Polyethylene Glycol Modification of Filgrastim Results in Decreased Renal Clearance of the Protein in Rats

Yang, Bing‐Bing; Lum, Peggy; Hayashi, Mike; Roskos, Lorin

doi:10.1002/jps.20024

Cited by 81 publications

(77 citation statements)

References 13 publications

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“…6) Several research groups have shown that the in vivo half-life and activity of rhG-CSF or its mutant can be increase by PEG conjugation using several different conjugation chemistry strategies. 9,16,[25][26][27][28][29][30][31] The results of conjugation between target therapeutic proteins and PEG, such as, the extent of modification, molecular weight, the structure of the PEG moiety (linear or branched), and the locations of PEG attachment, importantly affect in vitro biological activity and pharmacological properties. 6,32,33) It has been well established that inverse relationships exist between in vitro biological activity and the average molecular weights of PEG and the number of PEG units, whereas positive relationships exist between in vivo pharmacokinetics and pharmacodynamics and these average molecular weights.…”

Section: -Mono-pegylated Rhg-csf Positional Isomersmentioning

confidence: 99%

<i>In Vivo</i> Pharmacokinetics and Pharmacodynamics of Positional Isomers of Mono-PEGylated Recombinant Human Granulocyte Colony Stimulating Factor in Rats

Kang

Lee

2013

Biological & Pharmaceutical Bulletin

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Key words random PEGylation; covalent conjugation; individual positional isomer; in vitro biological activity; blood half-life PEGylation describes the chemical modification of therapeutic proteins by covalent conjugation with polyethylene glycol (PEG), a non-toxic, non-immunogenic polymer that is approved by U.S. Food and Drug Administration (FDA) for parental administration, that is used as a strategy to overcome the disadvantages associated with therapeutic proteins with a short half-life due to rapid clearance from the body.

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Section: -Mono-pegylated Rhg-csf Positional Isomersmentioning

confidence: 99%

<i>In Vivo</i> Pharmacokinetics and Pharmacodynamics of Positional Isomers of Mono-PEGylated Recombinant Human Granulocyte Colony Stimulating Factor in Rats

Kang

Lee

2013

Biological & Pharmaceutical Bulletin

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“…A new form of Filgrastim, modified by the addition of PEG, has been produced. A single dose of Pegfilgrastim results in sustained drug concentration in serum [17,20,22] thanks to the poly(ethylene glycol) modification of Filgrastim that causes decreased renal clearance of the protein [36]. Molineux et al [15] demonstrated that a single injection of Pegfilgrastim produced significantly elevated neutrophil counts for 5 days in hematologically normal mice or for 9 to 10 days in normal human volunteers.…”

Section: Infectionsmentioning

confidence: 99%

Pegfilgrastim compared with Filgrastim after autologous hematopoietic peripheral blood stem cell transplantation

Vanstraelen¹,

Frère²,

Ngirabacu

et al. 2006

Experimental Hematology

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“…PEGylation of small proteins, peptides, and oligonucleotides, has also become an increasingly common method of improving the half-life of biological products, mainly through reducing the urinary excretion of the molecule [3].…”

Section: General Mechanisms Of Peg-mediated Np Actionmentioning

confidence: 99%

Nanoparticle PEGylation for Cancer Therapy

Moffatt¹

2015

MOJPB

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Currently, there are more than 35 US FDA-approved NPs utilizing PEG in their biomedical applications. PEGylation, which is the addition of PEG to the NP formulation, provides immunity from the hostile biological environment. The 'stealth' property, further confers on the PEG-NP formulation benefits that are not normally provided by other polymers. This mini-review briefly describes the mechanisms of action, as well as the benefits and challenges of PEG and PEGylation in cancer therapy. General Mechanisms of PEG-Mediated NP ActionUpon administration, NPs are recognized and cleared from circulation by the phagocytes from the reticuloendothelial system (RES). The circulation time of the NPs is largely determined by their surface structure and their hydrophilicity/ hydrophobicity state that governs the amounts of opsonins absorbed. The process of opsonization (opsonin-NP binding) reduces the circulation time of the NPs. Reports indicate that the PEG polymer on the NP surface increases the circulation time by reducing this opsonization process, thereby preventing recognition by monocytes and macrophages, allowing the NPs to remain longer in the blood pool [1]. In addition to NP-RES interactions, poor circulation times can also arise from NP-NP interactions, where NPs with a high surface energy have a greater tendency to aggregate as described by the DerjaguinLandau-Verwey-Overbeek (DLVO) theory [2].PEGylation of small proteins, peptides, and oligonucleotides, has also become an increasingly common method of improving the half-life of biological products, mainly through reducing the urinary excretion of the molecule [3].Many other successful experimental assays depend on the ability to re-engineer the solubility, size, and other properties of drugs, peptides or proteins, in their interactions with PEG in an effort to increase the resident time in circulation. PEGylation, if empirically researched on, would become a very useful method of making these modifications. Benefits and Challenges of NP Applications of PEGThe maor benefits from the use of PEG in NP formulations derives from its "stealth' properties, as well as the increase in circulation times for the NP conjugates. Clearly, the addition of PEG to the NP formulation increases the retention and circulation time by reducing uptake by opsonins in the RES. It was reported previously that particles remained in rat circulation 40-times longer when coated than uncoated with PEG [4]. Additionally, incorporation of dioleoyl N-(monomethoxy polyethylene glycol succinyl) phosphotidylethanolamine (PEG-PE) into posphatidylcholine:cholesterol liposomes (1:1) increased the retention time from thirty minutes to five [5]. By virtue of the fact that PEG is hydrophilic, the serum and other solvent solubility also increases, further enhancing the circulation time. These merits also result in higher targeted and accumulated PEGylated NPs than non-PEGylated counterparts.

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Polyethylene Glycol Modification of Filgrastim Results in Decreased Renal Clearance of the Protein in Rats

Cited by 81 publications

References 13 publications

<i>In Vivo</i> Pharmacokinetics and Pharmacodynamics of Positional Isomers of Mono-PEGylated Recombinant Human Granulocyte Colony Stimulating Factor in Rats

<i>In Vivo</i> Pharmacokinetics and Pharmacodynamics of Positional Isomers of Mono-PEGylated Recombinant Human Granulocyte Colony Stimulating Factor in Rats

Pegfilgrastim compared with Filgrastim after autologous hematopoietic peripheral blood stem cell transplantation

Nanoparticle PEGylation for Cancer Therapy

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