Systemic and tumor disposition of platinum after administration of cisplatin or STEALTH liposomal-cisplatin formulations (SPI-077 and SPI-077 B103) in a preclinical tumor model of melanoma.
OBJECTIVE
SPI-077 and SPI-077 B103 are formulations of cisplatin encapsulated in pegylated STEALTH liposomes that accumulate in tumors. However, the extent to which active platinum (Pt) is released from the liposome is unknown. Thus, we evaluated the disposition of encapsulated and released Pt in plasma and tumors after administration of STEALTH liposomal and nonliposomal cisplatin.


METHODS
Cisplatin (10 mg/kg), SPI-077 (10 mg/kg), and SPI-077 B103 (5 mg/kg) were administered i.v. to mice bearing B16 murine melanoma tumors. Microdialysis probes were placed into the right and left sides of each tumor, and serial samples were collected from tumor extracellular fluid (ECF) after administration of each agent. After each microdialysis procedure, tumor samples were obtained at each probe site to measure total Pt and Pt-DNA adducts. In a separate study, serial plasma samples (three mice per time point) were obtained. Unbound Pt in tumor ECF and plasma, and total Pt in tumor homogenates were measured by flameless atomic absorption spectrophotometry. Area under the tumor ECF (AUC(ECF)) concentration versus time curves of unbound Pt were calculated. Intrastrand GG (Pt-GG) and AG (Pt-AG) Pt-DNA adducts were measured via (32)P-postlabeling.


RESULTS
Mean+/-SD peak concentrations of total Pt in tumor homogenates after administration of cisplatin, SPI-077, and SPI-077 B-103 were 3.2+/-1.9, 11.9+/-3.0, and 3.5+/-0.3 microg/g, respectively. After cisplatin, mean+/-SD AUC(ECF) of unbound Pt was 0.72+/-0.46 microg/ml.h. There was no detectable unbound Pt in tumor ECF after SPI-077 or SPI-077 B-103 treatment. Mean+/-SD peak concentration of Pt-GG DNA adducts after administration of cisplatin, SPI-077, and SPI-077 B-103 were 13.1+/-3.3, 3.5+/-1.3, and 2.1+/-0.3 fmol Pt/microg DNA, respectively.


CONCLUSIONS
This study suggests that more SPI-077 and SPI-077 B103 distribute into tumors, but release less Pt into tumor ECF, and form fewer Pt-DNA adducts than does cisplatin.
Zamboni
William C
WC
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15213, USA. zamboniwc@msx.upmc.edu
Gervais
Anne C
AC
Egorin
Merrill J
MJ
Schellens
Jan H M
JH
Zuhowski
Elleanor G
EG
Pluim
Dick
D
Joseph
Erin
E
Hamburger
Deborah R
DR
Working
Peter K
PK
Colbern
Gail
G
Tonda
Margaret E
ME
Potter
Douglas M
DM
Eiseman
Julie L
JL
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002945:Cisplatin / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D018736:DNA Adducts / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism*; D005260:Female; D007275:Injections, Intravenous; D008546:Melanoma, Experimental / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017551:Microdialysis; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D018736:DNA Adducts; D004273:DNA, Neoplasm; C484367:SPI-077 B103; C422270:SPI-77, liposomal; C057270:cisplatin-DNA adduct; D002945:Cisplatin