Tumor disposition of pegylated liposomal CKD-602 and the reticuloendothelial system in preclinical tumor models.

Abstract

Liposomes, such as pegylated-liposomal CKD-602 (S-CKD602), undergo catabolism by macrophages and dendritic cells (DCs) of the reticuloendothelial system (RES). The relationship between plasma and tumor disposition of S-CKD602 and RES was evaluated in mice bearing A375 melanoma or SKOV-3 ovarian xenografts. Area under the concentration-time curves (AUCs) of liposomal encapsulated, released, and sum total (encapsulated + released) CKD-602 in plasma, tumor, and tumor extracellular fluid (ECF) were estimated. A375 and SKOV-3 tumors were stained with cd11b and cd11c antibodies as measures of macrophages and DC. The plasma disposition of S-CKD602 was similar in both xenograft models. The ratio of tumor sum total AUC to plasma sum total AUC was 1.7-fold higher in mice bearing human SKOV-3 xenografts, compared with A375. The ratio of tumor ECF AUC to tumor sum total AUC was 2-fold higher in mice bearing human SKOV-3 xenografts, compared with A375. The staining of cd11c was 4.5-fold higher in SKOV-3, compared with A375 (P < 0.0001). The increased tumor delivery and release of CKD-602 from S-CKD602 in the ovarian xenografts, compared with the melanoma xenografts, was consistent with increased cd11c staining, suggesting that variability in the RES may affect the tumor disposition of liposomal agents.

• Authors: William C Zamboni, Julie L Eiseman, Sandra Strychor, Patricia M Rice, Erin Joseph, Beth A Zamboni, Mark K Donnelly, Jennifer Shurer, Robert A Parise, Margaret E Tonda, Ning Y Yu, Per H Basse
• Journal: Journal of liposome research (J Liposome Res) Vol. 21 Issue 1 Pg. 70-80 (Mar 2011) ISSN: 1532-2394 [Electronic] England
• PMID: 20528623 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Topoisomerase I Inhibitors
• belotecan
• Camptothecin

Topics

• Animals
• Area Under Curve
• Camptothecin (analogs & derivatives, pharmacokinetics, pharmacology)
• Chromatography, Liquid
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Humans
• Mass Spectrometry
• Mice
• Mononuclear Phagocyte System (drug effects)
• Topoisomerase I Inhibitors (pharmacokinetics, pharmacology)
• Xenograft Model Antitumor Assays