Superior Surface Protection of Gold Nanoparticles With Short-Chain PEG

Surface protection of gold nanoparticles is improved by using short-chain, alcohol-terminated dPEG® linkers rather than (2-mercaptopropanoyl)glycine (tiopronin) or mercapto-undecyl-tetraethyleneglycol, according to research findings from the lab of David E. Cliffel, Department of Chemistry, Vanderbilt University. Short-chain dPEG®s increase water solubility, are non-toxic, and show no immune response to anti-PEG antibodies at low concentrations.(1)

Surface protection and opsonization

Tiopronin and mercapto-undecyl-tetraethyleneglycol (Figure 1) have been used for monolayer surface protection of gold nanoparticles, but both have problems associated with their use. Using tiopronin as the monolayer for a gold nanoparticle surface above 40μM causes severe renal damage that ultimately kills test animals.(2) Mercapto-undecyl-tetraethyleneglycol has been shown to have poor water solubility when added to the cluster as the monolayer. To reduce the damage caused by tiopronin in vivo mercapto-undecyl-tetraethyleneglycol is added to the monolayer in high concentrations.(2) These high concentrations create anti-PEG antibodies to attack the cluster and make it unreactive by the mechanism known as opsonization.(1) Opsonization (Figure 2) occurs when anti-PEG antibodies react with the monolayer and render the cluster unreactive and is removed from the body.

Chemical structures of tiopronin and mercapto-undecyltetraethyleneglycol used in surface protection of gold nanoparticles.
Figure 1: Tiopronin (left) and mercapto-undecyltetraethyleneglycol (right) used in surface protection of gold nanoparticles
Process of Opsonization. Picture copyright 2011 by The Board of Trustees of the University of South Carolina. Used with permission.
Figure 2: Process of Opsonization. Picture copyright 2011 by The Board of Trustees of the University of South Carolina. http://www.microbiologybook.org/bowers/immune%20cells.htm Used with permission.

Short-chain dPEG® compounds enhance surface protection while avoiding opsonization

Short-chain, thiol-dPEG® compounds used in a mixed monolayer with tiopronin increase the water solubility of the tiopronin short-chain monolayer as compared to a mixed monolayer of tiopronin and mercapto-undecyltetraethyleneglycol. This increase in water solubility is attributed to the elimination of the akyl chain of the mercapto-undecyltetraethyleneglycol. A mixed monolayer containing 10% short-chain, alcohol-terminated dPEG® (Figure 3a) on the gold nanoparticle showed no renal damage or other toxicity.(1) The short-chain dPEG® apparently shields the cluster from opsonization and allows for fluid movement of the monolayer, which is thought to be the mechanism that thwarts opsonization.(1) Note that Quanta BioDesign sells the S-acetyl protected version of this alcohol as product number 10156 (see also Figure 3c).

Compounds used for surface protection studies. A. Thiol-PEG4-alcohol. B. Thiol-dPEG®4-acid (Quanta BioDesign PN10247). C. S-acetyl-thiol-dPEG®4-alcohol, which was not used in the study but is the S-acetyl-protected version of 3a. 3c is Quanta BioDesign product number 10156.
In studying surface protection of gold clusters, Thiol-PEG4-alcohol and Thiol-dPEG®4-acid were compared. A. Thio-PEG4-alcohol. B. Thiol-dPEG®4-acid (Quanta BioDesign PN10247). C. S-acetyl-dPEG®4-alcohol (Quanta BioDesign PN10156) which is the S-acetyl-protected version of 3a). This product was not used in this study, but it can be used for future, similar applications.

The short-chain dPEG® mixed monolayer showed no immune response in vivo. At a 10% molar exchange ratio using an alcohol-terminated short-chain dPEG® mixed monolayer, no immune response occurred in animal models. Red blood cell count increased at a 65-70% molar exchange ratio using a thiol-dPEG®-carboxy-terminated short chain dPEG® (Figure 3b), but again, no immune response occurred. This is Quanta BioDesign’s product number 10247. Surface protection of the gold nanoparticles was gained without the complication of anti-PEG antibodies or the serious problem of renal damage. These results favor use of short-chain dPEG® compounds in mixed monolayer with tiopronin instead of mercapto-undecyltetraethyleneglycol.(2)

PEG chain length affects in vivo residence time

PEG chain length directly affects residence time in the body. Short-chain dPEG®s have been shown to move through the body much faster (24 hours) than longer chains (2-4 weeks)(1) For applications where a short residence time is desirable, short-chain dPEG® compounds are a strong asset, because they provide high water solubility, no immune response, and no toxicity issues.

Short-chain dPEGs® make a difference in the biological aspect of surface protection chemistry. Quanta BioDesign is the inventor of, and world leader in, dPEG® technology with a vast range of products with varying length and terminal groups with high purity (>90%) for your convenience. If you do not see a product that you want, please call or e-mail for custom synthesis! We want to help you get the best out of your scientific application!

References

Simpson, C. A.; Agrawal, C. A.; Balinski, A; Harkness K. M.; Cliffel, D. E. Short-Chain PEG Mixed Monolayer Protected Gold Clusters Increase Clearance and Red Blood Cell Counts. ACS Nano, 2011, 5 (5), 3577–3584. http://pubs.acs.org/doi/abs/10.1021/nn103148x

Simpson, C. A.; Huffman, B. J.; Gerdon, A. E.; Cliffel, D. E. Unexpected Toxicity of Monolayer Protected Gold Clusters Eliminated by PEG-Thiol Place-Exchange Reactions. Chem. Res. Toxicol. 2010, 23, 1608–1616. http://pubs.acs.org/doi/abs/10.1021/tx100209t

Additional surface protection and surface modification products

Click here for general surface modification products from Quanta BioDesign.

Click here for metal surface modification products from Quanta BioDesign.

PN10156, S-acetyl-dPEG®4-alcohol

PN10160, S-acetyl-dPEG®8-alcohol

PN10939, S-acetyl-dPEG®12-alcohol

PN10247, Thiol-dPEG®4-acid

PN10183, Thiol-dPEG®8-acid

PN10850, Thiol-dPEG®12-acid

Lipoic acid (1,2-dithiolane-3-pentanoic acid), because of its strained 5-member dithiolane ring, provides superior dative bonding to gold surfaces and, hence, superior surface protection to gold surfaces. Quanta BioDesign, Ltd. offers several lipoic acid-functionalized dPEG® derivatives. A partial list of our line of such products is below:

PN10806, Lipoamido-dPEG®4-acid

PN10641, Lipoamido-dPEG®4-TFP ester

PN10807, Lipoamido-dPEG®8-acid

PN10642, Lipoamido-dPEG®8-TFP ester

PN10808, Lipoamido-dPEG®12-acid

PN10814, Lipoamido-dPEG®12-TFP ester

PN10811, Lipoamido-dPEG®24-acid

PN10643, Lipoamido-dPEG®24-TFP ester

You can see all of our lipoic acid derivatives in our Metal Surface Modification Reagents list.

Ian Hotham, B.S., received his B.S. in Chemistry from The Pennsylvania State University in Spring of 2013. Ian is a Process Development Chemist involved in process development and scale-up activities. You can connect with Ian on LinkedIn at www.linkedin.com/pub/ian-hotham/51/b28/a08

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