The Benefits and Challenges of PEGylating Small Molecules - Pharmaceutical Technology

Latest Issue
PharmTech

Latest Issue
PharmTech Europe

  • Search
  • Suppliers
  • Careers

Enter a company or product name

KeywordLocation
About Search
The Benefits and Challenges of PEGylating Small Molecules
Polyethylene glycol (PEG) conjugation is a highly effective technical and commercial strategy to develop macromolecules. The authors explain the benefits and process of PEGylation and how it may be applied to small molecules.
Jul 2, 2008
By: Timothy Riley, Jennifer Riggs-Sauthier
Pharmaceutical Technology

12345
Next »

A versatile technology based on repeating units of polyethylene glycol (PEG), known as PEGylation, was first described in the literature in 1977 (1). PEG is a water-soluble, amphiphilic, nontoxic, and nonimmunogenic compound. It is safely cleared from the body and is currently a component of seven approved macromolecular drugs administered parenterally. Although the primary use of PEGylation has been to improve the physicochemical properties of large molecules, it may also be used with small molecules, provided certain challenges are met.


STOCKBYTE/GETTY IMAGES
Small molecules have few sites to which PEGs can be attached without compromising their functionality. In addition, small molecules generally are delivered orally, and formulators believed that PEGylation would compromise oral bioavailability. These challenges have heretofore prevented the technology from being tried successfully on small molecules. A large-PEG prodrug approach to small-molecule PEGylation was unsuccessful. The strategy of permanently attaching a small PEG to a small molecule is unteseted and counterintuitive because low molecular weights are generally favored. These challenges in PEGylating small molecules have been overcome, however.

PEGs can be designed with various pharmacokinetic-altering architectures. They can be synthesized as linear, branched, or forked structures with functional groups at one or more termini to enable several conjugation strategies. Linkers covalently attach the molecule to the parent drug directly or indirectly. The choice of linkers enables PEG to be placed in various positions on the molecule. Placement can fine tune a drug's pharmacokinetic properties and maintain its efficacy. Overall, PEGylated molecules demonstrate enhanced solubility and stability, on the shelf and in vivo, and an improved safety profile.


Table I: Potential benefits of PEG technology.
Conjugation bonds can be stable or releasable to create entirely new compounds or novel prodrugs. Stable PEG linkages create new pharmaceutical entities with respect to such pharmacokinetic parameters as circulating half life, clearance, absorption, and bioavailability. PEGs may harm the pharmacodynamic properties of target binding because of steric hindrance. The releasable attachments used in PEG prodrugs enable controlled drug release through the choice of architecture, attachment sites, and linker molecules.


Table II: PEGylated macromolecular drugs.
PEGylation imparts valuable, and in some cases crucial, pharmacokinetic properties to macromolecules, whether stable molecules or prodrugs, and has emerged as the dominant strategy for improving macromolecular drugs. PEGylation is associated with numerous clinical benefits in these drugs, including increased efficacy, decreased side effects, and lower frequency of dosing (see Table I). Table II shows the current, macromolecular PEG landscape. The technology is applicable to many therapeutic areas (e.g., oncology, metabolic diseases, and infectious diseases) and to various macromolecular classes (e.g., cytokines, antibodies, enzymes, and aptamers).

12345
Next »

ADVERTISEMENT

post a comment
Please complete the form below to post your comment.
Bold = Required
Email Address Your email address will NOT be published.
Display Name appears with your comment
City
State
Country
Remember me: YesNo
Comment read our privacy policy
Note: does not support HTML
All comments submitted are subject to review, and may be delayed before posting. We reserve the right not to post comments.
About the Author

Timothy Riley


Timothy Riley, PhD, is vice-president of PEGylation research at Nektar Therapeutics, 490 Discovery Dr., Huntsville, AL 35806, tel. 800.457.1806, fax 256.533.4805. Articles by Timothy Riley

Jennifer Riggs-Sauthier

Jennifer Riggs-Sauthier is director of science and technology at Nektar Therapeutics, 490 Discovery Dr., Huntsville, AL 35806. Articles by Jennifer Riggs-Sauthier

LCGC E-mail Newsletters
Subscribe:Check the box next to each newsletter you wish to subscribe for:
| Weekly
| Monthly
| Monthly | Weekly
 Name:
 E-mail:

Survey
At this month's AAPS Annual Meeting & Exposition, several graduate students were awarded as young innovators. What are your thoughts on innovation and the next generation?
We need more young innovators and more students enrolling in pharma science programs
Our industry has just the right mix of young and old to keep innovation going
Age is irrelevant when it comes to innovation
We need more young innovators and more students enrolling in pharma science programs
25%
Our industry has just the right mix of young and old to keep innovation going
16%
Age is irrelevant when it comes to innovation
59%
View Results
Jim MillerOutsourcing OutlookJim Miller Facing Reality
Patricia Van ArnumIngredients InsiderPatricia Van Arnum Advancing Chiral Chemistry in API Synthesis
Faiz kermaniSpotlightFaiz Kermani Demographic time bomb
Rx-360 Takes on Europe, Talks to PharmTech in Podcast Series
Sanctions, Not Barcodes
Vaccines Finding Their Way in Novel Applications
Genzyme’s Friday the 13th
DTCA: Beneficial or Harmful?

FindPharma Custom Search
Featured Jobs

More Jobs

Source: Pharmaceutical Technology, 7/2/2008
Click here