Immunotargeting of liposomes to activated vascular endothelial cells: a strategy for site-selective delivery in the cardiovascular system.
Endothelial-selective delivery of therapeutic agents, such as drugs or genes, would provide a useful tool for modifying vascular function in various disease states. A potential molecular target for such delivery is E-selectin, an endothelial-specific cell surface molecule expressed at sites of activation in vivo and inducible in cultured human umbilical vein endothelial cells (HUVEC) by treatment with cytokines such as recombinant human interleukin 1beta (IL-1beta). Liposomes of various types (classical, sterically stabilized, cationic, pH-sensitive), each conjugated with mAb H18/7, a murine monoclonal antibody that recognizes the extracellular domain of E-selectin, bound selectively and specifically to IL-1beta-activated HUVEC at levels up to 275-fold higher than to unactivated HUVEC. E-selectin-targeted immunoliposomes appeared in acidic, perinuclear vesicles 2-4 hr after binding to the cell surface, consistent with internalization via the endosome/lysosome pathway. Activated HUVEC incubated with E-selectin-targeted immunoliposomes, loaded with the cytotoxic agent doxorubicin, exhibited significantly decreased cell survival, whereas unactivated HUVEC were unaffected by such treatment. These results demonstrate the feasibility of exploiting cell surface activation markers for the endothelial-selective delivery of biologically active agents via immunoliposomes. Application of this targeting approach in vivo may lead to novel therapeutic strategies in the treatment of cardiovascular disease.
Spragg
D D
DD
Vascular Research Division, Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Alford
D R
DR
Greferath
R
R
Larsen
C E
CE
Lee
K D
KD
Gurtner
G C
GC
Cybulsky
M I
MI
Tosi
P F
PF
Nicolau
C
C
Gimbrone
M A
MA
D002318:Cardiovascular Diseases / Q000188:drug therapy; D002319:Cardiovascular System / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004337:Drug Carriers; D016503:Drug Delivery Systems; D019040:E-Selectin / Q000276:immunology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007375:Interleukin-1 / Q000008:administration & dosage*; D008081:Liposomes; D011994:Recombinant Proteins / Q000008:administration & dosage
D004337:Drug Carriers; D019040:E-Selectin; D007375:Interleukin-1; D008081:Liposomes; D011994:Recombinant Proteins