Preparation and Characterization of Polyethylene-Glycol-Modified Salmon Calcitonins

Lee, Kang Choon; Tak, Kyung Kook; Park, Myung Ok; Lee, Jung Tae; Woo, Byung Ho; Yoo, Sun Dong; Lee, Hye Suk; DeLuca, Patrick P.

doi:10.1081/pdt-100101361

Cited by 40 publications

(18 citation statements)

References 13 publications

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“…To reduce metabolism, a linear lys-18-PEG 2K -sCT displayed enzymatic stability, reduced systemic clearance and enhanced hypocalcaemia following intra-duodenal administration to rats [34]. Another sCT-mPEG conjugate with mono-and di-mixtures also had reduced clearance and an extended T 1/2 compared to unmodified sCT [35]. For the sCT-Lys 18 -PEG conjugates, increased proteolytic stability and an extended T 1/2 are clearly associated with increased PEG MW [36].…”

Section: Discussionmentioning

confidence: 99%

PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights

Ryan

Frías²,

Wang

et al. 2011

Journal of Controlled Release

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Salmon calcitonin (sCT) was conjugated via cysteine-1 to novel combed-shaped endfunctionalised poly(PEG) methyl ether methacrylate) (sCT-P) comb-shaped polymers, to yield conjugates of total molecular weights (MW) inclusive of sCT: 6.5, 9.5, 23 and 40 kDa. The conjugates were characterised by HPLC and their in vitro and in vivo bioactivity was measured by cAMP assay on human T47D cells and following intravenous (i.v.) injection to rats, respectively. Stability against endopeptidases, rat serum and liver homogenates was assessed. There were linear and exponential relationships between conjugate MW with potency and efficacy respectively, however the largest MW conjugate still retained 70% of E max and an EC 50 of 3.7 nM. In vivo, while free sCT and the conjugates reduced serum [calcium] to a maximum of 15-30 % over 240 min, the half life (T½) was increased and the area under the curve (AUC) was extended in proportion to conjugate MW. Likewise, the polymer conferred protection on sCT against attack by trypsin, chymotrypsin, elastase, rat serum and liver homogenates, with the best protection afforded by sCT-P (40 kDa). Mathematical modelling accurately predicted the MW relationships to in vitro efficacy, potency, in vivo PK and enzymatic stability. With a significant increase in T½ for sCT, the 40 kDa MW comb-shaped PEG conjugate of sCT may have potential as a long-acting injectable formulation.

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Section: Discussionmentioning

confidence: 99%

PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights

Ryan

Frías²,

Wang

et al. 2011

Journal of Controlled Release

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“…It has demonstrated reduced immunogenicity, extended circulating half-life, and improved stability for these therapeutic agents. 1,2 PEGylated molecules are among the most challenging products to characterize because of the heterogeneity with respect to distribution in both the number and position of the attached PEG molecules, and the inherent polydispersity of PEG itself. 3 When developing PEGylated biomolecules as therapeutic agents, various points should be considered including characterization of starting materials (protein and PEG molecule), determination of PEGylation sites, and stoichiometry of PEG attachment.…”

mentioning

confidence: 99%

Optimization of the PEGylation process of a peptide by monitoring with matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry

Youn

Lee

2003

Rapid Comm Mass Spectrometry

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“…[15][16][17] Furthermore, it has been reported that hydrogel having PEG chain on its surface shows the mucoadhesive ability by interaction with mucosa. 18) In this study, we investigated the effect of PEGylating polycations on their permeation enhancement to develop superior absorption enhancers.…”

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confidence: 99%

Preparation and Evaluation of PEGylated Poly-L-ornithine Complex as a Novel Absorption Enhancer

Kamiya

Yamaki

Uchida

et al. 2017

Biological & Pharmaceutical Bulletin

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Polycationic compounds, such as poly-L-arginine and poly-L-ornithine (PLO), enhance the nasal absorption of hydrophilic macromolecular drugs. However, the bio availability corresponding to the dose of these enhancers has not been obtained in an open system study, where an administered solution is transferred to the pharynx because they do not exhibit mucoadhesion/retention in the nasal cavity. In this study, we prepared PEGylated-poly-L-ornithine (PEG-PLO) and investigated the effects of PEGylation on in vitro adhesion/retention properties, permeation enhancement efficiency, and cytotoxicity. PEG-PLO bearing 3-4 polyethylene glycol (PEG) chains per PLO molecule was more retentive than unmodified PLO on an inclined plate. The permeability of a model drug, FD-4, across Caco-2 cell sheets was enhanced by PEG-PLO as well as by PLO. PLO showed cytotoxicity at high concentrations, whereas PEG-PLO did not decrease cell viability, even above the concentration giving a sufficient enhancement effect. These findings suggest that PEGylation of polycationic absorption enhancers improves their adhesion/retention and decreases their cytotoxicity, which may lead to enhancers with greater utility.Key words poly-L-ornithine (PLO); polyethylene glycol (PEG); permeation enhancer Bioactive peptides, such as insulin, teriparatide, liraglutide, and somatropin, have been used widely as therapeutic drugs because of their intrinsic and effective activities, however, they have poor permeability across the epithelium because they are hydrophilic macromolecules. Orally administered peptides are often inactivated in the gastrointestinal tract, and thus peptides are usually administered as injectable formulations. However, injection can result in poor compliance because it is painful and burdensome. 1) Therefore, alternative routes of administration are required.The nasal mucosa has a large surface area for absorption because of its villus structure. Drugs absorbed across the nasal mucosa avoid the hepatic first pass effect because of the abundant vasculature under the nasal mucosa.2) The intranasal route is effective for absorbing high molecular weight drugs 3) and is usually not painful. Therefore, intranasal administration is an important alternative route to injection for peptides and proteins.Polycationic compounds, such as poly-L-arginine (PLA), poly-L-lysine, and poly-L-ornithine (PLO), enhance the transmucosal absorption of hydrophilic macromolecules.4,5) PLA enhances the paracellular permeability of rabbit nasal mucosa and Caco-2 cell sheets reversibly.6,7) The absorption of hydrophilic macromolecules across the nasal mucosa in rats is also increased by co-administration with PLA. 8) PLA enhances the permeability by altering the localization of tight junction proteins from the cell-cell junction to the intracellular space without causing cytotoxicity. 9) Therefore, polycationic absorption enhancers are useful in developing efficient transmucosal drug delivery systems.Nevertheless, it is difficult to increase the bioavailability of dr...

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Preparation and Characterization of Polyethylene-Glycol-Modified Salmon Calcitonins

Cited by 40 publications

References 13 publications

PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights

PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights

Optimization of the PEGylation process of a peptide by monitoring with matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry

Preparation and Evaluation of PEGylated Poly-L-ornithine Complex as a Novel Absorption Enhancer

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