Disulfide cross-linked Fab-aggregates: preparation and biodistribution.
The high-molecular-weight soluble aggregates of Fab fragments of murine antibodies against cardiac myosin were prepared as a potential long-circulating and low immunogenic pharmaceutical carriers by conjugation of thiolated Fab and Fab modified with succinimidyl 3-(2-pyridyldithio)propionate. The clearance time and biodistribution of 111In-radiolabeled aggregates were studied in normal and nude-mice bearing human breast tumor implant and in rabbits with experimental myocardial infarction. The aggregates had a prolonged circulation time (half clearance time ca. 3-5 h) and ability to concentrate in the tumor and in the necrotic area of infarcted myocardium. Similar tumor-to-normal and infarct-to-normal accumulation ratios (ca. 3 h in both cases) suggest that combination of long circulation with impaired filtration in necrotic tissues is responsible for this accumulation rather than a specific interaction. The aggregates prepared may serve as long-circulating drug carriers able to deliver pharmaceuticals into areas with affected and leaky vasculature.
Dalkara
S
S
Center for Imaging and Pharmaceutical Research, Massachusetts General Hospital, Charlestown 02129, USA. dalkara@tr-net.net.tr
Petrov
A
A
Trubetskoy
V S
VS
Khaw
B A
BA
Torchilin
V P
VP
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003432:Cross-Linking Reagents / Q000737:chemistry*; D004195:Disease Models, Animal; D004220:Disulfides / Q000737:chemistry*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D007205:Indium Radioisotopes; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D009203:Myocardial Infarction / Q000378:metabolism*; D009368:Neoplasm Transplantation; D011817:Rabbits
D003432:Cross-Linking Reagents; D004220:Disulfides; D004337:Drug Carriers; D007140:Immunoglobulin Fab Fragments; D007205:Indium Radioisotopes