| Taxol is extremely hydrophobic and difficult to formulate. Present-day cancer chemotherapy with taxol frequently causes hypersensitivity reactions due to the use of Cremophor(r) EL. To solve the problem, a series of novel water-soluble taxol prodrugs, "polymer-spacer-taxol" tripartite were designed and prepared. Their drug release property and anti-tumor activities in vitro and in vivo were investigated, and were associated with the structure character to establish the structure-activity relationship. In the dissertation, the following work has been done:1. Thirty-eight of four sets of water-soluble taxol prodrugs were prepared by attaching taxol to the backbone of polyethylene glycol (PEG) through different amino acids spacers. The effects of reaction conditions on production yields and the methods of prodrug separation and purification were investigated. The structure of products was identified initially and small molecular was proved to had been introduced into the products. 2. The physical and chemical properties of taxol prodrugs were determined, including drug load (i.e., the amount of taxol), aqueous solubility and stability of prodrugs. The molecular weights of PEG played a key role in the prodrug properties of drug load and aqueous solubility, while the former was affected partially by amino acid spacers as well. The aqueous solubility of prodrugs was up to 125~800 mg·mL-1 (i.e., 5~280 mg·mL-1 taxol). Aqueous stability studies showed that the amount of taxol released from prodrug PEG6k-DA-Pro-Taxol was lower than 8% of theoretical drug load when the aqueous solution of the prodrug was kept at 37℃ for 60h, which significantly indicated the wonderful stability of prodrugs. 3. The effects of pH and amino acid spacers on the release of taxol from prodrugs were investigated under simulated in vivo conditions. The release of taxol from prodrugs in phosphate buffer solution (PBS) and human plasmsa obeyed the first order kinetics. The pH values had remarkable effects on the drug release in PBS. The amino acid spacer affected the release of taxol through the change in microenvironment around the ester bond where taxol attached: the ( position of ester bond connected with electron withdrawing group was beneficial to the hydrolysis; the steric hindrance of bulky amino acid molecular may decrease the hydrolysis rate. In pH 7.4 PBS and plasma, the release of taxol from prodrugs was at the fastest rate with glycine as the spacer and at the slowest rate without amino acid spacers, which clearly demonstrated the regulation effects of amino acid spacers on taxol release. 4. The in vitro inhibition activity of taxol prodrugs against L1210,PG49 and MCF-7 tumor cell lines was investigated. The IC50 data indicated that the prodrugs showed better effects on the human tumor cell lines than on the murine cell line. The release rate of taxol from prodrugs, which was highly affected by the amino acid spacers as indicated above, accounted for the difference in anti-tumor activities of different prodrugs. Prodrugs with amino acid spacers such as glycine and alanine, which released taxol faster in the enzymatic hydrolysis conditions, displayed better anti-tumor activities. Morphological studies demonstrated that the prodrug killed the tumor cells by inducing apoptosis, which confirmed the release of taxol from prodrugs. 5. The inhibition activities in vitro of taxol prodrugs against murine leukemia L1210, B16 melanoma and human breast cancer Bcap-37 xenograph were investigated using PEG-DA-Pro-Taxol as the model. At a dose level 20 mg·kg-1, the increased life span of L1210 tumor-bearing mice reached 49.6%, the tumor inhibition values for Bcap-37 xenograft and B16 melanoma were 71.43% and 56.26% respectively, which stated the high activity of this prodrug on the three tumor models. Compared with taxol, the efficacy of prodrugs was poorer, which might result from the non-optimized drug dose and treatment schedule. Judging from the body weight changes of experiment mice, the prodrugs seemed to...
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