Preclinical Activity of Two Paclitaxel Nanoparticle Formulations After Intraperitoneal Administration in Ovarian Cancer Murine Xenografts

Abstract

Background

Epithelial ovarian cancer is associated with high mortality due to diagnosis at later stages associated with peritoneal involvement. Several trials have evaluated the effect of intraperitoneal treatment. In this preclinical study, we report the efficacy, pharmacokinetics and pharmacodynamics of intraperitoneal treatment with two approved nanomolecular formulations of paclitaxel (nab-PTX and mic-PTX) in a murine ovarian cancer xenograft model.

Methods

IC50 was determined in vitro on three ovarian cancer cell lines (OVCAR-3, SK-OV-3 and SK-OV-3-Luc IP1). EOC xenografts were achieved using a modified subperitoneal implantation technique. Drug treatment was initiated 2 weeks after engraftment, and tumor volume and survival were assessed. Pharmacokinetics and drug distribution effects were assessed using UHPLC-MS/MS and MALDI imaging mass spectrometry, respectively. Pharmacodynamic effects were analyzed using immunohistochemistry and transmission electron microscopy using standard protocols.

Results

We demonstrated sub-micromolar IC₅₀ concentrations for both formulations on three EOC cancer cell lines in vitro. Furthermore, IP administration of nab-PTX or mic-PTX lead to more than 2-fold longer survival compared to a control treatment of IP saline administration (30 days in controls, 66 days in nab-PTX treated animals, and 76 days in mic-PTX animals, respectively). We observed higher tissue uptake of drug following nab-PTX administration when compared to mic-PTX, with highest uptake after 4 hours post-treatment, and confirmed this lower uptake of mic-PTX using HPLC on digested tumor samples. Furthermore, apoptosis was not increased in tumor implants up to 24h post-treatment.

Conclusion

Intraperitoneal administration of both nab-PTX and mic-PTX results in a significant anticancer efficacy and survival benefit in a mouse OC xenograft model.

Keywords:

• ovarian
• peritoneal
• paclitaxel
• nanomedicine

Acknowledgments

Wim Ceelen is a senior clinical researcher from the Fund for Scientific Research – Flanders (FWO). This work was funded in part by a grant from the Flemish League against Cancer (Kom op Tegen Kanker). This paper is based on the thesis of Dr Charlotte Carlier. It has been published on the institutional website of Ghent University: https://biblio.ugent.be/publication/8575482.

Disclosure

The authors report no conflicts of interest in this work.