Bifunctional Multi-Arm PEG

4-Arm PEG-X/Y

Bifunctional 4-Arm PEG reagents have two functional groups X/Y with 1:3 ratio or 2:2 ratio. We started offering this series of special reagents as customs synthesis with the following combinations. We are also listing some of these reagents as regular catalog products that are ready to ship overnight.

We offer three ratios for each pair of functional groups. 1:3, 2:2 and 3:1. An example is listed below.

Amine(3)/Acid(1) – 3 amine groups and 1 acid group

Amine(2)/Acid(2) – 2 amine groups and 2 acid group

Amine(1)/Acid(3) – 1 amine groups and 3 acid group

8-Arm PEG-X/Y

Bifunctional 8-Arm PEG reagents have two functional groups X/Y with 1:7 ratio or 4:4 ratio. We started offering this series of special reagents as customs synthesis with the following combinations. We are also listing some of these reagents as regular catalog products that are ready to ship overnight.

We offer three ratios for each pair of functional groups. 1:7, 4:4 and 7:1. Other ratios may be also offered. An example is listed below.

Amine(1)/Acid(7) – 1 amine group and 7 acid groups

Amine(4)/Acid(4) – 4 amine groups and 4 acid groups

Amine(7)/Acid(1) – 7 amine groups and 1 acid group

Other pairs of functional groups include:

Amine/Biotin

Amine/Maleimide

Amine/Azide

Amine/Acrylamide

Amine/Thiol

Amine/Acid

Amine/FITC

Amine/Rhodamine

Biotin/Maleimide

Biotin/Azide

Biotin/Acid

Biotin/Thiol

Thiol/Acid

Maleimide/FITC

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Is Your Maleimide Thiol Chemistry Stable?

The typical PEG-maleimide-thiolreaction results in thiosuccinimide formation which is reversible, with PEG-maleimide elimination occurring slowly under biologically relevant conditions. The reversed reaction leads to the breakage of the maleimide-thiol linkage and the loss of PEG from the thiol/cysteine-containing molecules. If the maleimide-thiol chemistry does not work for your application, you may consider alternatives with much more stable bioconjugation.

Here are three examples:

  1. Carbonylacrylic PEG reagents as an improved alternative to PEG-maleimide. mPEG-Carbonylacrylic (mPEG-CA): Carbonylacrylic (CA) PEG reagents are for chemoselective cysteine bioconjugation and undergo rapid thiol Michael-addition under biocompatible conditions in stoichiometric amounts. Importantly, the conjugates formed between Carbonylacrylic PEG and thiol/cysteine-containing molecules are resistant to degradation in physiological conditions.
  2. PEG-Vinyl Pyridinium (PEG-VIP)reagents are a new class of thiol-selective PEGylation tools, and it offers an efficient and irreversible cysteine-selective bioconjugation method. The thiol selectivity and reactivity of the vinyl group is enabled by the quaternization of the nitrogen of the pyridine group, making the vinyl pyridinium an extremely reactive electrophile towards thiols. Importantly, the conjugates formed are resistant towards thiol exchange reactions or degradation.
  3. Self-hydrolyzing maleimide: Many antibody-drug conjugates (ADCs) are unstable
    in vivo because they are formed from maleimide-containing components conjugated to reactive thiols. These thiosuccinimide linkages undergo two competing reactions in plasma: elimination of the maleimide through a retro-Michael reaction, which results in loss of drug-linker from the ADC, and hydrolysis of the thiosuccinimide ring, which results in a derivative that is resistant to the elimination reaction. Drug-linker incorporating a basic amino group adjacent to the maleimide, positioned to provide intramolecular catalysis of thiosuccinimide ring hydrolysis. This basic group induces the thiosuccinimide to undergo rapid hydrolysis at neutral pH and room temperature. Once hydrolyzed, the drug-linker is no longer subject to maleimide elimination reactions, preventing nonspecific deconjugation.
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The Case for Protein PEGylation

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The Case for Protein PEGylation

A recent review article discussed in details the current status and future prospect of protein pegylation.

FDA approved pegylated drugs 2018

source: sciencedirect.com

 

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Biodegradable PEG Dendrimers

Creative PEGWorks is now offering a series of PEG Dendrimers with biodegradable building blocks. Dendrimers are functionalized with amine, acid, azide etc.

