Preparation Of Multifunctional Targeted Nanoparticles Formed From Quaternized Chitosan And Its Application In Drug Delivery System

The design and construction of more effective drug delivery system are very important. Octadecyl quaternized carboxymethyl chitosan (OQCMC) was synthesized through carboxymethyl chitosan (CMC) grafting with glycidyl octadecyl dimethylammonium chloride. Multifunctional targeted drug delivery systems, such as magnetic cationic polymeric liposomes (MCPL), PEG and trans-activating transcriptional activator protein (TAT) conjugated MCPL, PEG and folate conjugated MCPL and folate conjugated PLGA NPs, were designed by using OQCMC and its derivatives, cholesterol or PLGA.OQCMC exhibited excellent solubility both in water and organic solvents. It also had a lower cytotoxic effect compared with PEI (25kDa). OQCMC had high degree of crystallinity with good thermal stabilization. Self-assembled OQCMC micelles were evaluated as carrier of lipophilic drug, minocycline hydrochloride (MH). MH was incorporated into cross-linked ionic cores of micelles with remarkably high efficiency (22.7% w/w). MH loaded OQCMC polymeric micelles exhibited slow steady release profile over one week period at 37°C. Three kinds of drug-loaded NPs formed from OQCMC were obtained by microemulsion method. These NPs had small size (20nm) and were suitable as drug-carrier for hydrophilic drug-vincristine (VCR), and hydrophobic drug-indomethacin (IMC). The maximal drug loading efficiency of VCR-loaded NPs was 22.7%, the IMC-loaded NPs was 20.1%, and the co-delivery NPs of VCR and IMC were 12.2% and 10.0%, respectively.OQCMC in combination with cholesterol (Chol) could form stable vesicles with structure similar to that of conventional liposomes prepared from phosphatidylcholine/cholesterol (PC/Chol). Using different preparation methods, OQCMC/Chol could easily be made into nanoscale particles by encapsulating both hydrophilic and hydrophobic components. VCR was also encapsulated in the polymeric liposomes with high drug encapsulation efficiency (90.1%).A simple and rapid method was introduced to prepare superparamagnetic, controlled size and monodispersed MCPL by OQCMC and cholesterol. These superparamagnetic CPL were stable in aqueous phase with small size 15.3nm, high Zeta potential +41.20mV and high saturation magnetization 39.96 emu/g at 300 K. IMC and VCR encapsulation efficiency of MCPL were both above 90% and drug-loaded MCPL exhibited slow steady release at 37℃in PBS solution (pH=7.4).Hydrophilic Fe3O4 ferrofluid (LM) and BM can be encapsulated into CPL, simultaneously or respectively. The size of these stable hydrophilic magnetic nanospheres with functional groups (COOH, NH2) and controlled size (layer by layer method) ranges from 10nm to 120nm. A model hydrophobic drug IMC can be successfully filled in MCPL with high drug loading capacity 22%. The drug encapsulated MCPL have a long and controlled sustained release profile. PEG-modified OQCMC (PEG-OQCMC) and folate-modified OQCMC(FA-OQCMC) were obtained by grafting reaction. Multifunctional MCPL were prepared with IMC encapsulating by using PEG-OQCMC, OQCMC, FA-OQCMC and BM. The results showed that the hydrodynamic diameter of this NPs was 118nm, with polydispersity index 0.005, high Zeta potential +41.20mV and high saturation magnetization 28.6 emu/g. PEG and TAT conjugated MCPL were prepared and approved to across the blood-brain-barrier(BBB) of spinal cord injury by magnetic force.By the solvent evaporation method, the drug delivery system was prepared based on OQCMC, PLGA and hydroxyethyl cellulose. The targeted FA-OQCMC/PLGA NPs(FA NPs) were also prepared successfully with encapsulating VCR for Adenoid Cystic Carcinoma(ACC). The targeting effect of FA NPs is very clear compared with NPs without folate. VCR-loaded NPs had a longer sustained release profile for 2 weeks and FA NPs group has a better therapy effect due to its targeting effect of folate. The FA-OQCMC/PLGA/HEC NPs could be potentially applied for cancer cell targeted sustained delivery of various therapeutic agents.