Synthesis Of Novel Cyclodextrin Polymers And Study On Their Controlled Drug Release Mechanism

Cyclodextrin polymers and environmental sensitive polymers have been studied and applied extensively in the field of the biomedical materials. The combination with these two polymers possesses a potential application in controlled drug delivery system. In this paper, the novel cyclodextrin polymers were synthesized based on macromolecular design. The relationship between their molecular structure and physical properties was researched in detail. The mechanisms of controlled drug release were investigated by using two anti-cancer drugs, chlorambucil (CHL) and camptothecin (CPT), as the model medicines.In order to obtain novel cyclodextrin polymers, two kinds of cyclodextrin-containing reactive monomers were synthesized. Monomers were first synthesized including iodide substituted and carrying reactive group of β-CD-6-I and β-CD-6-CHO which can react with some functional polymers. Mono-[6-(2-acryloylaminoethyl) amino]-6-β-CD (β-CD-6-EA) and acryloyl-β-CD both carrying vinyl groups which can be polymerized with other functional monomers were also synthesized. The results indicated β-CD-6-EA can be obtained by using dicyclohexylcarbodiimide (DCC) as condensation agent with a higher yield. By using different reaction conditions and acylation agents including m-nitrophenyl esters, acrylyl chloride and acrylic acid, the different molecular structure with different substitution . degree of acryloyl-β-CD were synthesized. Two kinds of β-CD-containing acrylic monomers, β-CD-3-A and β-CD-6-A carrying the same vinyl groups, were prepared relying on their reactivity of different hydroxyl groups in cyclodextrin. Nuclear magnetic resonance (¹³C NMR) data indicated that, for β-CD-3-A, acylation occurs at C-2 and C-3 position of β-CD, and for β-CD-6-A, the acylation occurs at its C-2 and C-6 position, respectively.Two functional hydrogels, β-CD-DMA and β-CD-AAc, were synthesized by copolymerization of β-CD-3-A and β-CD-6-A with N,N-dimethylaminoethyl methacrylate (DMA) and acrylic acid (AAc) using a redox initiator system in aqueous solutions. The hydrogels were characterized by Infrared spectroscopy (IR) and element analysis. The equilibrium swelling experiments showed that the hydrogels possess pH-, ionic strength and thermo-sensitivities. However, due to the difference of monomer structures, the physical properties of hydrogels, especially their swellingbehavior in response to the external stimuli, exhibited certain difference. It can also be observed that the transition regions for both hydrogels decrease with the increase in contents of /2-CD-3-A or /2-CD-6-A. A novel /?-CD containing linear polymer (PDMA-/2-CD) which has both thermo- and pH-sensitives was synthesized by quatemization of poly-AfjV -dimethylaminoethyl methacrylate (PDMA) using iodide substituted fi-CD as quaternizing agent. The polymer was characterized by IR, 'H-NMR and element analysis. The aqueous solubility experiments showed that the polymer with 30.43(wt)%/?-CD still exhibited pH-, ionic strength and thermo-sensitivities. However, due to the introduction of hydroxyl groups in /?-CD and quaternizing tertiary amine groups, the solubility of novel polymer synthesized, in response to the external stimuli, was much weaker than that of PDMA. Moreover, the other yff-CD containing linear polymer was synthesized by immobilizing /3-CY) onto the linear chain of PVA through acetalization reaction. The optimum reaction condition was determined in which the feed weight ratio of /2-CD-6-CHO with PVA is 4:1 and reaction temperature is at 70°C for two hours. The macromolecular structures of PVA-/2-CD were characterized by IR and NMR.To understand the molecular interaction mechanism of inclusion complex between /?-CD and the medicine, the supra molecular interaction between parent /?-CD with varying drugs such as nicotine, CHL and CPT in aqueous solutions was studied by UV-vis spectrophotometric, 'H-NMR, fluorescence measurement, phase and solubility method. It was found that the inclusion complexes between fi-CD and drugs were indeed formed. The results were further demonstrated by a competitive inclusion process using phenolphthalein as a molecular probe. UV-vis spectrophotometric titration was used to calculate the stability constants of an inclusion complex between /3-CD and CHL in different pH buffer solutions at 10°C. It was found that the inclusion complexes with stoichiometry were formed with a ratio of 1:1 for the fi-CD and CHL under various experimental conditions. Besides, there exists a greater stability constant in pH=4 buffer solution at 10°C. For the system of /2-CD/CPT, the phase solubility method and fluorescence measurements showed that fi-CD and CPT can form inclusion complexes with a ratio of 1:1 under pH values of 2 and 11. The corresponding inclusion constants are 1.19 x 102 L/mol and 4.48 xlO3 L/mol, respectively. The solid inclusion complexes of /?-CD/nicotine, /2-CD/CHL and /2-CD/CPT were also prepared, and the results of IR, DSC and powder X-ray diffraction data indicated that there existnovel crystalline structures for inclusion complex. Then, the inclusion effects of PDMA-/2-CD were obtained by the method of UV-vis spectrophotometric titration using phenothalin as molecular probe, and the inclusion constant of PVA-/3-CD with CPT was also determined.The mechanisms of controlled release were studied by using the cyclodextrin polymer at different medium. The drug release behavior in different polymer matrixes presented marked difference in accordance with release media and the structure of polymers. For hydrogels /J-CD-DMA system, it was observed that due to the inclusion of /?-CD with the CHL, the release rate was lower than in PDMA. However, for the hydrogels /?-CD-AAc, the release rate for CHL was higher than in PAAc. The release rate at pH=6.8 was also higher than of at pH=2.0. In addition, The release of CPT from PVA-/J-CD films showed that due to the formation of inclusion complex of PVA-/2-CD with the drug, the solubility of the CPT increases greatly. And the cumulative release rate and extent can be effectively improved with the increase in P-CD content. A chitosan film containing /3-CD (/3-CD-SUS/CTS) was obtained by sodium succinate /?-cyclodextrin ester (/^CD-SUS) cross-linked with chitosan (CTS) via electrostatic.interaction. Turbidimetric titration revealed that there are electrostatic interactions between /2-CD-SUSO and CTS. The film showed pH value sensitivity depending on degree of ionzation as well as its the swelling ratio. The release behavior of CPT from the inclusion complex film indicated that the release ratio of CPT is affected by inclusion of /2-CD-SUS with CPT as well as ionic interaction of /KD-SUS with CTS.