Coordination Bonding Based Mesoporous Silica PH Responsive Drug Delivery System

Ordered mesoporous materials have attracted increasing attention for their unique properties, including high specific surface areas, large pore volume and controllable pore size between 2 to 50 nm. They have great potential applications in various fields, such as adsorption and separation, catalysis, electrochemistry and drug delivery. Mesoporous material is a good candidate for hosting“smart”delivery systems that release the encapsulated drugs in response to external stimuli, such as pH, temperature, light irradiation and chemicals. Of these stimuli–responsive systems, the pH–sensitive system is of special interest. The extracellular pH of tumors is more acidic (pH 5.7–6.8) than that of blood and normal tissue, and the pH values in endosomes and lysosomes reach values as low as 5.5 and 5.0, respectively.In most cases, pH-responsive drug delivery systems have been constructed based on the formation or destruction of chemical interactions, such as hydrophobic effects, electrostatic interactions, hydrogen bonding and covalent bonding, by varying the pH value. Herein, a pH responsive drug delivery system based on the coordination bonds has been developed for the first time and its designability has been investigated in details. According to the pH sensitivity of various coordination bonds, organic group functionalized mesoporous silica nanoparticles were employed as typical carriers for hosting metal ion binders and guest molecules to form a“host-metal-guest”architecture. The cleavage of either the“host-metal”or the“metal-guest”coordination bond, in response to pH variations, gives rise to a significant release of guest molecules under designated pH conditions. The responsive pH onset of this pH–responsive system could be well tuned by controlling the type of metal ions and the properties of the functional groups of the guest molecule.Chapter 2. Construction and feasibility of a pH-responsive delivery system. Firstly, the pH sensitivity of various coordination bonds has been evaluated. The formation, cleavage, and pH sensitivity of the coordination bonds between metal ions and ligand molecules with different functional groups have been tested by UV spectroscopy. The formation and cleavage of the coordinate bonds are sensitive to the change in external pH, which gives rise to the effective loading and release of the guest molecules at designated pH of the medium. Secondly, organic group functionalized mesoporous silica nanoparticles with particle size of 50-400 nm and pore size of ³.5 nm have been synthesized by using anionic surfactant as template through co-structure directing method.Chapter 3. Amino group functionalized mesoporous silica for pH-responsive delivery system. Firstly, according to the drug molecular structure, two types architectures have been constructed: (i) a“NH₂-metal-drug”architecture, when anti-cancer drug with binding groups were used,; (ii) a“NH₂-metal-vector?drug”architecture, when anti-cancer drug with no significant binding groups were used, a vector bearing binding groups was employed, which was bonded to the model drug via covalent bond. Secondly, for pH-responsive delivery of anti-cancer drug with small molecular size (MX, DNR and DOX), some factors have been investigated: (i) the structure of the drug, (ii) the loading amount of amino groups on mesopore surface, (iii) the metal ions, (iv) the counter anionic ions of metal ions. The results show that a designated responsibility of pH-responsive delivery system could be well achieved by carefully choosing factors shown above.Chapter 4. Amino group functionalized large pore mesoporous silica for pH–responsive drug delivery system. Amino group functionalized mesoporous nanoparticles with pore size of 7.2–7.8 nm and particles of 500–800 nm in length and 300–500 nm in width have been obtained through post-synthesis method and co–condensation method. These large pore materials could be utilized as carriers for the drugs with large molecular size. BLM has been chosen as a model anti–cancer drug with large molecular size (3⁴ nm) and iron, essential for organisms, has been utilized for coordination bond center for both amino group and BLM. The coordination bonding based“NH₂–Fe–BLM”architecture can be easily formed on the amino groups functionalized mesopore surface. The anti–cancer drugs can be released under mildly acidic conditions (pH=6) by cleavage of either side of the“NH₂–Fe”or“Fe–BLM”coordination bonding triggered by pH reduction. After further functionalization of quaternary ammonium groups on the particle surface, mesoporous nanoparticles have good dispersity due to the static electrical repulsion; and good cell penetrating properties could be owed to positively charged quaternary ammonium groups.Chapter 5. A pH-responsive drug delivery system based on coordination bonding in a mesostructured surfactant/silica hybrid. To prevent the complexity in preparation and increase loading amount of drugs, a facile one-pot fabrication of a“host–metal–drug”coordination bonding system in a mesostructured surfactant/silica hybrid was developed. The mesostructure has been achieved by self-assembly of non-toxic and biocompatible F127 Pluronic non-ionic surfactant and silica source through real liquid crystal templating route, in which F127 acts as the host molecules. Metal ions such as Zn, Cu and Fe, and drugs have been introduced simultaneously into the mesostructure synthesis systems, to form“F127–metal–drug”coordination bonding architecture. The cleavage of the coordination bonds that are sensitive to variations in external pH, gives rise to the release of the drug under weak acidic conditions (pH 5.0-6.0). Furthermore, the pH-responsibility has been confirmed by cell assay and in-vivo tumor test, opening up new opportunities for the potential application as implants in anti-tumor therapies.Chapter 6. A biodegradable mesoporous chitosan/silica hybrid for pH-responsive drug delivery system. CTS as a functional linear polymer can be utilized in drug delivery system due to some excellent properties, such as non–toxicity, biocompatibility and biodegradation. Furthermore, chitosan is particularly attractive in regard to the presence of abundant amino groups. By introducing CTS into the framework of mesoporous hybrid, CTS can be utilized as“host”part in this pH-responsive delivery system based on coordination bonds. A biodegradable mesoporous chitosan/silica hybrid has been synthesized by self-assembly of F127, and biodegradable chitosan and silica source through a real liquid-crystal templating route. On the basis of chitosan/silica mesostructured hybrid, a“NH₂–Zn–DNR”has been constructed and the pH responsive release of DNR from“NH₂–Zn–DNR”coordination bonding system was achieved. A pH-responsive delivery of drug can be achieved using biodegradable mesoporous hybrid as carriers.