Carboxymethyl Chitosan/N-trimethyl Chitosan Coated Liposomes For Oral Curcumin Delivery

Oral administration is the most widely used method of delivering drugs. Oral administration of drugs can simplify treatment and save time, in addition, patients are more receptive to it. Nevertheless, delivering anticancer drug orally often leads to a low bioavailability owing to first-pass effect and barriers to physical absorption in the epithelium. Chitosan (CS), a natural cationic polysaccharide, attracts increasing concern in oral drug delivery field because of its favorable biocompatibility, histocompatibility as well as its ability to open tight junctions (TJs) between intestinal epithelial cells and facilitate paracellular transport of drugs. Liposomes are closed spherical vesicles composed of a lipid bilayer and have been taken as a promising drug delivery system in recent years. Chitosan coating on liposomes has been found to increase their stability and to provide them with mucoadehsive properties. Moreover, there are abundant functional groups such as hydroxyl and amino groups on the backbone of chitosan, so that some biologically active molecules can be introduced to the chitosan coated liposomes by covalent bonds.Carboxymethyl chitosan (CMCS) was synthesized from the carboxymethylation reaction of chitosan under soft conditions and could be soluble in neutral pH. N-trimethyl chitosan was synthesized from the trimethylation reaction of chitosan.The relusts of fourier transform infrared Spectrum showed that carboxymethyl or N-trimethyl groups were covalently connected onto chitosan molecular skeleton.The preparation and properties of Carboxymethyl chitosan/N-trimethyl chitosan coated liposomes (CMCS/TMC-LP) were studied and compared with those of liposomes and N-trimethyl chitosan coated liposomes (TMC-LP). CMCS/TMC-LPs were spherical in shape with a classic core-shell structure. Compared with cliposomes and TMC-LP, CMCS/TMC-LP had larger size with an average diameter of 161.6 nm while that of liposomes is around 119.2nm. After coated Carboxymethyl chitosan/N-trimethyl chitosan,CMCS/TMC-LP had better physical stability. After storage for 14days, the average particle size of liposomes changed from 119.2nm to 567.3 nm due to aggregation and fusion. However, the average particle size of CMCS/TMC-LP had few changes in the same conditions. These changes may attribute to the Carboxymethyl chitosan/N-trimethyl chitosan layer coated on liposomes. The rise in zeta potential of nanoparticles can increase the repelling forces between the nanoparticles and in this way, the stability of nanoparticles could be improved.Curcumin (CUR), a model anticancer drug, was loaded in liposome, TMC-LPs and CMCS/TMC-LPs. Drug release of them was studied in various pH media with different enzyme, simulating the complete GI environment by the dynamic dialysis method, the results indicated that the CMCS/TMC-LPs exhibited favorable gastric acid tolerance and sustained-release behavior in simulating small intestinal fluid.Liposome, TMC-LP, CMCS/TMC-LP were given orally. Pharmacokinetics and tissue distribution results showed that CMCS/TMC-LP exhibited the highest absolute bioavailability(38%), nearly 6.33 folds and 3.17 folds higher than those obtained by Liposome and TMC-LP, organs were excised at 24 h after administration of those nanoparticles. Liver, spleen and lung in CMCS/TMC-LP showed significantly higher CUR level compare with other groups, demonstrating that CMCS/TMC-LP could significantly increase circulation time of CUR in body.Above results obtained in the present work implied that CMCS/TMC-LPs had great potential to be applied as safe and effective oral drug delivery.