Disulfides are used extensively in reversible cross-linking because of the ease of reduction into click-reactive thiols. However, the free-radical scavenging properties upon reduction are often under-considered. The free thiols produced upon reduction of this disulfide material mimic the cellular reducing chemistry (glutathione) that serves as a buffer against acute oxidative stress. A nanoparticle formulation producing biologically relevant concentrations of thiols may not only provide ample chemical conjugation sites, but potentially be useful against severe acute oxidative stress exposure, such as in targeted radioprotection. In this work, we describe the synthesis and characterization of highly thiolated poly (β-amino ester) (PBAE) nanoparticles formed from the reduction of bulk disulfide cross-linked PBAE hydrogels. Degradation-tunable PBAE hydrogels were initially synthesized containing up to 26 wt % cystamine, which were reduced into soluble thiolated oligomers and formulated into nanoparticles upon single emulsion. These thiolated nanoparticles were size-stable in phosphate buffered saline consisting of up to 11.0 ± 1.1 mM (3.7 ± 0.3 mmol thiol/g, n = 3 M ± SD), which is an antioxidant concentration within the order of magnitude of cellular glutathione (1–10 mM).
Digital Object Identifier (DOI)
The project described was supported by Grant Number R25CA153954 from the National Cancer Institute.
The following are available online at https://www.mdpi.com/2310-2861/4/4/80/s1, Figure S1: Mass spectrometry of thiolated oligomers, Figure S2: SEM of thiolated HEDA/CA nanoparticles at high concentration (4 mg/mL) forming a film at droplet boundary, and particle characteristics, Figure S3: Particle conjugation with NPM.
Lakes, Andrew L.; Puleo, David A.; Hilt, J. Zach; and Dziubla, Thomas D., "Highly Thiolated Poly (Beta-Amino Ester) Nanoparticles for Acute Redox Applications" (2018). Chemical and Materials Engineering Faculty Publications. 66.