在黑色素瘤临床前肿瘤模型中，给予顺铂或隐形脂质体顺铂制剂（SPI-077和SPI-077 B103）后铂的全身和肿瘤分布情况。

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.

作者信息

Zamboni William C, Gervais Anne C, Egorin Merrill J, Schellens Jan H M, Zuhowski Elleanor G, Pluim Dick, Joseph Erin, Hamburger Deborah R, Working Peter K, Colbern Gail, Tonda Margaret E, Potter Douglas M, Eiseman Julie L

机构信息

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

出版信息

Cancer Chemother Pharmacol. 2004 Apr;53(4):329-36. doi: 10.1007/s00280-003-0719-4. Epub 2003 Dec 12.

DOI:10.1007/s00280-003-0719-4

PMID:14673619

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 (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.

摘要

目的

SPI-077和SPI-077 B103是包裹于聚乙二醇化隐形脂质体中的顺铂制剂，可在肿瘤中蓄积。然而，活性铂（Pt）从脂质体中的释放程度尚不清楚。因此，我们评估了给予隐形脂质体顺铂和非脂质体顺铂后，血浆和肿瘤中包裹的和释放的Pt的处置情况。

方法

将顺铂（10mg/kg）、SPI-077（10mg/kg）和SPI-077 B103（5mg/kg）静脉注射给荷B16小鼠黑色素瘤肿瘤的小鼠。将微透析探针置于每个肿瘤的左右两侧，在给予每种药物后从肿瘤细胞外液（ECF）中收集系列样本。每次微透析操作后，在每个探针部位获取肿瘤样本以测量总Pt和Pt-DNA加合物。在另一项研究中，获取系列血浆样本（每个时间点3只小鼠）。通过无火焰原子吸收分光光度法测量肿瘤ECF和血浆中的游离Pt以及肿瘤匀浆中的总Pt。计算肿瘤ECF中游离Pt的浓度-时间曲线下面积（AUC(ECF)）。通过（32）P后标记法测量链内GG（Pt-GG）和AG（Pt-AG）Pt-DNA加合物。

结果

给予顺铂、SPI-077和SPI-077 B-103后，肿瘤匀浆中总Pt的平均±标准差峰值浓度分别为3.2±1.9、11.9±3.0和3.5±0.3μg/g。给予顺铂后，游离Pt的平均±标准差AUC(ECF)为0.72±0.46μg/ml·h。SPI-077或SPI-077 B-103治疗后，肿瘤ECF中未检测到游离Pt。给予顺铂、SPI-077和SPI-077 B-103后，Pt-GG DNA加合物的平均±标准差峰值浓度分别为13.1±3.3、3.5±1.3和2.1±0.3 fmol Pt/μg DNA。