Nanoscopic tumor tissue distribution of platinum after intraperitoneal administration in a xenograft model of ovarian cancer.
There is increasing interest in the treatment of advanced stage ovarian cancer (OC) using intraperitoneal (IP) delivery of platinum (Pt)-based chemotherapy. The antitumor efficacy of IP chemotherapy is determined by efficient tumor tissue penetration. Although it is assumed that Pt penetration is limited to a few millimeters after IP delivery, little is known on the distribution of Pt in different tumor compartments at the ultrastructural level following IP administration. Here, using synchrotron radiation X-ray fluorescence spectrometry (SR-XRF) and laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS), Pt distribution and penetration in OC peritoneal xenografts were determined at nanometer scale after IP chemoperfusion of cisplatin at 37-38°C or 40-41°C (hyperthermic). Using principal component analysis (PCA) the presence of phosphorus, manganese, calcium, zinc, iron, bromine, and sulfur was correlated with the distribution of Pt, while k-means analysis was used to quantify the amount of Pt in weight% in tumor stroma and in tumor cells. The results showed a heterogeneous distribution of Pt throughout the tumor, with an accumulation in the extracellular matrix. LA-ICP-MS mappings indicated significantly higher concentrations of Pt (P=0.0062) after hyperthermic chemoperfusion of cisplatin, while SR-XRF demonstrated a deeper tissue Pt penetration after hyperthermic treatment. Using PCA, it was showed that Pt co-localizes with bromine and sulfur. No differences were observed in Pt distribution regarding tumor cells and stroma, when comparing normo- vs. hyperthermic treatment. In conclusion, SR-XRF and LA-ICP-MS are suitable and highly sensitive techniques to analyze the penetration depth and distribution of Pt-based drugs after IP administration. To the best of our knowledge, this is the first experiment in which the distribution of Pt is analyzed at the cellular level after IP administration of cisplatin.
Department of Surgery, Laboratory of Experimental Surgery, Ghent University Hospital, B-9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University Hospital, B-9000 Ghent, Belgium. Electronic address: charlotte.carlier@ugent.be.
Charlotte
C
Carlier
Department of Analytical Chemistry, Ghent University, Krijgslaan 281-S12, B-9000 Ghent, Belgium. Electronic address: brecht.laforce@ugent.be.
Brecht
B
Laforce
Department of Analytical Chemistry, Ghent University, Krijgslaan 281-S12, B-9000 Ghent, Belgium. Electronic address: stijn.vanmalderen@ugent.be.
Stijn J M
SJM
Van Malderen
Department of Surgery, Laboratory of Experimental Surgery, Ghent University Hospital, B-9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University Hospital, B-9000 Ghent, Belgium. Electronic address: Felix.Gremonprez@ugent.be.
Félix
F
Gremonprez
European Synchrotron Radiation Facility (ESRF), FR-38043 Grenoble Cedex, France. Electronic address: remi.tucoulou@esrf.fr.
Remi
R
Tucoulou
European Synchrotron Radiation Facility (ESRF), FR-38043 Grenoble Cedex, France. Electronic address: julie.villanova@esrf.fr.
Julie
J
Villanova
Department of Radiation Oncology and Experimental Cancer Research, Laboratory of Experimental Cancer Research, Ghent University, B-9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University Hospital, B-9000 Ghent, Belgium. Electronic address: olivier.dewever@ugent.be.
Olivier
O
De Wever
Department of Analytical Chemistry, Ghent University, Krijgslaan 281-S12, B-9000 Ghent, Belgium.
Laszlo
L
Vincze
Department of Analytical Chemistry, Ghent University, Krijgslaan 281-S12, B-9000 Ghent, Belgium. Electronic address: frank.vanhaecke@ugent.be.
Frank
F
Vanhaecke
Department of Surgery, Laboratory of Experimental Surgery, Ghent University Hospital, B-9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University Hospital, B-9000 Ghent, Belgium. Electronic address: wim.ceelen@ugent.be.
Wim
W
Ceelen
D000818:Animals; D002118:Calcium / Q000493:pharmacokinetics; D002945:Cisplatin / Q000493:pharmacokinetics; D003300:Copper / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D005260:Female; D005334:Fever / Q000378:metabolism; D064593:Heterografts / Q000378:metabolism / Q000648:ultrastructure; D007274:Injections, Intraperitoneal; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000648:ultrastructure*; D010758:Phosphorus / Q000493:pharmacokinetics; D010984:Platinum / Q000493:pharmacokinetics*; D013052:Spectrometry, X-Ray Emission / Q000379:methods; D013455:Sulfur / Q000493:pharmacokinetics; D014018:Tissue Distribution; D015032:Zinc / Q000493:pharmacokinetics
D010758:Phosphorus; D010984:Platinum; D013455:Sulfur; D003300:Copper; D015032:Zinc; D002945:Cisplatin; D002118:Calcium
Hyperthermia; Intraperitoneal; LA-ICP-MS; Ovarian cancer; Pt distribution; Synchrotron radiation-XRF