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FDA Latest Industry Guidance for Liposome Drug Products

Creative PEGWorks

Liposome Drug Products
Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation
It provides specific labeling requirements for liposome versus pegylated liposome.
The nonproprietary name of a drug product approved under the Federal Food, Drug, and Cosmetic Act is its established name, which , in most instances , will be the United States
Pharmacopeia (USP) drug product monograph title for that product. If there is no USP monograph for the liposome drug product, you should refer to 21 CFR 299.4, USP General
Chapter <1121> Nomenclature, and the USP Nomenclature Guidelines. The liposome drug product nonproprietary name should include terminology to express that the product is a liposome or a pegylated liposome. Examples:
[DRUG] Liposome Type X [DOSAGE FORM]
[DRUG] Pegylated Liposome Type X [DOSAGE FORM]

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Marketed PEGylated Drugs Approved by FDA and in Europe

via Marketed PEGylated Drugs Approved by FDA and in Europe

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Marketed PEGylated Drugs Approved by FDA and in Europe

Creative PEGWorks

An excellent review article is published by scientists from Nektar Therapeutics, Bayer, Jansen, and Baxalta Innovations GmbH in the journal of Journal of Pharmaceutical Sciences.

Journal of Pharmaceutical Sciences 105 (2016) 460-475
Since 1990, 12 PEGylated biopharmaceuticals have been introduced into the market place as drugs for human use (Table 1).Eleven are PEGylated protein biopharmaceuticals and one is aPEGylated aptamer (Macugen) administered intravitreally. Adagen®, Krystexxa®,
Neulasta®, Oncaspar®, PEG-Intron®, Somavert®, and Plegridy® are PEGylated with PEG molecules having molecular weight of 5-20kDa. Cimzia®, Macugen®, Mircera®, Omontys®, and Pegasys®are PEGylated with PEG molecules of 30 or 40 kDa.
Marketed PEGylated Drugs

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Looking for a better method to improve your PEGylation yield?

Are you looking for a better way to improve your PEGylation yield? I bet you are. Keep reading then……..

Many parameters affect PEGylation process. The surface accessibility of the reactive site of amino acids is the most critical. On protein surfaces, there exist hydrophobic patches and concaves that expel water and thus hydrophilic PEGs. Reactive sites such as cysteine residues can be buried inside the hydrophobic domains. This makes the PEGs hardly contact the free thiols. It has to contact to react. Improving the surface accessibility of reactive sites such as cysteine residues is demonstrated to improve PEGylation efficiency. How to achieve this?

The answer is to temporarily unfold protein structures such as changing pH values, ionic strength or even externally applied stress, all of which could potentially change the protein conformation to allow PEGylation, followed by re-forming the native 3D structure.

Just be smart, and sometimes a bit crazy to try different things. A paper in one ACS journal of Bioconjugate Chemistry doi: 10.1021/acs.bioconjchem.7b00531 solved this problem by applying high pressure to the PEGylation process. At 250 mega-pascals, 90% of protein human ciliary neurotrophic factor (CNTF) was PEGylated without using excess of PEG reagents, which normally have to be used to achieve even a low degree such as 5-10% of PEGylation. Upon PEGylation, the protein reversibly refolds.

Go ahead to try it.

Looking for a better method to improve your PEGylation yield?

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FDA Latest Industry Guidance for Liposome Drug Products

Liposome Drug Products
Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation
It provides specific labeling requirements for liposome versus pegylated liposome.
The nonproprietary name of a drug product approved under the Federal Food, Drug, and Cosmetic Act is its established name, which , in most instances , will be the United States
Pharmacopeia (USP) drug product monograph title for that product. If there is no USP monograph for the liposome drug product, you should refer to 21 CFR 299.4, USP General
Chapter <1121> Nomenclature, and the USP Nomenclature Guidelines. The liposome drug product nonproprietary name should include terminology to express that the product is a liposome or a pegylated liposome. Examples:
[DRUG] Liposome Type X [DOSAGE FORM]
[DRUG] Pegylated Liposome Type X [DOSAGE FORM]
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