Pharmacokinetics of succinylated proteins and dextran sulfate in mice: Implications for hepatic targeting of protein drugs by direct succinylation via scavenger receptors

doi:10.1016/0378-5173(94)90231-3

International Journal of Pharmaceutics

Volume 105, Issue 1, 25 April 1994, Pages 19-29

https://doi.org/10.1016/0378-5173(94)90231-3 Get rights and content

Abstract

The disposition characteristics of three types of ¹¹¹In-labeled succinylated proteins, succinylated Superoxide dismutase (Suc-SOD; Mol. Wt 34000), bovine serum albumin (Suc-BSA; Mol. Wt 70000) and uricase (Suc-UC; Mol. Wt 130000) and [¹⁴Qdextran sulfate (DS; Mol. Wt 8000) after intravenous injection were studied in mice. At a dose of 1 mg/kg, [¹¹¹In]Suc-BSA and [¹¹¹In]Suc-UC were taken up by the liver to a great extent whereas [¹¹¹In]Suc-SOD was rapidly excreted into the urine without marked hepatic uptake. [¹¹¹In]Suc-BSA was preferentially localized in non-parenchymal cells of the liver. Rapid urinary excretion was observed for [¹⁴C]DS, however, it accumulated in the liver. Hepatic uptake of [¹¹¹In]Suc-BSA and [¹⁴C]DS was suppressed at a higher dose (100 mg/kg), suggesting a saturable uptake process. Pharmacokinetic analysis revealed that hepatic uptake clearances of [¹¹¹In]Suc-BSA, [¹¹¹In]Suc-UC and [¹⁴C]DS were 15.8-, 7.2- and 10.4-fold higher than that of [¹¹¹In]Suc-SOD, respectively, at 1 mg/kg. Hepatic uptake of [¹¹¹In]Suc-BSA was significantly inhibited by simultaneous administration of excess amounts of other negatively charged macromolecules, such as maleylated BSA (Mal-BSA), heparin, DS and polyinosinic acid (poly[I]), typical ligands for scavenger receptors. On the other hand, native BSA, cationized BSA (Cat-BSA), galactosylated and mannosylated BSA (Gal- and Man-BSA), carboxymethyl dextran (CM-dex) and polycytidylic acid (poly[C]) were not effective inhibitors. Thus, this is the first report that protein drugs can be targeted to liver non-parenchymal cells by direct succinylation through scavenger receptors in vivo. In addition, the importance of molecular weight or total number of anionic charges per protein molecule was suggested.

References (43)

S. Acton et al.
The collagenous domains of macrophage scavenger receptors and complement Clq mediate their similar but not identical, binding specificities for polyanionic ligands
J. Biol. Chem.
(1993)
T. Doi et al.
Charged collagen structure mediates the recognition of negatively charged macromolecules by macrophage scavenger receptors
J. Biol. Chem.
(1993)
T. Fujita et al.
Therapeutic effects of Superoxide dismutase derivatives modified with mono- and polysaccharides on hepatic injury induced by ischemia/ reperfusion
Biochem. Biophys. Res. Commun.
(1992)
E.J.F. Franssen et al.
Hepatic and intrahepatic targeting of an anti-inflammatory agent with human serum albumin and neoglycoproteins as carrier molecules
Biochem. Pharmacol.
(1993)
D. Hnatowich et al.
The preparation and labeling of DTPA-coupled albumin
Int. J. Appl. Radiat Isot.
(1982)
S. Horiuchi et al.
Characterization of a membrane-associated receptor from rat sinusoidal liver cells that binds formaldehyde-treated serum albumin
J. Biol. Chem.
(1985)
S. Horiuchi et al.
Scavenger functions of sinusoidal liver cells: Acetylated lowdensity lipoprotein is endocytosed via a route distinct from formaldehyde-treated serum albumin
J. Biol. Chem.
(1985)
R.W. Jansen et al.
Formaldehyde treated albumin contains monomeric and polymeric forms that are differently cleared by endothelial and Kupffer cells of the liver: Evidence for scavenger receptor heterogeneity
Biochem. Biophys. Res. Commun.
(1991)
M. Krieger et al.
Molecular flypaper, host defence and atherosclerosis: Structure binding properties and functions of macrophage scavenger receptors
J. Biol. Chem.
(1993)
A.M. Pearson et al.
Polynucleotide binding to macrophage scavenger receptors depends on the formation of hase-quartet-stabilized four-strand helices
J. Biol. Chem.
(1993)

C.F. Roos et al.

