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Cancer Res. 2017 Jun 1;77(11):2964-2975. doi: 10.1158/0008-5472.CAN-16-1741. Epub 2017 Apr 17.

A Squalene-Based Nanomedicine for Oral Treatment of Colon Cancer.

Author information

1
Institut Galien Paris-Sud, UMR 8612, CNRS; Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
2
INSERM U938, Centre de Recherche Saint-Antoine, Paris, France.
3
Institut Universitaire de Cancérologie, Pierre et Marie Curie (UPMC) Sorbonne Universités, Paris, France.
4
INSERM U1149, CNRS ERL8252, Centre de Recherche sur l'Inflammation, Paris, France.
5
Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Bichat, Paris, France.
6
Département de Pharmacologie, Pierre et Marie Curie (UPMC) Sorbonne Universités, Faculté de Médecine, Site Pitié-Salpêtrière, Paris, France.
7
Laboratoire de Toxicologie, Faculté de Pharmacie, Nantes, France.
8
Assistance publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Nord Val de Seine Bichat-Claude Bernard, Service d'Anatomo-Pathologie, Paris, France.
9
Institut Galien Paris-Sud, UMR 8612, CNRS; Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France. patrick.couvreur@u-psud.fr.

Abstract

Nanotechnology offers many possibilities to improve drug treatments, including with regard to drug pharmacology. The current study reports a simple approach to improve cisplatin efficacy in the treatment of colon cancer through the creation of orally administered squalenoylated nanoparticles loaded with cisplatin (SQ-CDDP NP). Cytotoxic effects of SQ-CDDP NP were assessed in human colonic cells and in mouse models of intestinal cancer. In cell culture, SQ-CDDP NP exhibited at least 10-fold greater cytotoxic potency compared with uncomplexed cisplatin, reflecting an enhancement in intracellular accumulation and DNA platination. Mechanistic investigations showed that SQ-CDDP NP stimulated ROS production, expression of heavy metal-inducible and stress-inducible genes, stress kinase cascades, and apoptosis. In ApcMin/+ mice, a model of intestinal tumorigenesis, oral administration of SQ-CDDP NP curtailed spontaneous tumor formation and azoxymethane-induced colon carcinogenesis with no apparent evidence of tissue toxicity. Our results offer preclinical validation of a nanocarrier formulation that can safely improve chemotherapeutic efficacy, address risks of drug resistance, and improve patient compliance by enabling oral administration. Cancer Res; 77(11); 2964-75. ©2017 AACR.

PMID:
28416486
DOI:
10.1158/0008-5472.CAN-16-1741
[Indexed for MEDLINE]
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