Covalent linkage of carboxypeptidase G2 to soluble dextrans—I

Melton, Roger G.; Wiblin, C.; Foster, R. L.; Sherwood, R.F.

doi:10.1016/0006-2952(87)90387-x

Cited by 49 publications

(8 citation statements)

References 20 publications

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“…It has been recognized that chemical conjugation of drugs with water-soluble polymers can modify the pattern of drug distribution in the body, resulting in not only an increase in therapeutic efficacy but also a decrease in side effects (Kaneo et al 1988;Melton et al 1987;Takakura et al 1987;Hashida et al 1990;Yoshimoto et al 1986;Bendich et al 1982;Ashihara et al 1978;Hershfield et al 1987;Przybyski et al 1978;Yamaoka et al 1993;Yamaoka et al 1994). The fate in the body of drug-polymer conjugates has been demonstrated to depend on their physicochemical and biological properties, such as molecular size, electric charge, and biological affinity of the conjugates Barrowcliffe et al 1990).…”

mentioning

confidence: 99%

Tumor accumulation of poly(ethylene glycol) with different molecular weights after intravenous injection

1997

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Body distribution of poly(ethy1ene glycol) (PEG) with different molecular weights (MWs) was investigated after intravenous injection into mice with a tumor mass of their back subcutis and footpad to evaluate the effect of PEG molecular weight on the tumor accumulation. PEG did not exhibit specific affinity for any organs and PEG with higher MW tended to remain in the blood circulation of tumor-bearing mice longer than PEG with lower MW, similarly to normal mice. PEG accumulated at the tumor tissue to a significantly higher extent than at the normal tissue, irrespective of the molecular weight and the tumor loading site. Such high tumor accumulation of PEG increased with an increase in the size of the tumor mass, leveling off at a certain size. This size dependence was in accord with that of the vasculature volume in the tumor tissue. Because PEG extravasates to the interstitial space of the tumor, the tumor accumulation seems to be governed mainly by the level of hyperpermeable vasculature. The PEG molecules accumulated at the tumor tissue were retained longer than those at the normal tissue. The tumor accumulation of PEG became maximal at MW around 200,000. A pharmacokinetic study demonstrated that the accumulation rate of PEG at the tumor tissue was higher than that at the normal tissue and decreased with increasing molecular weight. On the other hand, the higher the molecular weight of PEG, the longer the retention time in the blood circulation. It is likely that the balance between these two factors, the accumulation rate of PEG and the blood retention, results in maximal accumulation of PEG with a medium molecular weight.

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confidence: 99%

Tumor accumulation of poly(ethylene glycol) with different molecular weights after intravenous injection

1997

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“…The threshold for renal clearance of dextran is ∼40 kDa, as indicated by studies of both unconjugated dextran as well as fluorescein–dextran conjugates . Studies of carboxypeptidase–dextran conjugates in tumor‐bearing Balc/c mice showed that elimination of dextran is size‐dependent, with conjugates containing large dextran moieties exhibiting the longest half‐life . This notion was further supported by PK studies of fluorescein–dextran conjugates in rats .…”

Section: Carbohydrate Polymersmentioning

confidence: 88%

“…[33] Studies of carboxypeptidase-dextran conjugates in tumor-bearing Balc/c mice showedt hat elimination of dextrani ss ize-dependent, with conjugates containingl arge dextran moieties exhibiting the longest halflife. [34] This notion was furthers upported by PK studies of fluorescein-dextran conjugates in rats. [24, 33b] Gel filtration studies of the fluorescein-dextran conjugates demonstrated al inear relationship between dextran size and column retention time, with larger dextransd isplaying shorterr etention times.…”

Section: Dextran Conjugationmentioning

confidence: 96%

“…Other examples include dextran conjugates of asparaginase, carboxypeptidase G 2 , and hemoglobin, respectively, as well as CMD‐insulin conjugates …”

Section: Carbohydrate Polymersmentioning

confidence: 99%

“…The improved PK profile and the increased resistance toward H 2 O 2 inactivation further translated into improved pharmacological properties of the SOD-dextran conjugate, as visualized by ac arrageenan-induced paw edema test. [32b] Other examples include dextran conjugates of asparaginase, [45] carboxypeptidase G 2 , [34,46] andh emoglobin, [47] respectively,asw ell as CMD-insulin conjugates. [48]…”

Section: Dextran Conjugationmentioning

confidence: 99%

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Half‐Life Extension of Biopharmaceuticals using Chemical Methods: Alternatives to PEGylation

2016

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Peptides and proteins constitute a vast pool of excellent drug candidates. Evolution has equipped these molecules with superior drug-like properties such as high specificity and potency. However, native peptides and proteins suffer from an inadequate pharmacokinetic profile, and their outstanding pharmacological potential can only be realized if this issue is addressed during drug development. To overcome this challenge, a variety of half-life extension techniques relying on covalent chemical modification have been developed. These methods include PEGylation, fusion to unstructured polypeptide-based PEG mimetics, conjugation of large polysaccharides, native-like glycosylation, lipidation, fusion to albumin or the Fc domain of IgG, and derivatization with bio-orthogonal moieties that direct self-assembly. This review provides an overview of available conjugation chemistries, biophysical properties, and safety data associated with these concepts. Moreover, the effects of these modifications on peptide and protein pharmacokinetics are demonstrated through key examples.

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Pegylation: Camouflage of Proteins, Cells, and Nanoparticles Against Recognition by the Body's Defense Mechanism

Cho¹,

Park²,

Park³

et al. 2010

Pharmaceutical Sciences Encyclopedia

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Polyethylene glycol (PEG) is becoming a standard polymer for chemical modification of proteins and peptides to enhance their pharmaceutical properties. PEGylation is increasingly used for attaching PEG to various objects, such as peptides, proteins, cells and other biologically active materials. This article focuses on pegylation of proteins, which has brought numerous clinically useful products and triggered explosive interest in polymers in the field of pharmaceutical biotechnology.

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Covalent linkage of carboxypeptidase G2 to soluble dextrans—I

Cited by 49 publications

References 20 publications

Tumor accumulation of poly(ethylene glycol) with different molecular weights after intravenous injection

Tumor accumulation of poly(ethylene glycol) with different molecular weights after intravenous injection

Half‐Life Extension of Biopharmaceuticals using Chemical Methods: Alternatives to PEGylation

Pegylation: Camouflage of Proteins, Cells, and Nanoparticles Against Recognition by the Body's Defense Mechanism

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