Chitosan Derivatives And Their Drug Controlled Release Applications

In recent years, renewable, non-polluting natural polymers have been in favor of increasing concern, chitosan with good biocompatibility and biodegradability is attracted more and more attention. However, chitosan does not dissolve in water, only dissolves in a small amount of dilute acid (HAc, HCl), therefore, its applications in the biomedical field have been greatly restricted. The solubility, physical and chemical properties and biophysical properties of chitosan derivatives are quite different from that of chitosan, even opposite to chitosan. A large number of experimental results show that chitosan derivatives with designed structure not only have water-solubility, amphiphilicity, biodegradability and low toxicity, but also have hemocompatibility and good cytocompatibility. Self-assembles of these amphiphilic chitosan derivatives with bioactivities make them good candidate as the drug carriers of controlled release. For example, o-carboxymethyl chitosan aggregates can load and delivery the anti-cancer drug camptothecin, N-succinyl-chitosan aggregated in aqueous solution to form more regular spherical particles and can be used to load protein drug effectively. In this paper, the molecular design principle was used to synthesize the amphiphilic and biocompatible N-maleic acylation chitosan (NMCS) and N-carboxymethyl chitosan (NCECS). The emulsion interfacial free radical polymerization was developed to prepare the NMCS nanocapsules; the emulsion interfacial condensation polymerization was introduced to prepare nanocapsules for the drug controlled release.Firstly, NMCS and NCECS were synthesized and characterized by means of infrared spectroscopy (FT-IR), nuclear magnetic resonance (H-NMR), X-ray diffraction (XRD), thermal gravimetric analysis (TGA) and studied their biological and physical properties.The aggregation behaviors of the NMCS and NCECS were studied through the viscometry, fluorescence spectroscopy, micro-titrator (ITC), atomic force microscope (AFM), scanning electron microscopy (SEM). The aggregation mechanisms of NMCS and NCECS in aqueous solution were discussed. NMCS can be aggregated into fibers with a diameter of 2.5μm and length of 100μm at ten times concentration (0.5 mg/ml) higher than the cac (0.05 mg/ml) of NMCS. The driving force of aggregation is considered to be the hydrogen bonds and hydrophobic interactions. NCECS aggregated into nanoparticles with a size ranging from 40 to 100 nm. The aggregation mechanism is the hydrophilic/hydrophobic and hydrogen bonding interactions.The viscometry, transmission electron microscopy (TEM), dynamic light scattering (DLS) were utilized to study the effects of pH value and salt (kinds (NaCl and CaCl2) and concentrations) on the aggregation behaviors of NMCS. The results showed that viscosity first increased and then decreased with the pH increased and decreased in viscosity with the salt concentration increased.Cell culture and cell activity studies showed that both NMCS and NCECS behaved good cytocompatibility. To improve the hemocompatibility, NMCS was grafted with HEMA. Better hemocompatibility was achieved at higher content of HEMA in the NMCS-g-PHEMA.TEM, field emission scanning electron microscope (FESEM), DLS were utilized to study the morphology and size distribution of the nanocapsules. Nanocapsules P-NMCS (cross-linking density and wall thickness) formed through NMCS oil-in-water emulsion polymerization loaded antihypertensive drugs felodipine. The results showed that drugs release can be controlled by adjusting the cross-linking density and wall thickness. NCECS reacted with 1,3,5-benzenetricarbonyl trichloride (TMC) through water-in-oil emulsion directional polymerization to form the nanocapsules TMCECS loaded simulation protein (BSA), results showed that the nanocapsules can be achieved at a controlled release.Amphiphilic chitosan derivatives with the biocompatibility have a potential application as controlled release drug carriers.