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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

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Abstract

Purpose

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 (AUCECF) concentration versus time curves of unbound Pt were calculated. Intrastrand GG (Pt-GG) and AG (Pt-AG) Pt-DNA adducts were measured via 32P-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 μg/g, respectively. After cisplatin, mean±SD AUCECF of unbound Pt was 0.72±0.46 μg/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/μg DNA, respectively.

Conclusion

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.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15213, USA

    William C. Zamboni

  2. Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA

    William C. Zamboni & Merrill J. Egorin

  3. Program of Molecular Therapeutics and Drug Discovery, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA

    William C. Zamboni, Anne C. Gervais, Merrill J. Egorin, Elleanor G. Zuhowski, Erin Joseph, Deborah R. Hamburger & Julie L. Eiseman

  4. Department of Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA

    Merrill J. Egorin & Julie L. Eiseman

  5. Department of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Jan H. M. Schellens & Dick Pluim

  6. ALZA Corporation, Mountain View, CA 94043, USA

    Peter K. Working, Gail Colbern & Margaret E. Tonda

  7. Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA

    Douglas M. Potter

  8. Hillman Cancer Research Center, University of Pittsburgh Cancer Institute, Room G.26, 5117 Center Ave, Pittsburgh, PA 15213, USA

    William C. Zamboni

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  1. William C. Zamboni
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Zamboni, W.C., Gervais, A.C., Egorin, M.J. et al. 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. Cancer Chemother Pharmacol 53, 329–336 (2004). https://doi.org/10.1007/s00280-003-0719-4

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