Prolonged Half‐Life in the Circulation of a Chemical Conjugate Between a Pro‐Urokinase Derivative and Human Serum Albumin

Breton, Jérôme; Pezzi, Nieves; Molinari, Agnese; Bonomini, Luisella; Lansen, J.; Buitrago, Gonzalo González de; Priéto, Ignacio

doi:10.1111/j.1432-1033.1995.0563d.x

Cited by 10 publications

(6 citation statements)

References 35 publications

(25 reference statements)

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“…Although the liver uptake of deltal25-rscu-PA was completely blocked by GST-RAP still a relatively rapid clearance from the circulation was observed, probably due to extra-hepatic uptake of this rather small molecule (31.8 kDa). The latter is in line with Breton et al (53) who showed that a conjugate of deltal25-rscu-PA with serum albumin injected in monkeys shows a dramatic increase in serum half-life compared to deltal25-rscu-PA alone. It is thought that the conjugation with albumin protects the deltal25-rscu-PA molecule probably for extravascularization.…”

Section: Discussionsupporting

confidence: 90%

The Role of the Low-Density Lipoprotein Receptor-Related Protein (LRP) in the Plasma Clearance and Liver Uptake of Recombinant Single-chain Urokinase-type Plasminogen Activator in Rats

Kaaden¹,

Rijken²,

Kruijt³

et al. 1997

Thromb Haemost

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SummaryUrokinase-type plasminogen activator (u-PA) is used as a thrombolytic agent in the treatment of acute myocardial infarction. In vitro, recombinant single-chain u-PA (rscu-PA) expressed in E.coli is recognized by the Low-Density Lipoprotein Receptor-related Protein (LRP) on rat parenchymal liver cells. In this study we investigated the role of LRP in the liver uptake and plasma clearance of rscu-PA in rats. A preinjection of the LRP inhibitor GST-RAP reduced the maximal liver uptake of 125I-rscu-PA at 5 min after injection from 50 to 30% of the injected dose and decreased the clearance of rscu-PA from 2.37 ml/min to 1.58 ml/min. Parenchymal, Kupffer and endothelial cells were responsible for 40, 50 and 10% of the liver uptake, respectively. The reduction in liver uptake of rscu-PA by the preinjection of GST-RAP was caused by a 91 % and 62% reduction in the uptake by parenchymal and Kupffer cells, respectively. In order to investigate the part of rscu-PA that accounted for the interaction with LRP, experiments were performed with a mutant of rscu-PA lacking residues 11-135 (= deltal25- rscu-PA). Deletion of residues 11-135 resulted in a 80% reduction in liver uptake and a 2.4 times slower clearance (0.97 ml/min). The parenchymal, Kupffer and endothelial cells were responsible for respectively 60, 33 and 7% of the liver uptake of 125I-deltal25-rscu-PA. Preinjection of GST-RAP completely reduced the liver uptake of delta 125-rscu-PA and reduced its clearance to 0.79 ml/min. Treatment of isolated Kupffer cells with PI-PLC reduced the binding of rscu-PA by 40%, suggesting the involvement of the urokinase-type Plasminogen Activator Receptor (u-PAR) in the recognition of rscu-PA. Our results demonstrate that in vivo LRP is responsible for more than 90% of the parenchymal liver cell mediated uptake of rscu-PA and for 60% of the Kupffer cell interaction. It is also suggested that u-PAR is involved in the Kupffer cell recognition of rscu-PA.

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Section: Discussionsupporting

confidence: 90%

The Role of the Low-Density Lipoprotein Receptor-Related Protein (LRP) in the Plasma Clearance and Liver Uptake of Recombinant Single-chain Urokinase-type Plasminogen Activator in Rats

Kaaden¹,

Rijken²,

Kruijt³

et al. 1997

Thromb Haemost

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“…8 The circulation half-lives of the drugs have been reported to dramatically increase when the drug is conjugated with albumin. 9 Increasing the circulation half-life of the formulation by reducing its uptake by the reticuloendothelial system has been shown to improve the targeting efficiency of the formulation to the arthritic paws of rats. 10 There are several reports on the use of long circulating liposomes to target the drugs to the arthritic joints.…”

Section: Introductionmentioning

confidence: 99%

Albumin microspheres as carriers for the antiarthritic drug celecoxib

et al. 2005

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The present study investigates the preparation of celecoxib-loaded albumin microspheres and the biodistribution of technetium-99m ((99m)Tc)-labeled celecoxib as well as its microspheres after intravenous administration. Microspheres were prepared using a natural polymer BSA using emulsification chemical cross-linking method. The prepared microspheres were characterized for entrapment efficiency, particle size, and in vitro drug release. Surface morphology was studied by scanning electron microscopy. Biodistribution studies were performed by radiolabeling celecoxib (CS) and its microspheres (CMS) using (99m)Tc and injecting arthritic rats intravenously. The geometric mean diameter of the microspheres was found to be 5.46 microm. In vitro release studies indicated that the microspheres sustained the release of the drug for 6 days. Radioactivity measured in different organs after intravenous administration of celecoxib solution showed a significant amount of radioactivity in the liver and spleen. In case of celecoxib-loaded microspheres, a significant amount of radioactivity accumulated in the lungs. No significant difference (P > .1) in the radioactivity was observed between the inflamed joint and the noninflamed joint following intravenous injection of (99m)Tc-CS. However, in case of the microspheres (CMS), the radioactivity present in the inflamed joint was 2.5-fold higher than in the noninflamed joint. The blood kinetic studies revealed that celecoxib-loaded albumin microspheres exhibited prolonged circulation than the celecoxib solution.

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“…Intravenous administration of the drugs coupled with Albumin has been reported to improve the targeting efficiency of the drug to arthritic regions [13]. The circulation halflives of the drugs have been reported to dramatically increase when the drug is conjugated with albümin [14]. Increasing the circulation half-life of the formulation by reducing its uptake by the reticuloendothelial system has been shown to improve the targeting efficiency of the formulation to the arthritic paws of rats [15].…”

Section: Introductionmentioning

confidence: 99%