Synthesis Of Polylactic Acid-modified Carboxymethyl Chitosan Nanocomposite Hydrogels And Their Research In Drug Delivery

Malignant tumors are one of the major public health problems worldwide,seriously threatening people’s life and health and quality of life.Most of the existing widely used anti-tumor drugs are used systemically,and there are a large number of hydrophobic drugs,which seriously affect the physical and mental health of patients,and the traditional drug delivery methods inevitably have problems such as low drug utilization,large fluctuations in drug concentration,and easy to produce drug resistance.Therefore,a drug delivery system with long cycle,sustained release,realization of hydrophobic drug loading,improvement of drug concentration and bioavailability at tumor sites,and reduction of damage to normal tissues continue to be continued.In this project,a nanocomposite hydrogel drug delivery system of polypaclitaxel（PTX）-polyethylene glycol（PEG）micellar complex carboxymethyl chitosan（CMCS）grafted polylactic acid（PLA）hydrogel was constructed,and its related properties were studied.In this subject,the CMCS-PLA hydrogel carrier was constructed first.Polylactic acid（PLA）with different degrees of polymerization was synthesized by ring-opening polymerization of D,L-lactide with water as the initiator.PLA with different degrees of polymerization were combined with carboxymethyl chitosan by cross-linking agents 1-ethyl-3-（3-dimethylaminopropyl）carbodiimide（EDC）and N-hydroxysuccinimide（NHS）.Sugar（CMCS）was grafted to obtain CMCS-PLA hydrogel.The resulting hydrogels were characterized by ¹H NMR,Fourier transform infrared spectroscopy,and thermogravimetric analysis.The swelling and weight loss behaviors of four groups of hydrogel systems were studied,which were closely related to whether the hydrogel had hydrophobic blocks and the molecular weight of the hydrophobic blocks.The drug release behavior of four groups of hydrogel systems was studied,and CMCS-PLA hydrogel had a more stable and slower release effect than CMCS hydrogel.Meet the needs of PTX applications.In order to improve the solubility of PTX in aqueous solution,PTMC-PEG diblock micelles were prepared.Seven biodegradable PTMC-PEG diblock copolymers with different molecular weights were prepared by ring-opening polymerization of trimethylene carbonate（TMC）initiated by PEG terminal hydroxyl groups.The diblock copolymers were prepared as micelles by co-solvent evaporation method.The obtained copolymer micelles were characterized by NMR,gel permeation chromatography and critical micelle concentration analysis.The micelles showed a spherical structure with uniform particle size observed by transmission electron microscopy and dynamic light scattering.The drug release behavior of seven micellar systems was studied,and it was found that in vitro drug release in p H 7.4 phosphate buffered saline solution at 37°C,all seven micellar systems showed drug release phenomenon,and then released slowly for up to 20 days.Moreover,the drug release is greatly affected by the molecular weight of the hydrophobic segment PTMC.By adjusting the molecular weight of the hydrophilic component PEG and the hydrophobic component PTMC,the drug release rate of the micelles can be adjusted.The biocompatibility of CMCS-PLA hydrogel system and PTMC-PEG micellar system was studied from three aspects of blood compatibility,cytocompatibility and tissue compatibility.Both systems will not cause hemolysis,have good anticoagulant effect,and have no toxic effects on mouse fibroblasts（L929）and zebrafish embryos.The comprehensive results showed that,as the primary evaluation index of biomaterials,CMCS-PLA hydrogel system and PTMC-PEG micelles showed excellent biocompatibility and met the most basic application requirements of biomedical materials.Finally,CMCS-PLA₂₀ hydrogel and PTMC₂₄₀₀-PE_G2000 micelles were selected to construct a PTX-loaded nanocomposite hydrogel drug delivery system.The requirements for local delivery of anti-tumor drugs have been realized.In vitro drug release studies were performed.Compared with single hydrogel system and micellar system,nanocomposite hydrogel drug delivery system solves the problem of drug burst release.Long-term sustained release of hydrophobic drugs is achieved,and PTX is slowly released for up to 25 days.And in the in vitro anti-tumor experiment,it showed high-efficiency anti-tumor activity on lung cancer human alveolar basal epithelial cells and cervical cancer cells.In summary,nanocomposite hydrogel drug delivery system is of great significance as a local drug delivery carrier to deliver anticancer drugs for the treatment of solid tumors or the prevention of postoperative recurrence.