lead to impaired response to cisplatin. In ovarian cancer intraperitoneal therapy, nanoparticle formulation can improve the cisplatin's pharmacokinetics and safety profile.

Purpose: This work aimed to investigate the chemo-sensitivity of ovarian cancer SKOV3 cells upon short-term (72h) single treatment of cisplatin and cisplatin-loaded biodegradable nanoparticles (Cis-NP). The aim was then to determine the therapeutic properties of Cis-NP in vivo using a SKOV3-luc cells' xenograft model in mice.

Methods: Cell cytotoxicity was assessed after the exposure of the cell culture to cisplatin or Cis-NP. The effect of treatments on EMT and CSC-like phenotype was studied by analyzing a panel of markers by flow cytometry. Intracellular platinum concentration was determined by inductively coupled plasma mass spectrometry (ICS-MS), and gene expression was evaluated by RNAseq analysis. The efficacy of intraperitoneal chemotherapy was evaluated in a SKOV3-luc cells' xenograft model in mice, through a combination of bioluminescence imaging, histological, and immunohistochemical analyses.

Results: We observed in vitro that short-term treatment of cisplatin has a critical role in determining the potential induction of chemoresistance, and a nanotechnology-based drug delivery system can modulate it. The RNAseq analysis underlines a protective effect of nanoparticle system according to their ability to down-regulate several genes involved in chemoresistance, cell proliferation, and apoptosis. The highest intracellular platinum concentration obtained with Cis-NP treatment significantly improved the efficacy. Consistent with in vitro results, we found that Cis-NP treatment in vivo can significantly reduce tumor burden and aggressiveness compared to the free drug.

Conclusion: Nanoparticle-mediated cisplatin delivery may serve as an intracellular depot impacting the cisplatin pharmacodynamic performance at cellular levels. These features may contribute to improving the drawbacks of conventional intraperitoneal therapy, and therefore will require further investigations in vivo.

Keywords: Ca125; SKOV3; apoptosis; cisplatin resistance; epithelial-mesenchymal transition; nanoparticle; ovarian cancer.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cisplatin / chemistry
  • Cisplatin / metabolism
  • Cisplatin / pharmacology*
  • Cisplatin / therapeutic use
  • Down-Regulation / drug effects
  • Drug Carriers / chemistry*
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Humans
  • Intracellular Space / metabolism*
  • Mice
  • Nanomedicine / methods*
  • Nanoparticles / chemistry*
  • Ovarian Neoplasms / drug therapy*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Drug Carriers
  • Cisplatin

Grants and funding

This research was funded by a Ministry of Health “Ricerca Corrente” Grant to IRCSS Burlo Garofolo, n°19/2016, by “Bando POR FESR 20142020. Attività 1.3.b”, project title: “TICheP: Tecnologie Innovative per la Chemioterapia Personalizzata”, by Ministry of Health “5 per mille anno 2016” Grant to IRCSS Burlo Garofolo, project title: “A preclinical platform from human ovarian cancer cells to investigate potential cisplatin resistance markers”, by Associazione Italiana per la Ricerca sul Cancro (AIRC, grant # IG-23643) and by Italian Ministry of Health (grant # RF-2018-12365425).