Role of formulation composition in folate receptor-targeted liposomal doxorubicin delivery to acute myelogenous leukemia cells.
Targeted drug delivery has the potential to improve the efficacy of a therapeutic agent while reducing its side effects. The folate receptor type beta (FR-beta) is a cell surface marker selectively expressed in the leukemic cells of approximately 70% of acute myeloid leukemia (AML) patients. Upregulation of FR-beta may also be selectively induced in AML cells by treatment with all-trans-retinoic acid (ATRA). In this study, the role of formulation composition in FR-targeted liposomal doxorubicin (DOX) delivery to AML cells was investigated. Liposomal formulations with a variable percentage of folate-polyethylene glycol distearoyl phosphatidylethanolamine (f-PEG-DSPE) were synthesized and evaluated for FR-beta-targeted DOX delivery in MV4-11 AML cells in vitro and for their pharmacokinetic properties in vivo. The formulation containing 0.5 mol % f-PEG-DSPE exhibited the highest efficiency of cellular uptake and in vitro cytotoxicity, as well as a long systemic circulation time in mice. In MV4-11 cells, the binding and cytotoxicity of FR-targeted liposomal DOX based on this formulation was also enhanced by ATRA-induced FR-beta upregulation.
Lu
Yanhui
Y
Division of Pharmaceutics, College of Pharmacy, Department of Internal Medicine, The Ohio State University, 500 W. 12th Avenue, Columbus, OH 43210, USA.
Wu
Jun
J
Wu
Jianmei
J
Gonit
Mefsin
M
Yang
Xiaojuan
X
Lee
Alice
A
Xiang
Guangya
G
Li
Hong
H
Liu
Shujun
S
Marcucci
Guido
G
Ratnam
Manohar
M
Lee
Robert J
RJ
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000009:adverse effects / Q000378:metabolism* / Q000627:therapeutic use; D016503:Drug Delivery Systems; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism*; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008813:Mice, Inbred ICR; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology
D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D008081:Liposomes; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D014212:Tretinoin; D004317:Doxorubicin