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.

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 (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. 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.

Inter- and intratumoral disposition of platinum in solid tumors after administration of cisplatin.

One possible explanation for variable tumor response within a single patient may be related to delivery of chemotherapeutic agents to the tumors. Microdialysis was used to evaluate inter- and intratumoral disposition of unbound platinum (Pt) after cisplatin administration to mice bearing B16 murine melanoma tumors or H23 human NSCLC xenografts. Before i.v. dosing with cisplatin (3 or 10 mg/kg), microdialysis probes were placed into the right and left sides of each tumor, and serial extracellular fluid (ECF) samples were collected for 2 h. After microdialysis, tumor samples were obtained at each probe site to measure total Pt and Pt-DNA adducts. In a separate study, serial plasma samples (n = 3 mice/time point) were obtained between 5 min and 2 h. Unbound Pt in tumor ECF and plasma and total Pt in tumor homogenates were measured by flameless atomic absorption spectrophotometry. Pt-DNA adducts in tumor samples were measured via (32)P-postlabeling. Area under the plasma (AUC(P)) and tumor ECF (AUC(ECF)) concentration-time curves of unbound Pt were calculated. Factor VIII expression was measured by immunohistochemistry in tumor samples. After administration of 3 or 10 mg/kg of cisplatin to mice bearing B16 tumors, there was a proportional increase in AUC(PL) with dose; however, there was not a proportional increase in AUC(ECF). There was a relatively high (30-fold) inter- and low (2.5-fold) intratumoral variability in AUC(ECF). AUC(ECF) correlated better with Pt-DNA adduct formation than did total Pt concentration in tumors. There was no relationship between Factor VIII expression and Pt exposure in tumors. The variable penetration of Pt from plasma into tumor ECF may be associated with variable response of tumors.