Physicochemical and antitumor characteristics of some polyamino acid prodrugs of mitomycin C

Int. J. Pharm.

(1984)

W.C. Shen et al.

cis-Aconityl spacer between daunomycin and macromolecular carriers: A model of pH-sensitive linkage releasing drug from a lysosomotropic conjugate

Biochem. Biophys. Res. Commun.

(1981)

Y. Takakura et al.

Control of pharmaceutical properties of soybean trypsin inhibitor by conjugation with dextran: II. Biopharmaceutical and pharmacological properties

J. Pharm. Sri.

(1989)

Y. Takakura et al.

Control of pharmaceutical properties of soybean trypsin inhibitor by conjugation with dextran: I. Synthesis and characterization

J. Pharm. Sci.

(1989)

T.J.C. Van Berkel et al.

Different fate in vivo of oxidatively modified low density lipoprotein in rats: Recognition by various scavenger receptors on Kupffer and endothelial liver cells

J. Biol. Chem.

(1991)

M. Baba et al.

Mechanism of inhibitory effect of dextran sulfate and heparin on replication of human immunodeficiency virus in vitro

P.E. Bickel et al.

Rabbit aortic smooth muscle cells express inducible macrophage scavenger receptor messenger RNA that is absent from endothelial cells

J. Clin. Invest.

(1992)

R. Blomhoff et al.

Clearance of acetylated low density protein by liver endothelial cells: Implications for hepatic cholesterol metabolism

J. Biol. Chem.

(1985)

B.A. Brown et al.

Pharmacokinetics of the monoclonal antibody B72.3 and its fragments labeled with either ¹²⁵I and ¹²⁵In

Cancer Res.

(1987)

M.S. Brown et al.

The scavenger receptor cell pathway for lipoprotein degradation: Specificity of the binding site that mediates the uptake of negatively-charged LDL by macrophages

J. Supermol. Struct.

(1980)

E. Diener et al.

Specific immunosuppresion by immunotoxins containing daunomycin

Science

(1986)

Cited by (71)

