title: 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.
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.
  
  
  
  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.
authors.affiliation: Department of Chemical and Materials Engineering, Chang Gung University, Taoyuan, 33302, Taiwan, Republic of China.
authors.forename: Li-Jyuan
authors.initials: LJ
authors.lastname: Luo
authors.affiliation: Institute of Biochemical and Biomedical Engineering, Chang Gung University, Taoyuan, 33302, Taiwan, Republic of China; Biomedical Engineering Research Center, Chang Gung University, Taoyuan, 33302, Taiwan, Republic of China; Center for Tissue Engineering, Chang Gung Memorial Hospital, Taoyuan, 33305, Taiwan, Republic of China; Department of Ophthalmology, Chang Gung Memorial Hospital, Taoyuan, 33305, Taiwan, Republic of China; Department of Materials Engineering, Ming Chi University of Technology, New Taipei City 24301, Taiwan, Republic of China. Electronic address: jylai@mail.cgu.edu.tw.
authors.forename: Jui-Yang
authors.initials: JY
authors.lastname: Lai
mesh_terms: D000180:Acrylic Resins / Q000138:chemical synthesis* / Q000737:chemistry; D060433:Administration, Ophthalmic; D000818:Animals; D002152:Calorimetry, Differential Scanning; D002264:Carboxylic Acids / Q000737:chemistry*; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D065546:Drug Liberation; D042783:Endothelial Cells / Q000473:pathology; D004728:Endothelium, Corneal / Q000473:pathology; D005780:Gelatin / Q000737:chemistry*; D005901:Glaucoma / Q000188:drug therapy*; D008970:Molecular Weight; D044367:Phase Transition; D010862:Pilocarpine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011817:Rabbits; D012160:Retina / Q000473:pathology; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013997:Time Factors; D014867:Water
chemical_list: D000180:Acrylic Resins; D002264:Carboxylic Acids; D004337:Drug Carriers; D013438:Sulfhydryl Compounds; D010862:Pilocarpine; D014867:Water; C052970:poly-N-isopropylacrylamide; D005780:Gelatin
keywords: Alkyl chain length; Antiglaucoma drug delivery; Gelatin-g-poly(N-isopropylacrylamide); Monothiol-terminated alkyl carboxylic acid