Tumor disposition of pegylated liposomal CKD-602 and the reticuloendothelial system in preclinical tumor models.
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.
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina 27599-7360, USA. zamboni@email.unc.edu
William C
WC
Zamboni
Julie L
JL
Eiseman
Sandra
S
Strychor
Patricia M
PM
Rice
Erin
E
Joseph
Beth A
BA
Zamboni
Mark K
MK
Donnelly
Jennifer
J
Shurer
Robert A
RA
Parise
Margaret E
ME
Tonda
Ning Y
NY
Yu
Per H
PH
Basse
D000818:Animals; D019540:Area Under Curve; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D012157:Mononuclear Phagocyte System / Q000187:drug effects*; D059004:Topoisomerase I Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D059004:Topoisomerase I Inhibitors; C116963:belotecan; D002166:Camptothecin