Dextran-based engineering: a leap in novel drug delivery
2023, Natural Biopolymers in Drug Delivery and Tissue Engineering
Dextran is a biocompatible, non-toxic and non-immunogenic natural polymer widely employed as a drug carrier. The resistance to proteolytic degradation, non-specific cell adhesion, the possibility of structural modifications, its cost-effectiveness etc., have made it a hot topic of research. The enhanced features of the dextran polymer extended its application to various drug delivery applications, where it has attained a significant role in chemotherapy. It benefits anticancer therapy by effectively reducing the toxic and side effects of chemotherapeutic drugs in the human body. It permits targeted drug delivery, which diminishes the possibility of nearby cell damage, which is common in traditional chemotherapies. Apart from the significant role in anticancer therapies, the therapeutic potential of dextran complexes is extended to imaging techniques, oral delivery of insulin and various other therapies. When the physicochemical properties of the native dextran limit its application, the drawbacks can be conquered by altering the backbone of this natural polysaccharide through various reactions to graft semisynthetic, synthetic and natural polymers. A detailed review of the various properties of dextran, along with its basic structure, other features, therapeutic potential and applications, are discussed here in this chapter.
Strategies for persistent retention of macromolecules and nanoparticles in the blood circulation
2022, Journal of Controlled Release
The enhanced permeability and retention (EPR) effect has been the gold standard in developing drug delivery systems for passive tumor targeting. Although the importance of this concept remains unchanged, some controversies have arisen. In this review, various strategies for tumor targeting using macromolecules and nanoparticles based on the EPR effect are discussed from the viewpoint of pharmacokinetics. Overall, such strategies seek to retain therapeutic material in the blood circulation, which is a key factor for successful targeting. Strategies using macromolecules, including antibody–drug conjugates, serum albumin-based delivery systems, PEGylated recombinant proteins, and stealth liposomes as well as nanoparticle-based strategies such as those based on lipid nanoparticles, and polymeric micelles, have been discussed. The feasibility of small extracellular vesicles, a new class of nanosized delivery carriers, is also discussed.
Topical application of zwitterionic chitosan suppresses neutrophil-mediated acute skin inflammation
2020, International Journal of Biological Macromolecules
Citation Excerpt :
However, several studies have provided some clue. For example, succinylated proteins are specifically taken up by scavenger receptor SR-BI [45,46] and also SR-BI-mediated uptake of lipids attenuates neutrophil activation [47]. Therefore, SR-BI may be one of the receptors responsible for ZWC's suppression of neutrophil activation.
Zwitterionic chitosan (ZWC), a water-soluble succinylated chitosan derivative, has anti-inflammatory activities with therapeutic effects on sepsis and colitis. However, it remains unknown whether ZWC has any influence on skin inflammation. Here, we investigated the role of ZWC in the tape-stripping-induced acute skin inflammation model. Topical application of ZWC to the wounded area significantly reduced skin lesion compared with PBS controls. Since tape-stripping-induced skin inflammation is mediated by neutrophils, we examined if ZWC has any suppressive effects on neutrophil's function. ZWC treatment downregulated the skin recruitment of neutrophils, subsequently reducing inflammatory responses by keratinocytes. ZWC also suppressed LPS-induced inflammatory responses of neutrophils in vitro, indicating a direct effect of ZWC on neutrophils. Moreover, such anti-inflammatory effects of ZWC extended to other immune cells such as basophils in the spleen. Overall, our results support that ZWC may be used as a therapeutic material to control acute skin inflammation.
Role of pharmacokinetic consideration for the development of drug delivery systems: A historical overview
2020, Advanced Drug Delivery Reviews
Citation Excerpt :
Due to this anatomical nature of the liver which offers a wide surface area available for electrostatic interaction, cationic macromolecules such as poly l-lysine, cationized bovine serum albumin (BSA), diethylaminoethylated dextran with a molecular weight of 70 kDa highly distribute to the liver based on adsorption on the negatively charged cell surface [46,47]. On the other hand, strongly anionic macromolecules such as dextran sulfate and succinylated anionic BSA are taken up by thehepatic nonparenchymal cells via scavenger receptor-mediated endocytosis [48]. Saturation of uptake processes is also demonstrated for hepatic uptake of both cationic and strongly anionic polymers at doses of 1 mg/kg and 100 mg/kg.
Drug delivery system is defined as a system or technology to achieve optimum therapeutic effects of drugs through precise control of their movements in the body. In order to optimize function of drug delivery systems aiming at targeting, their whole-body distribution profiles should be systematically evaluated and analyzed, where pharmacokinetic analysis based on the clearance concepts plays important role. Organ perfusion experiments combined with statistical moment analysis further supply detailed information on drug disposition at organ and cellular levels. Based on general relationship between physicochemical properties and distribution profile, macromolecular prodrugs or polymer conjugates of proteins are rationally designed and further introduction of ligand structure brings cell-specific delivery for them. These approaches are also applicable for particulate carriers such as liposomes and offer various opportunities for biological drugs such as nucleic acid drugs for their delivery. Mechanistic approach for dermal absorption analysis based on physiological skin model offers another opportunity in rational design of drug delivery. Potential of drug delivery technology in future medicines such as cell therapy and nanomaterial platform application is further discussed in relation to pharmacokinetic consideration.
Geometry and surface characteristics of gold nanoparticles influence their biodistribution and uptake by macrophages
2011, European Journal of Pharmaceutics and Biopharmaceutics
Citation Excerpt :
The reduced uptake of spherical particles in the presence of serum suggests that their uptake is opsonin-independent and is probably through direct recognition by scavenger receptors. It is known that scavenger receptors recognize anionic particles and facilitate uptake by the RES [50–52]. Negatively charged spherical particles can potentially bind to available cationic sites on the macrophage surface and be recognized by scavenger receptors while adsorption of proteins on their surface may alter their overall charge, prevent such interaction and result in fewer uptake.
Spherical and rod-shaped gold nanoparticles with surface poly(ethylene glycol) (PEG) chains were characterized for size, shape, charge, poly dispersity and surface plasmon resonance. The nanoparticles were injected intravenously to 6–8-week-old female nu/nu mice bearing orthotopic ovarian tumors, and their biodistribution in vital organs was compared. Gold nanorods were taken up to a lesser extent by the liver, had longer circulation time in the blood, and higher accumulation in the tumors, compared with their spherical counterparts. The cellular uptake of PEGylated gold nanoparticles by a murine macrophage-like cell line as a function of geometry was examined. Compared to nanospheres, PEGylated gold nanorods were taken up to a lesser extent by macrophages. These studies point to the importance of gold nanoparticle geometry and surface properties on transport across biological barriers.
Fetuin mediates hepatic uptake of negatively charged nanoparticles via scavenger receptor
2007, International Journal of Pharmaceutics
We tried to evaluate the possible involvement of fetuin in the scavenger receptors (SRs)-mediated hepatic uptake of polystyrene nanospheres with the size of 50 nm (NS-50), which has surface negative charge (zeta potential = −21.8 ± 2.3 mV). The liver perfusion studies in rats revealed that the hepatic uptake of NS-50 pre-coated with fetuin (NS-50-fetuin) was significantly inhibited by poly inosinic acid (poly I), a typical inhibitor of SRs, whereas that of plain NS-50 or NS-50 pre-coated with BSA (NS-50-BSA) was not. The uptake of NS-50-fetuin by cultured Kupffer cells was also significantly inhibited by poly I, and anti-class A scavenger receptors (SR-A) antibody, suggesting that fetuin on NS-50 mediated the recognition and internalization of NS-50 by Kupffer cells and at least SR-A would be responsible for the uptake. Taken that Western blot analysis confirmed that fetuin certainly adsorbed on the surface of NS-50 after the incubation of NS-50 with serum, the results obtained in the present study indicate that fetuin would be one of the serum proteins that were substantially involved in the hepatic uptake of NS-50 via SRs.

