International Journal of Nanomedicine (Jan 2024)
Preclinical Activity of Two Paclitaxel Nanoparticle Formulations After Intraperitoneal Administration in Ovarian Cancer Murine Xenografts
Abstract
Jesse Demuytere,1,* Charlotte Carlier,1,* Leen Van de Sande,1 Anne Hoorens,2 Kaat De Clercq,3 Silvia Giordano,4 Lavinia Morosi,4 Cristina Matteo,4 Massimo Zucchetti,4 Enrico Davoli,4 Jo Van Dorpe,2 Chris Vervaet,3 Wim Ceelen1 1Department of GI Surgery, Ghent University Hospital, and Cancer Research Institute Ghent (CRIG), Ghent, Belgium; 2Department of Pathology, Ghent University Hospital, Ghent, Belgium; 3Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium; 4Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri - IRCCS, Milano, Italy*These authors contributed equally to this workCorrespondence: Wim Ceelen, Department of GI Surgery, Ghent University Hospital, Route 1275, Corneel Heymanslaan 10, Ghent, B-9000, Belgium, Tel +32 9 332 6251, Email [email protected]: 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
