Studies On The Design, Synthesis, And Structure-performance Relationship Of The Calcium Carbonate/Target Molecules Hybrid Micro/Nano Carriers Of Anti-tumor Drugs

Currently, malignant tumor is one of the major fatal diseases seriously threating the human lives.Furthermore, tumor cases has been increased continuously in worldwide. Currently, the most commonapproach to treat the tumor is limited to the chemotherapy, radiotherapy and clinical-surgical therapy.However, these conventional treatments have various of inherent shortcomings, such as the poor watersolubility, low specificity, strong side effects and obvious drug resistance of the anticancer drugs. Inaddition, the current drug delivery systems own some problems, such as poor biocompatibility, complexityof the synthesis process, potential toxicity and poor specificity. Targeting agents (targeting drug deliverysystem) have the important application potentials to overcome the above defects, including theimprovement of the drug efficacy, reduce of the dosage, dosing frequency and side effects.Compared with the synthetic polymers, calcium carbonate exhibits many advantages to be used as thedrug carrier, such as the excellent biocompatibility and biodegradable, acid sensitivity, simple synthesis andfacile surface modification, etc,. In addition, the targeted carriers can be easily prepared by combining thetargeting ligands with calcium carbonate and exhibit the significant application potentials in targeteddelivery and controlled sustained release of anticancer drugs. Therefore, the studies about the applicationsof calcium carbonate as drug carriers have attracted tremendous attention in recent years.In this thesis, the following aspects were studied in detail:(1) Using three different targeted ligands including folic acid (FA), chondroitin sulfate (CS), andhyaluronic acid (HA) as organic matrices and targeted molecules, which can specific interacted with theover-expressed receptors in cancer cells, targeting ligands-calcium carbonate hybrid micro/nano materialswith different morphologies and polymorphs were successfully prepared through a facile one-pot method.The morphologies, structures and compositions of the products were characterized through various methods,such as SEM, FE-SEM, TEM, HRTEM, XRD, FT-IR, TG-DSC, etc. The results showed that theas-prepared hybrid micro/nano materials were hollow spheres and mesoporous rods with the diameter inthe range of1~3μm. The hierarchical hybrid materials were composed of small nanoparticles with about100nm in diameter. The contents of targeting ligands in the hybrid materials were in the range of1%~6%. (2) Using the anticancer drug doxorubicin hydrochloride (DOX) as the model drug, the three kinds ofhybrid materials were used as drug carriers to preform the drug adsorption-release in vitro assay. Inaddition, the loading and release profile of the DOX were determined by using fluorescent microscopy andUV-visible absorption spectroscopy. The results showed that the DOX could be efficiently loaded into thethree different carriers. Furthermore, the DOX could be sustained released from the carriers under weakacidic conditions with pH-dependent feature. This showed that these drug-loaded carriers has importantpotential applications in the targeted delivery and controlled sustained release of the anticancer drugs.(3) Using cervical carcinoma cells (HeLa) and Chinese hamster lung cells (V79-4) as models of tumorcells and normal cells, the antitumor activities of the three DOX-loaded hybrid materials were studied.TEM observation results showed that the three drug-loaded hybrid materials could specifically surroundedaround the tumor cells and internalized by tumor cells to exert the antitumor effects of the DOX. MTTassay results showed that the antitumor activities of the DOX could be efficiently enhanced using the threehybrid materials as the carriers. Moreover, the specificity of the DOX could be significantly increased,about2-3times of the free DOX.In summary, the drug-loaded hybrid materials could be specifically delivered to the tumor cellsthrough the specific interactions between the targeting ligands and the over-expressed receptors of thetumor cells. Subsequently, the drug-loaded hybrid materials could be internalized into the tumor cellsthroug the receptor mediated endocytosis to sustained release the antitumor drugs to treat the tumors. As thepromising potential targeted delivery carriers of the antitumor drugs, the as-prepared targetingligands-calcium carbonate hybrid materials should be studied in vivo. The results can develop the strongtheoretical bases for the design and preparation of the active targeted carriers of antitumor drugs with idealbiocompatibility, biodegradability and low residual toxicity to efficiently treat the human tumors.