Thiol functionalized polymethacrylic acid-based hydrogel microparticles for oral insulin delivery.
In the present study thiol functionalized polymethacrylic acid-polyethylene glycol-chitosan (PCP)-based hydrogel microparticles were utilized to develop an oral insulin delivery system. Thiol modification was achieved by grafting cysteine to the activated surface carboxyl groups of PCP hydrogels (Cys-PCP). Swelling and insulin loading/release experiments were conducted on these particles. The ability of these particles to inhibit protease enzymes was evaluated under in vitro experimental conditions. Insulin transport experiments were performed on Caco-2 cell monolayers and excised intestinal tissue with an Ussing chamber set-up. Finally, the efficacy of insulin-loaded particles in reducing the blood glucose level in streptozotocin-induced diabetic rats was investigated. Thiolated hydrogel microparticles showed less swelling and had a lower insulin encapsulation efficiency as compared with unmodified PCP particles. PCP and Cys-PCP microparticles were able to inhibit protease enzymes under in vitro conditions. Thiolation was an effective strategy to improve insulin absorption across Caco-2 cell monolayers, however, the effect was reduced in the experiments using excised rat intestinal tissue. Nevertheless, functionalized microparticles were more effective in eliciting a pharmacological response in diabetic animal, as compared with unmodified PCP microparticles. From these studies thiolation of hydrogel microparticles seems to be a promising approach to improve oral delivery of proteins/peptides.
Biosurface Technology Division, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, India.
S
S
Sajeesh
C
C
Vauthier
C
C
Gueutin
G
G
Ponchel
Chandra P
CP
Sharma
D000284:Administration, Oral; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D048271:Chitosan / Q000494:pharmacology; D002942:Circular Dichroism; D016503:Drug Delivery Systems; D017097:Electric Impedance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007003:Hypoglycemia / Q000188:drug therapy; D007328:Insulin / Q000008:administration & dosage* / Q000627:therapeutic use*; D007422:Intestines / Q000187:drug effects; D008297:Male; D053758:Nanoparticles / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000494:pharmacology; D011109:Polymethacrylic Acids / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D017550:Spectroscopy, Fourier Transform Infrared; D013438:Sulfhydryl Compounds / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007328:Insulin; D011109:Polymethacrylic Acids; D013438:Sulfhydryl Compounds; C030613:polymethacrylic acid; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D011092:Polyethylene Glycols; D048271:Chitosan