Introduction: Given that glaucoma is a chronic disease occurring in elderly patients and requiring lifelong treatment, the development of antiglaucoma formulation is of high clinical importance. In addition to ocular hypertension, oxidative stress has been considered as one of the causes of glaucoma although disease progression is usually associated with poorly understood pathophysiology. To enhance the therapeutic efficacy of pilocarpine-containing biodegradable in situ gelling copolymers, the functionalization of biomaterial carriers with gallic acid (GA) is attempted here to improve the total antioxidant status in glaucomatous eyes. We pay particular attention to the role of GA content in the development of multifunctional polymers as cytoprotective antiglaucoma drug delivery systems.
Materials and Methods: The GA-functionalized gelatin-g-poly(N-isopropylacrylamide) (GN) biodegradable in situ gelling copolymers were synthesized by redox technique. After radical reaction in the presence of water-soluble redox initiators for different times (30-180 min), the multifunctional GNGA polymers with varying GA contents were characterized by phosphomolybdenum. The phase transition temperature, in vitro degradability, and drug release profile of polymeric carriers were determined. The antioxidant activity of various GNGA polymers was evaluated using an in vitro cell culture model of oxidative stress and an in vivo animal model of experimental glaucoma. All animal procedures were approved by the Institutional Review Board and were carried out in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.
Results and Discussion: By adjusting the reaction time, the structure of multifunctional GNGA polymers can be controlled. The total antioxidant activity is significantly increased with increasing redox reaction time (P < 0.05). Our data demonstrate that the introduction of large amount of hydrophilic GA molecules in the copolymers leads to significantly higher phase transition temperature and weight loss. The pilocarpine loading capacity is greatly affected by the temperature triggered sol-gel phase transition and hydrophilicity of GNGA polymers. Although the sustained drug release patterns are found, the polymeric carriers with different GA contents present distinct drug release rates. It is noted that the GA content-related degradation behavior seems to control the concentration of released drug. The incorporation of large amount of GA into the copolymers can achieve more rapid drug release. After 2 days of incubation, insufficient therapeutic drug concentration is detected. The polymeric carriers with optimized GA content exhibit better antioxidant activity against oxidative stress and ability to improve antioxidant status of ocular anterior chamber.
Conclusion: The present study suggests that the GA content in the multifunctional polymers may have a profound influence on the delivery performance and therapeutic efficacy of cytoprotective antiglaucoma drug carriers.
This study was supported by grant MOST104-2314-B-182-008-MY3 from the Ministry of Science and Technology of Republic of China.
References:
[1] Lai, J.-Y.*, Hsieh, A.-C. (2012) “A gelatin-g-poly(N-isopropylacrylamide) biodegradable in situ gelling delivery system for the intracameral administration of pilocarpine”, Biomaterials, 33(7), 2372-2387. [Featured as Key Scientific Journal Article in LeadDiscovery] [Featured as Key Scientific Article in Global Medical Discovery]
[2] Lai, J.-Y.* (2013) “Biodegradable in situ gelling delivery systems containing pilocarpine as new antiglaucoma formulations: effect of a mercaptoacetic acid/N-isopropylacrylamide molar ratio”, Drug Des. Dev. Ther., 7, 1273-1285. [Featured on MDLinx.com and Ranked by the Team of Physician Editors as Number 2 on Ophthalmology Site from the Latest Literature] [Featured as Key Scientific Article in Global Medical Discovery]
[3] Lai, J.-Y.*, Luo, L.-J. (2015) “Antioxidant gallic acid-functionalized biodegradable in situ gelling copolymers for cytoprotective antiglaucoma drug delivery systems”, Biomacromolecules, 16(9), 2950-2963.