Site-specific targeting of nanoparticle prednisolone reduces in-stent restenosis in a rabbit model of established atheroma.
OBJECTIVE
TRM-484 is a novel drug consisting of nanoparticles of prednisolone with high affinity to chondroitin sulfate proteoglycans (CSPGs). This may allow for neointimal suppression via directed targeting to areas of injury at systemic concentrations low enough to avoid adverse side effects known to occur with oral delivery of steroids.


RESULTS
Atherosclerotic New Zealand white Rabbits were implanted with bare metal stents and randomized to receive intravenous TRM-484 at doses of 1 mg/kg or 0.32 mg/kg starting at the day of stenting and continuing 3 times a week for the duration of the study. Control animals received empty liposomes (placebo) or saline infusion. Stented arterial segments were harvested at 42 days and processed for histomorphometry and immunohistochemistry. Tissue and plasma levels were determined along with confocal microscopic analysis to determine distribution of rhodamine-labeled TRM-484 at various time points. TRM-484 was exclusively observed at sites of stent-induced injury, with absence of drug in contralateral nonstented arteries. Tissue concentration of stented arteries exceeded that of contralateral nonstented arteries by 100-fold 24 hours after administration of 1 mg/kg TRM-484 and resulted in significant reduction of percent stenosis compared to saline and placebo treated rabbits (22.5+/-4.4 versus 31.0+/-8.4 and 29.5+/-8.1%, P<0.03).


CONCLUSIONS
TRM-484 at doses of 1 mg/kg resulted in significant suppression of in-stent neointimal growth in atherosclerotic rabbits. Site-specific targeting by this nanoparticle steroid in injured atherosclerotic areas might be a valuable and cost-effective approach for the prevention of in-stent restenosis.
Joner
Michael
M
Deutsches Herzzentrum Muenchen und Medizinische Klinik, Klinikum rechts der Isar, Muenchen, Germany.
Morimoto
Katsumi
K
Kasukawa
Hiroaki
H
Steigerwald
Kristin
K
Merl
Sabine
S
Nakazawa
Gaku
G
John
Michael C
MC
Finn
Aloke V
AV
Acampado
Eduardo
E
Kolodgie
Frank D
FD
Gold
Herman K
HK
Virmani
Renu
R
D000800:Angioplasty, Balloon / Q000009:adverse effects* / Q000295:instrumentation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D001550:Benzamidines / Q000737:chemistry*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D018925:Chemokines / Q000378:metabolism; D003251:Constriction, Pathologic; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000737:chemistry*; D005240:Feasibility Studies; D006801:Humans; D007083:Iliac Artery / Q000187:drug effects / Q000293:injuries; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D008081:Liposomes; D008670:Metals; D018613:Microscopy, Confocal; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D053758:Nanoparticles; D011239:Prednisolone / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011474:Prosthesis Design; D011817:Rabbits; D055502:Secondary Prevention; D015607:Stents; D013997:Time Factors
C450860:3,5-dipentadecyloxybenzamidine hydrochloride; D000893:Anti-Inflammatory Agents; D001550:Benzamidines; D018925:Chemokines; D005227:Fatty Acids; D008081:Liposomes; D008670:Metals; D011239:Prednisolone