Biodegradable Carboxymethyl Chitosan-Polylactic Acid Hydrogels For Controlled Drug Release

Carboxymethyl chitosan (CMCS) is obtained from carboxymethylation of chitosan, the second largest polysaccharide after cellulose. It possesses the outstanding properties of chitosan such as biocompatibility, biodegradability, and biological activity. In contrast to chitosan with high degree of crystallinity and poor water solubility due to strong hydrogen bonding, CMCS is easily water soluble and has been widely used for applications in many fields such as medicine, pharmacology, agriculture, health care and so on. CMCS macromolecules contain numerous amino and carboxyl groups, which allows chemical modification of CMCS by attachment of other molecules, thus improving the physico-chemical and mechanical properties of CMCS.Polylactic acid (PLA) is a biodegradable synthetic polymer with good biocompatibility, mechanical properties, and degradation properties. It is widely used for various biomedical applications such as surgical sutures, artificial bone, drug carrier, tissue repair and regeneration devices. However, PLA is highly crystalline and hydrophobic, which greatly limits its applications in tissue engineering and drug release. Grafting of PLA onto the carboxymethyl chitosan backbone should allow to conbine the properties of both components, including biocompatibility, biodegradability, biological activity and mechanical properties. Moreover, the resulting grafted copolymers are amphiphilic with both hydrophilic and hydrophobic domains, which presents great interest for drug release applications.Paclitaxel (PTX) is one of the most efficient antitumor drugs commonly used for the treatment of breast, cancer, ovarian cancer, lung cancer, etc. But PTX is poorly water soluble, and can be hardly absorbed. A drug carrier is thus needed to improve its bioavailability.The aim of this work was to develop CMCS-PLA hydrogels for controlled delivery of both hydrophilic and hydrophobic drugs. Various low molecular weight CMCS samples were obtained by degradation of CMCS in the presence of H2O2. The influence of factors such as reaction time, H2O2 amount, reaction temperature, on the molecular weight of the resulting CMCS samples was considered. CMCS hydrogels were obtained by crosslinking the amine and carboxyl groups of CMCS, and CMCS-PLA hydrogels were obtained under similar conditions by attaching PLA with a carboxyl endgroup to the CMCS backbone. Water soluble 1-ethyl-3-(3-dimethyl-aminopropyl)-1-carbodiimide (EDC) was used together with N-hydroxysuccinimide (NHS) to couple amino and carboxyl groups to form amide bonds. Paclitaxel was added to the reaction system, yielding PTX-loaded hydrogels CMCS-PTX and CMCS-PLA-PTX. Characterization techniques such as IR, DSC, and TGA were used to determine the structure and properties of PTX-loaded hydrogels. Different release media that affect the drug release rate were also explored. Hydrochloric acid was added to CMCS, CMCS-PTX, CMCS-PLA, CMCS-PLA-PTX hydrogels to observe the change of solution colour. Visual observation proved that PTX was effectively loaded in both kinds of hydrogel. FTIR spectroscopy showed the typical bands of PLA and CMCS, indicating that PLA was successfully grafted onto the CMCS. DSC measurements showed that crosslink density of hydrogels increases with increasing EDC/NHS amounts. CMCS-PLA and CMCS-PLA-PTX present similar TGA profiles, showing that addition of PTX does not change the thermal stability of hydrogels. In drug release behavior studies, different media conditions that may have an impact on drug release rate were explored. After our experiments, we concluded that the PBS-swollen drug-loaded hydrogels had a relative faster release rate than the lysozyme-swollen one.