Thermoresponsive hydrogels as a new ocular drug delivery platform to the posterior segment of the eye.
OBJECTIVE
To characterize thermoresponsive hydrogels (liquids at room temperature, gels at body temperature) as a novel drug delivery platform to the posterior segment.


METHODS
Thermoresponsive hydrogels were synthesized using poly(N-isopropylacrylamide) (PNIPAAm), cross-linked with poly(ethylene glycol) diacrylate (PEG-DA). Proteins were then encapsulated into the hydrogels, including bovine serum albumin (BSA), immunoglobulin G (IgG), and, finally, bevacizumab and ranibiumab. By varying the degree of cross-linker density, the rate of protein release could be adjusted. The rate of release was assessed at various time points with Bradford assay, and the bioactivity of the released anti-vascular endothelial growth factor agents was studied in an in vitro cell culture assay.


RESULTS
Cross-linked PNIPAAm hydrogel exhibited a fast and reversible phase change with alteration in temperature. The rate of protein release was examined as a function of cross-link density. Release profiles of the proteins showed that there was an initial burst of release within 48 hours, and then a steady state was reached, which was sustained for approximately 3 weeks. Hydrogels with less cross-linking showed faster release and yielded a more pliable gel for intravitreal injection via small-gauge needles. Examination of the gels after the release experiment revealed significant residual entrapped protein.


CONCLUSIONS
Thermoresponsive hydrogels were successfully synthesized and exhibited fast and reversible phase changes. The gel was able to encapsulate and release various proteins. Current formulation of the gel will be modified to extend the release time and to be made fully biodegradable. Thermoresponsive hydrogels appear to be a promising, minimally invasive platform for extended drug delivery to the posterior segment.
Kang Derwent
Jennifer J
JJ
Department of Biomedical Engineering, Pritzker Institute of Biomedical Science and Engineering, Illinois Institute of Technology, Chicago, Illinois, USA.
Mieler
William F
WF
D000178:Acrylamides / Q000737:chemistry; D000180:Acrylic Resins; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000633:toxicity; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000633:toxicity; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D001682:Biological Availability; D016503:Drug Delivery Systems; D004730:Endothelium, Vascular / Q000187:drug effects; D016650:Fluorescein-5-isothiocyanate; D020100:Hydrogels / Q000737:chemistry*; D007074:Immunoglobulin G / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D000069579:Ranibizumab; D051381:Rats; D020318:Rats, Long-Evans; D012160:Retina / Q000187:drug effects*; D012710:Serum Albumin, Bovine / Q000493:pharmacokinetics; D013696:Temperature; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
D000178:Acrylamides; D000180:Acrylic Resins; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D020100:Hydrogels; D007074:Immunoglobulin G; D011108:Polymers; D042461:Vascular Endothelial Growth Factor A; C437167:poly(ethylene glycol)diacrylate; C052970:poly-N-isopropylacrylamide; D012710:Serum Albumin, Bovine; D000068258:Bevacizumab; D011092:Polyethylene Glycols; D016650:Fluorescein-5-isothiocyanate; D000069579:Ranibizumab