Locally delivered nanoencapsulated tyrphostin (AGL-2043) reduces neointima formation in balloon-injured rat carotid and stented porcine coronary arteries.
Local delivery of antiproliferative drugs encapsulated in biodegradable nanoparticles (NP) has shown promise as an experimental strategy for preventing restenosis development. A novel PDGFRbeta-specific tyrphostin, AGL-2043, was formulated in polylactide-based nanoparticles and was administered intraluminally to the wall of balloon-injured rat carotid and stented pig coronary arteries. The disposition and elimination kinetics within the vessel wall, as well as the antirestenotic potential of the novel drug and delivery system, were evaluated. The efficacy and the local drug elimination kinetics were affected by the size of the NP and the drug-carrier binding mode. Despite similar arterial drug levels 90 min after delivery in rats, small NP were more efficacious in comparison to large NP (90 and 160 nm, respectively). AGL-2043 selectively inhibited vascular SMC in a dose-dependent manner. The antiproliferative effect of nanoencapsulated tyrphostin was considerably higher than that of surface-adsorbed drug. In the pig model, intramural delivery of AGL-2043 resulted in reduced in-stent neointima formation in the coronary arteries over control despite similar degrees of wall injury. The results of this study suggest that locally delivered tyrphostin AGL-2043 formulated in biodegradable NP may be applicable for antirestenotic therapy independent of stent design or type of injury.
Heiden Department of Cardiology, Bikur Cholim Hospital, Jerusalem, Israel.
Shmuel
S
Banai
Michael
M
Chorny
S David
SD
Gertz
Ilia
I
Fishbein
Jianchuan
J
Gao
Louise
L
Perez
Galila
G
Lazarovichi
Aviv
A
Gazit
Alexander
A
Levitzki
Gershon
G
Golomb
D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects; D000818:Animals; D001807:Blood Vessel Prosthesis / Q000009:adverse effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D020099:Coated Materials, Biocompatible / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D023903:Coronary Restenosis / Q000473:pathology* / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology*; D006083:Graft Occlusion, Vascular / Q000473:pathology / Q000517:prevention & control; D007267:Injections; D008297:Male; D008422:Materials Testing; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D043942:Nanotubes / Q000737:chemistry; D014677:Pharmaceutical Vehicles / Q000008:administration & dosage / Q000737:chemistry*; D011091:Polyesters / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D015607:Stents / Q000009:adverse effects; D013552:Swine; D016896:Treatment Outcome; D020032:Tyrphostins / Q000008:administration & dosage* / Q000493:pharmacokinetics
D020099:Coated Materials, Biocompatible; D014677:Pharmaceutical Vehicles; D011091:Polyesters; D020032:Tyrphostins; C494191:tyrphostin AGL-2043; C033616:poly(lactide)