Enhancement of the efficacy of an antagonist of an extracellular receptor by attachment to the surface of a biocompatible carrier.
OBJECTIVE
In order to improve the in vitro and in vivo efficacy of an integrin antagonist (IA) of the extracellular domain of the alphavbeta3 integrin, a receptor upregulated on tumor neovasculature, the IA was attached to the surface of a dextran-coated liposome (DCL). IA-DCLs were characterized in vitro, and the pharmacokinetic and antitumor properties were assessed in vivo.


METHODS
The in vitro binding properties were measured with purified integrin, endothelial cells, and melanoma cells. The pharmacokinetic parameters were measured in healthy mice with 14C-labeled IA-DCLs and anti-tumor efficacy was assessed with the M21 human melanoma xenograft mouse model.


RESULTS
In vitro, IC50 values for IA-DCLs and IA are similar, and IA-DCLs inhibit cell proliferation relative to controls. IA-DCLs are stable in serum, and the pharmacokinetic half-life in mice is 23 h. In the M21/mouse model, statistically significant inhibition of tumor growth was observed for mice treated with IA-DCLs, whereas controls including saline, DCLs lacking IA, and cyclo(RGDfV) were ineffective. Increased apoptosis and a reduction in vessel counts relative to controls were present in tumors from animals treated with IA-DCLs.


CONCLUSIONS
These results demonstrate that IA-DCLs are potent anti-angiogenic therapeutic agents with superior in vivo activity and pharmacology compared to unmodified IA.
Wartchow
Charles A
CA
Targesome Inc., Palo Alto, California 94303, USA.
Alters
Susan E
SE
Garzone
Pamela D
PD
Li
Lingyun
L
Choi
Steven
S
DeChene
Neal E
NE
Doede
Tina
T
Huang
Linong
L
Pease
John S
JS
Shen
Zhimin
Z
Knox
Susan J
SJ
Cleland
Jeffrey L
JL
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D001672:Biocompatible Materials; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003911:Dextrans; D004337:Drug Carriers; D004339:Drug Compounding; D016503:Drug Delivery Systems; D042783:Endothelial Cells / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D020287:In Situ Nick-End Labeling; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D008081:Liposomes; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D014018:Tissue Distribution
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001672:Biocompatible Materials; D003911:Dextrans; D004337:Drug Carriers; D039302:Integrin alphaVbeta3; D008081:Liposomes