Rational Design of a Potent, Long-Lasting Form of Interferon:  A 40 kDa Branched Polyethylene Glycol-Conjugated Interferon α-2a for the Treatment of Hepatitis C

Bailon, Pascal; Palleroni, Alicia V.; Schaffer, Carol A.; Spence, Cheryl; Fung, Wen-Jian; Porter, Jill E.; Ehrlich, G.; Pan, Wen; Xu, Zhixin; Modi, Marlene; Farid, and Adrienne; Berthold, Wolfgang; Graves, Mary C.

doi:10.1021/bc000082g

Cited by 585 publications

(429 citation statements)

References 25 publications

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“…A well-cited example is PEGylated interferon α-2a (Pegasys®, Roche, USA). The 40 kDa branched PEG conjugate retained only 7% of the antiviral activity of the native protein, but still displayed improved PK following weekly injections in vivo in hepatitis C patients [33]. In contrast, bioactivity analysis from the T47D cAMP assay indicated that the potency and efficacy of sCT-P of increasing MW compared well to native sCT, with sCT-P (40 kDa) retaining 72% of the maximum bioactivity.…”

Section: Discussionmentioning

confidence: 92%

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: 92%

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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show abstract

“…Pegylation has been shown to improve the pharmacokinetics of proteins, polymers and small molecules (18)(19)(20)(21). Conjugation of hydrophilic PEG onto polymers hinders the adsorption of opsonins, preventing their recognition by the reticuloendothelial system (RES) (22).…”

Section: Introductionmentioning

confidence: 99%

Contrast-Enhanced MRI-Guided Photodynamic Cancer Therapy with a Pegylated Bifunctional Polymer Conjugate

et al. 2008

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Purpose-To study contrast-enhanced MRI guided photodynamic therapy with a pegylated bifunctional polymer conjugate containing an MRI contrast agent and a photosensitizer for minimally invasive image-guided cancer treatment.Methods-Pegylated and non-pegylated poly-(L-glutamic acid) conjugates containing mesochlorin e 6 , a photosensitizer, and Gd(III)-DO3A, an MRI contrast agent, were synthesized. The effect of pegylation on the biodistribution and tumor targeting was non-invasively visualized in mice bearing MDA-MB-231 tumor xenografts with MRI. MRI-guided photodynamic therapy was carried out in the tumor bearing mice. Tumor response to photodynamic therapy was evaluated by dynamic contrast enhanced MRI and histological analysis.Results-The pegylated conjugate had longer blood circulation, lower liver uptake and higher tumor accumulation than the non-pegylated conjugate as shown by MRI. Site-directed laser irradiation of tumors resulted in higher therapeutic efficacy for the pegylated conjugate than the nonpegylated conjugate. Moreover, animals treated with photodynamic therapy showed reduced vascular permeability on DCE-MRI and decreased microvessel density in histological analysis.Conclusions-Pegylation of the polymer bifunctional conjugates reduced non-specific liver uptake and increased tumor uptake, resulting in significant tumor contrast enhancement and high therapeutic efficacy. The pegylated poly(L-glutamic acid) bifunctional conjugate is promising for contrast enhanced MRI guided photodynamic therapy in cancer treatment.

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“…The PEG-IFN-α 2b (12 kDa) is more rapidly absorbed (with an absorption half-life of 4.6 h), presents a wide volume of body distribution (approximately 0.99 L/ kg) and a mean elimination time of 40 h. However, PEG-IFN-α 2a (40 kDa) is absorbed more slowly (absorption half-life, 50 h), its distribution is restricted to well-vascularized organs with good perfusion, such as the liver, and it remains detectable in the serum for one week (approximately 65 h elimination half-life) [6,12,13].…”

Section: Pharmacological Characteristics Of the Pegylated Interferonsmentioning

confidence: 99%

Basic aspects of the treatment for hepatitis C: mechanisms of action of interferon alpha and ribavirin and the bases of individualization

2007

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Rational Design of a Potent, Long-Lasting Form of Interferon: A 40 kDa Branched Polyethylene Glycol-Conjugated Interferon α-2a for the Treatment of Hepatitis C

Cited by 585 publications

References 25 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

Contrast-Enhanced MRI-Guided Photodynamic Cancer Therapy with a Pegylated Bifunctional Polymer Conjugate

Basic aspects of the treatment for hepatitis C: mechanisms of action of interferon alpha and ribavirin and the bases of individualization

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