Superior Plasma Retention of a Cross-Linked Human Serum Albumin Dimer in Nephrotic Rats as a New Type of Plasma Expander

Abstract

ABSTRACT:Human serum albumin (HSA) is used clinically as a plasma expander in patients with hypoalbuminemia and can also function as a drug carrier. However, the administered HSA is readily eliminated from the blood circulation under pathological conditions, especially the nephrotic syndrome. In this study, we present data on the pharmacokinetics of a structurally defined HSA dimer [two HSA molecules that are cross-linked by reaction with 1,6-bis(maleimido)hexane via Cys34] in nephrotic rats and its superior circulation persistence, owing to the molecular size effect. The half-time (t 1/2 ) of the HSA dimer persisted in the circulation 1.3 times longer than that of monomeric HSA in normal rats, primarily because of the suppression of the accumulation of the HSA dimer in the skin and muscle. In nephrotic rats, the t 1/2 of the HSA monomer decreased considerably, whereas the HSA dimer remained unaltered in the blood stream, similar to that for normal rats. As a result, the t 1/2 of the HSA dimer was 2-fold longer than that of the HSA monomer. This longer t 1/2 can be attributed to the fact that accumulation in the kidney and urinary excretion of the HSA dimer were significantly suppressed. The cross-linked HSA dimer shows a longer blood circulation than native HSA monomer in nephrotic rats, which can be attributed to the suppression of renal filtration and leakage into the extravascular space. This HSA dimer has the potential for use as a drug carrier, new plasma expander, and an artificial albumin-based oxygen carrier under a high glomerular permeability condition such as nephrosis.

Cross-linked human serum albumin dimer has the potential for use as a plasma-retaining agent for the fatty acid-conjugated antidiabetic drugs

“…To evaluate the progression of diabetic nephropathy, we determine the urinary protein concentration in the rat model of diabetic nephropathy at 14 days after STZ administration. The urinary protein in the diabetes model rat was 12.7 ± 3.5 mg/day, which was much less than that of the nephritic rats induced by doxorubicin (213 ± 28 mg/day) but was close to that of normal rats (8.0 ± 3.4 mg/day) [9]. In addition, the urinary excretion of the HSA monomer and dimer in STZ‐induced diabetic nephropathy rat were similar to those in normal rat [9].…”

“…The urinary protein in the diabetes model rat was 12.7 ± 3.5 mg/day, which was much less than that of the nephritic rats induced by doxorubicin (213 ± 28 mg/day) but was close to that of normal rats (8.0 ± 3.4 mg/day) [9]. In addition, the urinary excretion of the HSA monomer and dimer in STZ‐induced diabetic nephropathy rat were similar to those in normal rat [9]. Furthermore, although glomerulus damage was observed in the STZ‐induced diabetic nephropathy model rats from the PAS staining (Figure g), Scr and BUN concentrations in the STZ‐induced diabetic nephropathy model rats were at about the same level as those of the control rats (Figure e and f).…”

“…For the pharmacokinetic experiments, the HSA monomer and dimer were radiolabeled with 111 In as previously reported [9]. Both 111 In‐labeled HSA monomer and dimer were mixed with unlabeled HSA monomer and dimer, respectively, to adjust the protein concentration before use in the pharmacokinetic experiments.…”

“…Although these measures could prolong the blood retention of albumin polymers, the drug binding capacity HSA is compromised. We previously reported HSA dimer prepared by cross‐linking two HSA molecules with 1,6‐bis(maleimido)hexane (BMH)[8] showed superior plasma retention property compared with HSA monomer in the doxorubicin‐induced nephrotic rat model [9]. In addition, the length of BMH seems to be sufficiently long (16.1 Å), permitting HSA dimer to preserve the structural properties of native HSA monomer including ligand binding capacity and blood compatibility [8,10].…”

S-Nitrosated human serum albumin dimer as novel nano-EPR enhancer applied to macromolecular anti-tumor drugs such as micelles and liposomes

“…Previous studies have shown that HSA-Dimer has a longer circulation time than the monomeric form of HSA [16,17]. Moreover, the HSA-Dimer has also an enhanced accumulation in solid tumor via an increased EPR effect due to its large molecular size (molecular weight: 130 kDa, size in crystal form: 30 nm) [18].…”