Chemical coupling of thiolated chitosan to preformed liposomes improves mucoadhesive properties.
OBJECTIVE
To develop mucoadhesive liposomes by anchoring the polymer chitosan-thioglycolic acid (chitosan-TGA) to the liposomal surface to target intestinal mucosal membranes.


METHODS
Liposomes consisting of phosphatidylcholine (POPC) and a maleimide-functionalized lipid were incubated with chitosan-TGA, leading to the formation of a thioether bond between free SH-groups of the polymer and maleimide groups of the liposome. Uncoated and newly generated thiomer-coated liposomes were characterized according to their size, zeta potential, and morphology using photon correlation spectroscopy and transmission electron microscopy. The release behavior of calcitonin and the fluorophore/quencher-couple ANTS/DPX (8-aminonaphthalene-1,3,6-trisulfonic acid/p-xylene-bis- pyridinium bromide) from coated and uncoated liposomes, was investigated over 24 hours in simulated gastric and intestinal fluids. To test the mucoadhesive properties of thiomer-coated and uncoated liposomes in-vitro, we used freshly excised porcine small intestine.


RESULTS
Liposomes showed a concentration-dependent increase in size - from approximately 167 nm for uncoated liposomes to 439 nm for the highest thiomer concentration used in this study. Likewise, their zeta potentials gradually increased from about -38 mV to +20 mV, clearly indicating an effective coupling of chitosan-TGA to the surface of liposomes. As a result of mucoadhesion tests, we found an almost two-fold increase in the mucoadhesion of coupled liposomes relative to uncoupled ones. With fluorescence microscopy, we saw a tight adherence of coated particles to the intestinal mucus.


CONCLUSIONS
Taken together, our current results indicate that thiomer-coated liposomes possess a high potential to be used as an oral drug-delivery system.
Institute of Biophysics and Nanosystems Research, Austrian Academy of Sciences, Graz, Austria.
Kerstin
K
Gradauer
Caroline
C
Vonach
Gerd
G
Leitinger
Dagmar
D
Kolb
Eleonore
E
Fröhlich
Eva
E
Roblegg
Andreas
A
Bernkop-Schnürch
Ruth
R
Prassl
D000268:Adhesiveness / Q000187:drug effects*; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D048271:Chitosan / Q000008:administration & dosage / Q000737:chemistry*; D006651:Histocytochemistry; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry*; D008301:Maleimides / Q000737:chemistry; D008856:Microscopy, Fluorescence; D009281:Naphthalenes / Q000737:chemistry; D010316:Particle Size; D010713:Phosphatidylcholines / Q000737:chemistry; D011726:Pyridinium Compounds / Q000737:chemistry; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013552:Swine; D013864:Thioglycolates / Q000737:chemistry
D008081:Liposomes; D008301:Maleimides; D009281:Naphthalenes; D010713:Phosphatidylcholines; D011726:Pyridinium Compounds; D013438:Sulfhydryl Compounds; D013864:Thioglycolates; C046466:N,N'-4-xylylenebis(pyridinium); C043592:maleimide; C017487:2-mercaptoacetate; D048271:Chitosan; C046465:8-amino-1,3,6-naphthalenetrisulfonic acid