View all citing articles on Scopus

^a: Present address: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607 (Japan).

^b: Present address: Faculty of Pharmaceutical Sciences, Set sunan University, Osaka 573-01 (Japan).

View full text

Pharmacokinetics of succinylated proteins and dextran sulfate in mice: Implications for hepatic targeting of protein drugs by direct succinylation via scavenger receptors

Abstract

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Pharmacol.

Int. J. Appl. Radiat Isot.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Int. J. Pharm.

Biochem. Biophys. Res. Commun.

J. Pharm. Sri.

J. Pharm. Sci.

J. Biol. Chem.

Mechanism of inhibitory effect of dextran sulfate and heparin on replication of human immunodeficiency virus in vitro

Rabbit aortic smooth muscle cells express inducible macrophage scavenger receptor messenger RNA that is absent from endothelial cells

J. Clin. Invest.

Clearance of acetylated low density protein by liver endothelial cells: Implications for hepatic cholesterol metabolism

J. Biol. Chem.

Pharmacokinetics of the monoclonal antibody B72.3 and its fragments labeled with either 125I and 125In

Cancer Res.

The scavenger receptor cell pathway for lipoprotein degradation: Specificity of the binding site that mediates the uptake of negatively-charged LDL by macrophages

J. Supermol. Struct.

Specific immunosuppresion by immunotoxins containing daunomycin

Science

Pharmacokinetics of the monoclonal antibody B72.3 and its fragments labeled with either ¹²⁵I and ¹²⁵In