Anti-Fouling/Non-Fouling Surfaces

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When is the non-specific adsoptionundesirable?

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Non-Fouling Surface Compositions

Synthetic Hydrophilic Surfaces

PEG Polymers, Hydrogels and Adsorbed Surfactants

PEG, PEG-HG, PEG-PU, Pluronics.Neutral Polymers: PHEMA; PVP etc.Phosphoryl Choline Polymers.

Zwitterion polymersGas discharge deposited coating.

Tetraglyme, PEG Surfactants, Vinyl (EG)2

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Non-Fouling Surface CompositionsNatural Hydrophilic Surfaces

Passivating Protein Monolayers:Eg: Albumin, Casein.

Polysaccharides:Eg: Dextran, Hyaluronic Acid.

Glycoproteins:Eg: Mucins.

Phosphoryl Choline Polymers.Zwitterion polymers

Liposaccharides:Eg: Gangliosides. Used as Stealth Liposomes

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Non-Fouling Surface Compositions

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Where did the idea of PEGlyatingsurfaces come from?

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The need for PEGylation

The Novel Proteins and Peptides have become important

new drugs with advent of a revolution in Biotechnology.

More than 80 Poly Peptide Drugs are marketed in The

U.S.

More than 350 Proteins and Peptides are

undergoing clinical trails right now.

About a third of Drug candidates in clinical trails are

Poly peptides.

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The purpose of PEGylation

To Improve drug solubility

To Reduce dosage frequency, without diminished efficacy with

potentially reduced toxicity

To Extend circulating life

To Increase drug stability

To Enhance protection from proteolytic degradation

Opportunities for new delivery formats and dosing regimens

To Extend patent life of previously approved drugs

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How does the PEGs Work?PEGylation increases the half-life of the biomolecule in the body via

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Reducing Kidney Filtration

•PEGylation significantly increases the apparent size of the conjugated drug compound

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Method for the activation of PEG molecules

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Conjugation Chemistry

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Conjugation Chemistry

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In Protein Drug Delivery:

PEGASYS: PEGylated alpha-interferons for use in the treatment of

chronic hepatitis C and hepatitis-B(Hoffman-La Rochen)

ADAGEN: receivedapproval for the treatment of severe combined

immunodeficiency(SCID), a disease associated with an inherited

deficiency of adenosine deaminase36.

PEG-Intron: PEGylated alpha-interferons for use in the treatment of

chronic hepatitis C and hepatitis B(Schering-Plough / Enzon)

Oncaspar: PEGylated L-asparaginase for the treatment of acute

lymphoblastic leukemia in patients who are hypersensitive to the native

unmodified form of L-asparaginase (Enzon).

Neulasta: PEGylated recombinant methionyl human granulocyte

colony stimulating factor for severe cancer chemotherapy-induced

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Pegfilgrastim (Neulasta), which was approved in 2002, is a pegylated

form of the earlier drug filgrastim (Neupogen). Both contain

recombinant methionyl human G-CSF,which is known as filgrastim.

The drugs stimulate the production of the infection fighting white

blood cells (neutrophils) that are depleted by cancer chemotherapy.

Whereas filgrastim requires daily injections for about 14 days,

pegfilgrastim requires one injection per chemotherapy cycle.

A pegylated form of human growth hormone antagonist called

pegvisomant (Somavert) is being developed for the treatment of

ACROMEGALY.

Pegvisomant has been approved in Europe, and is awaiting FDA

approval in the US.

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Are There Special Properties to PEG That are Important to its ActionAs a Non-Fouling Surface Composition?

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DSC showing two endothermic peaksAfter freezing and slowly thawing.

Note that the peaks are sensitive to The MW of PEG.

Poly(Ethylene Glycol) chemistry: Biotechnical and Biomedical Applications, J. M. Harris, Ed., Plenum, New York, 1992

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How to Immobilize PEG on Surfaces

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Nagaoka et al 1983

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Is there a critical MW below which PEG loses its anti-fouling character?

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Protein(Radius R)

Water

End-on attachedPEG chains(length l)

D

Model by Jeon et al.

Gombotz and Hoffman 1993

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How can one get a high surface density of PEGs if they have anExcluded volume and repel each other?

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“Glyme” Coatings

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