Enhanced adhesion of ligand-conjugated biodegradable particles to colitic venules.
The expression of certain endothelial cell adhesion molecules (ECAMs) is increased in the vasculature of the inflamed bowel (e.g., colitis), thereby providing an opportunity for targeted drug delivery. We recently demonstrated that biodegradable particles conjugated with ligands to ECAMs exhibit significant selective adhesion to ECAM expressing endothelium. In the present study, we used a murine model of colitis to determine whether poly(lactic acid)-poly(ethylene glycol) particles conjugated with a VCAM-1 ligand (alpha-V) exhibit enhanced adhesion to colitic vasculature. In post-capillary venules of the colon, significantly more alpha-V particles accumulate in colitic mice relative to (i) control mice (i.e., selectivity) and (ii) particles bearing a control ligand (i.e., ligand efficiency). The selectivity and ligand efficiency of alpha-V particles were a function of the total number of particles infused. The highest selectivity observed within our test regime was 3, while ligand efficiency increased linearly with the number of particles injected to a value of 24. This work represents a significant step towards achieving a targeted drug delivery scheme for the treatment of inflammatory bowel disease and indicates that the efficiency of targeting is dependent on the dose regime.
Sakhalkar
Harshad S
HS
Department of Chemical Engineering, Ohio University, Athens, Ohio 45701, USA.
Hanes
Justin
J
Fu
Jie
J
Benavides
Uruguaysito
U
Malgor
Ramiro
R
Borruso
Cheri L
CL
Kohn
Leonard D
LD
Kurjiaka
David T
DT
Goetz
Douglas J
DJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001710:Biotin; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D003106:Colon / Q000098:blood supply; D016264:Dextran Sulfate / Q000008:administration & dosage; D004337:Drug Carriers / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D042783:Endothelial Cells / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008863:Microspheres; D011091:Polyesters; D011092:Polyethylene Glycols; D011108:Polymers; D011137:Polystyrenes; D012235:Rhodamines / Q000008:administration & dosage; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D014699:Venules / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D004337:Drug Carriers; D008024:Ligands; D011091:Polyesters; D011108:Polymers; D011137:Polystyrenes; D012235:Rhodamines; D019010:Vascular Cell Adhesion Molecule-1; C469934:poly(lactic acid)-poly(ethylene glycol)-biotin; D011092:Polyethylene Glycols; D001710:Biotin; D016264:Dextran Sulfate