Nanotechnology-Based Cisplatin Intracellular Delivery to Enhance Chemo-Sensitivity of Ovarian Cancer.
Animals
Antineoplastic Agents
/ chemistry
Apoptosis
/ drug effects
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cisplatin
/ chemistry
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
Ca125
SKOV3
apoptosis
cisplatin resistance
epithelial-mesenchymal transition
nanoparticle
ovarian cancer
Journal
International journal of nanomedicine
ISSN: 1178-2013
Titre abrégé: Int J Nanomedicine
Pays: New Zealand
ID NLM: 101263847
Informations de publication
Date de publication:
2020
2020
Historique:
received:
23
01
2020
accepted:
28
05
2020
entrez:
9
8
2020
pubmed:
9
8
2020
medline:
20
9
2020
Statut:
epublish
Résumé
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. 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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
OBJECTIVE
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
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
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
CONCLUSIONS
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.
Identifiants
pubmed: 32764921
doi: 10.2147/IJN.S247114
pii: 247114
pmc: PMC7368240
doi:
Substances chimiques
Antineoplastic Agents
0
Drug Carriers
0
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4793-4810Informations de copyright
© 2020 Bortot et al.
Déclaration de conflit d'intérêts
The authors report no conflicts of interest in this work.
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