Studies On Functional Nano/Microspheres Based On Chitosan Derivatives For Drug Delivery

Controlled drug delivery technology has attracted increasing attention since this technology offers numerous advantages compared to conventional therapeutic systems, by prolonging duration time, reducing side effects, and thus improving the therapeutic efficiency. Biodegradable polymers and some inorganic compounds have been extensively untilized as the drug carriers. Among them, nature polysaccharides have been widely used as drug delivery carriers because of their good biocompatibility and biodegradability. The research focus of this thesis has been concentrated on functional hybrid nano/microspheres based on chitosan derivatives for drug deliveryIn Chapter 1, the classification, properties of natural polymers as drug carriers are introduced. The recent progress in nano-sized drug delivery systems and targeting drug delivery systems are reviewed, with the emphasis on chitosan based nano/microparticles as drug carriers and natural polymer/inorganic hybrid drug delivery systems are introduced.In Chapter 2, calcium carbonate/carboxymethyl chitosan (CaCO3/CMC) hybrid microspheres and nanospheres were prepared by the precipitation of calcium carbonate in the aqueous solution containing CMC. Through adjusting the preparation conditions, the size of CaCO3/CMC hybrid particles could be easily controlled at micro- to nano-meter ranges with relatively narrow size distributions. The obtained microspheres and nanospheres were characterized by SEM, FTIR, XPS, TGA and DSC. The size and size distribution were measured by a particle size analyzer. Doxorubicin hydrochloride (DOX·HC1), a water-soluble anticancer drug, was loaded in the hybrid microspheres and nanospheres with a high encapsulation efficiency. The in vitro drug release showed that the release of DOX·HC1 from the microspheres and nanospheres could be effectively sustained. This study shows the CaCO3/CMC hybrid micro/nanospheres are also suitable for the controlled release of hydrophilic drugs.In Chapter 3, hydrophobic drug paclitaxel was loaded in the porous CaCO3/CMC hybrid microspheres. Due to the porous structure of the CaCO3/CMC hybrid microspheres, the drug could be easily loaded inside the microspheres with a high encapsulation efficiency. The drug loaded miscrospheres were characterized by SEM and TGA. Due to the extramely low water solubility of paclitaxel, the in vitro drug release was evaluated in the PBS containing 0.1% Tween 80. Because of the existence of the surfactant, paclitaxel could be released out gradually. Our study shows the CaCO3/CMC hybrid microspheres are also suitable for the controlled release of hydrophobic drugs.In Chapter 4, chitosan-cyclodextrin nanospheres were prepared by in situ formation through Michael addition between N-maleated chitosan (NMC) and per-6-thio-β-cyclodextrin sodium salt in an aqueous medium. This facile preparation method did not involve any organic solvent and surfactant. Through adjusting the preparation conditions, the nanospheres with relatively narrow size distributions could be obtained. The obtained nanospheres were characterized by TEM and particle size analyzer. Doxorubicin hydrochloride (DOX·HC1), a water soluble anticancer drug, was loaded in the nanospheres with a high encapsulation efficiency. The in vitro drug release showed that the release of DOX·HC1 from the nanospheres could be effectively sustained. The cytotoxicity evaluation showed the drug loaded nanospheres exhibited efficient inhibition on HeLa cells.In Chapter 5, calcium phosphate/carboxymethyl chitosan (CaP/CMC) hybrid nanospheres were prepared by the precipitation of calcium phosphate in the aqueous solution containing CMC. The obtained nanospheres were characterized by SEM, XPS and TGA. Doxorubicin hydrochloride (DOX·HC1), a water-soluble anticancer drug, was loaded in the nanospheres with a high encapsulation efficiency. The in vitro drug release showed that the release of DOX·HC1 from the nanospheres could be effectively sustained. After drug loading, the nanospheres were decorated by KALA peptide by self-assembly through electrostatic interactions. The size and size distribution of the nanospheres were measured by a particle size analyzer. The KALA decorated nanospheres exhibits an increased size and a decreased zeta potential. The effect of KALA content on the HeLa cell inhibition was studied. The in vitro study shows that the cell inhibition effect could be significantly enhanced by the presence of KALA and the cytotoxicity increases with increasing KALA content due to the enhanced cell uptake.