Abstract
Tailoring the length of a sulfide containing linker adjusts the hydrolysis of a drug-linked ester bond to values appropriate for once-a-week administrations. A model drug of paclitaxel was coupled using a hydrolyzable linker to a poly(ethylene glycol) macromonomer, via a conjugate addition reaction between a thiol and an acrylamide. The macromonomers were synthesized in three steps with an average overall yield of 70%. By changing the length of the linker from 3-sulfanylpropionyl to 4-sulfanylbutyryl, the half-life time of the release of the drug could be increased from 4.2 ± 0.1 to 14.0 ± 0.2 days. Drug-containing hydrogels were prepared by radical photopolymerization of these macromonomers with either the 3-sulfanylpropionyl or the 4-sulfanylbutyryl linker. The release of the drug from these hydrogels followed similar trends as the release of the drug from the soluble polymer-drug conjugates. The synthetic methodology employed does not involve the use of coupling reagents in the final conjugation between the drug and the polymer, excluding the presence of potential toxic residuals. The conjugation method is relatively simple and is applicable to nearly any hydroxyl-containing drugs.
| Original language | English |
|---|---|
| Pages (from-to) | 291-300 |
| Number of pages | 10 |
| Journal | Journal of Controlled Release |
| Volume | 95 |
| Issue number | 2 |
| DOIs | |
| State | Published - Mar 5 2004 |
| Externally published | Yes |
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Keywords
- Conjugate addition
- Drug release
- Hydrogels
- Poly(ethylene glycol)
- Prodrugs
ASJC Scopus subject areas
- Pharmaceutical Science
Cite this
The effect of the linker on the hydrolysis rate of drug-linked ester bonds. / Schoenmakers, Ronald G.; Van De Wetering, Petra; Elbert, Donald L.; Hubbell, Jeffrey A.
In: Journal of Controlled Release, Vol. 95, No. 2, 05.03.2004, p. 291-300.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The effect of the linker on the hydrolysis rate of drug-linked ester bonds
AU - Schoenmakers, Ronald G.
AU - Van De Wetering, Petra
AU - Elbert, Donald L.
AU - Hubbell, Jeffrey A.
PY - 2004/3/5
Y1 - 2004/3/5
N2 - Tailoring the length of a sulfide containing linker adjusts the hydrolysis of a drug-linked ester bond to values appropriate for once-a-week administrations. A model drug of paclitaxel was coupled using a hydrolyzable linker to a poly(ethylene glycol) macromonomer, via a conjugate addition reaction between a thiol and an acrylamide. The macromonomers were synthesized in three steps with an average overall yield of 70%. By changing the length of the linker from 3-sulfanylpropionyl to 4-sulfanylbutyryl, the half-life time of the release of the drug could be increased from 4.2 ± 0.1 to 14.0 ± 0.2 days. Drug-containing hydrogels were prepared by radical photopolymerization of these macromonomers with either the 3-sulfanylpropionyl or the 4-sulfanylbutyryl linker. The release of the drug from these hydrogels followed similar trends as the release of the drug from the soluble polymer-drug conjugates. The synthetic methodology employed does not involve the use of coupling reagents in the final conjugation between the drug and the polymer, excluding the presence of potential toxic residuals. The conjugation method is relatively simple and is applicable to nearly any hydroxyl-containing drugs.
AB - Tailoring the length of a sulfide containing linker adjusts the hydrolysis of a drug-linked ester bond to values appropriate for once-a-week administrations. A model drug of paclitaxel was coupled using a hydrolyzable linker to a poly(ethylene glycol) macromonomer, via a conjugate addition reaction between a thiol and an acrylamide. The macromonomers were synthesized in three steps with an average overall yield of 70%. By changing the length of the linker from 3-sulfanylpropionyl to 4-sulfanylbutyryl, the half-life time of the release of the drug could be increased from 4.2 ± 0.1 to 14.0 ± 0.2 days. Drug-containing hydrogels were prepared by radical photopolymerization of these macromonomers with either the 3-sulfanylpropionyl or the 4-sulfanylbutyryl linker. The release of the drug from these hydrogels followed similar trends as the release of the drug from the soluble polymer-drug conjugates. The synthetic methodology employed does not involve the use of coupling reagents in the final conjugation between the drug and the polymer, excluding the presence of potential toxic residuals. The conjugation method is relatively simple and is applicable to nearly any hydroxyl-containing drugs.
KW - Conjugate addition
KW - Drug release
KW - Hydrogels
KW - Poly(ethylene glycol)
KW - Prodrugs
UR - http://www.scopus.com/inward/record.url?scp=1242293727&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=1242293727&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2003.12.009
DO - 10.1016/j.jconrel.2003.12.009
M3 - Article
VL - 95
SP - 291
EP - 300
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
IS - 2
ER -