The Effect of Glutathione as Chain Transfer Agent in PNIPAAm-Based Thermo-responsive Hydrogels for Controlled Release of Proteins

• Published in: Pharmaceutical research 2014-03, Vol.31 (3), p.742-753
• Main Authors: Drapala, Pawel W., Jiang, Bin, Chiu, Yu-Chieh, Mieler, William F., Brey, Eric M., Kang-Mieler, Jennifer J., Pérez-Luna, Victor H.
• Format: Article
• Language: English
• Subjects: Acrylic Resins - chemistry; Acrylic Resins - metabolism; Animals; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Cattle; Delayed-Action Preparations - chemistry; Delayed-Action Preparations - metabolism; Drug delivery systems; Glutathione - chemistry; Glutathione - metabolism; Hydrogels; Hydrogels - chemistry; Hydrogels - metabolism; Immunoglobulin G - administration & dosage; Immunoglobulins; Lactates - chemistry; Lactates - metabolism; Medical Law; Pharmaceutical sciences; Pharmacology/Toxicology; Pharmacy; Polyethylene Glycols - chemistry; Polyethylene Glycols - metabolism; Proteins; Research Paper; Temperature; Transition Temperature
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-013-1195-0

ABSTRACT Purpose To control degradation and protein release using thermo-responsive hydrogels for localized delivery of anti-angiogenic proteins. Methods Thermo-responsive hydrogels derived from N-isopropylacrylamide (NIPAAm) and crosslinked with poly(ethylene glycol)-co-(L-lactic acid) diacrylate (Acry-PLLA- b -PEG- b -PLLA-Acry) were synthesized via free radical polymerization in the presence of glutathione, a chain transfer agent (CTA) added to modulate their degradation and release properties. Immunoglobulin G (IgG) and the recombinant proteins Avastin® and Lucentis® were encapsulated in these hydrogels and their release was studied. Results The encapsulation efficiency of IgG was high (75–87%) and decreased with CTA concentration. The transition temperature of these hydrogels was below physiological temperature, which is important for minimally invasive therapies involving these materials. The toxicity from unreacted monomers and free radical initiators was eliminated with a minimum of three buffer extractions. Addition of CTA accelerated degradation and resulted in complete protein release. Glutathione caused the degradation products to become solubilized even at 37°C. Hydrogels prepared without glutathione did not disintegrate nor released protein completely after 3 weeks at 37°C. PEGylation of IgG postponed the burst release effect. Avastin® and Lucentis® released from degraded hydrogels retained their biological activity. Conclusions These systems offer a promising platform for the localized delivery of proteins.