The Role of Alkyl Chain Length of Monothiol-Terminated Alkyl Carboxylic Acid in the Synthesis, Characterization, and Application of gelatin-g-poly(N-isopropylacrylamide) Carriers for Antiglaucoma Drug Delivery

Li-Jyuan Luo, Jui-Yang Lai

Acta Biomater. 2017 Feb;49:344-357.

PMID: 27890728

Abstract:

To improve ocular bioavailability and extend pharmacological response, this study aims to investigate the role of alkyl chain length of monothiol-terminated alkyl carboxylic acids in the synthesis, characterization, and application of gelatin-g-poly(N-isopropylacrylamide) (GN) biodegradable in situ gelling carriers for antiglaucoma drug delivery. In the presence of mercaptoacetic acid (MAA), mercaptopropionic acid (MPA), mercaptobutyric acid (MBA), or mercaptohexanoic acid (MHA) as a chain transfer agent, the carboxylic end-capped poly(N-isopropylacrylamide) samples were prepared by free radical polymerization technique. Our results showed that with increasing alkyl chain length, the hydrophobicity of thermo-responsive polymer segments significantly increased, mainly due to an increase in CH stretching frequencies. In addition, the greater hydrophobic association favored the decrease in both phase transition temperature and weight loss of GN copolymers, thereby accelerating their temperature-triggered gelation process and retarding the degradation progress under physiological conditions. The benefits from these features allowed the pilocarpine carriers to increase drug payload and extend drug release. Irrespective of carbon number of monothiol-terminated alkyl carboxylic acid, the synthesized GN materials exhibited high tolerance to corneal endothelial cells without any evidence of inhibited proliferation, viability loss, inflammatory stimulation, and functional abnormality, indicating good biocompatibility. Results of clinical observations and histological examinations demonstrated that the therapeutic efficacies in treating glaucomatous damage are in response to in vivo drug release profiles from various intracamerally injected GN carriers. The research findings suggest the influence of alkyl chain length of chain transfer agent-mediated polymer hydrophobicity and degradability on pharmacological bioavailability and action of pilocarpine in a glaucomatous rabbit model.
Statement of significance:
Considering that glaucoma is a chronic disease that requires long-term medical therapy to preserve vision in patients, it is highly desirable to augment pharmacological bioavailability and govern release profile by tuning the properties of drug delivery carriers. For the first time, the present study provide striking evidence that the alkyl chain length of monothiol-terminated alkyl carboxylic acid related to the synthesis of biodegradable in situ gelling copolymers plays a key role in molecular functionalization of intracameral delivery systems for ocular administration and controlled release of antiglaucoma medications. The therapeutic efficacies in treating glaucomatous damage are in response to in vivo pilocarpine release profiles modulated by the carbon number of thermo-responsive polymer segment-mediated carrier hydrophobicity and degradability.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
LS74671	Poly(N-isopropylacrylamide), carboxylic acid terminated			Price