Studies On Preparation, Characterization And Preliminary Applications Of Biocompatible,Stimuli-Responsive,Hydrophilic And Polymeric Micelles & Hollow Spheres

Due to their unique structure and properties, nano-materials become a hot subject in material science. Self-assembly is the most efficient way to prepare various functional materials with ordered structure on multi-scales. Self-assemby of polymer chains to nano-materials is one of the mostly active research areas. Among these materials, polymeric hollow spheres have attracted special attention because of their stable structure and potential ability to encapsulate large-sized or large quantity of guest molecules.There are many routes to fabricate polymeric hollow spheres by self-assembly. The traditional route to prepare hollow spheres using block copolymer micelles as precursor is multi-step and fairly difficult. It includes the following steps: synthesizing block copolymer composed of cross-linkable block and degradable block, micellization of the block copolymer in a selective solvent, fixing the micelle structure by shell cross-linking and finally, the degradation of the micelle core. In recent years, our group has developed several new approaches to obtain "noncovalently connected micelles" (NCCM) based on so-called "block-copolymer-free" strategies. Differing from the traditional block copolymer micelles, the NCCMs have noncovalent interactions (mainly hydrogen bonding) connecting the core chains and the shell chains. Using NCCM as precursor, we can easily obtain hollow spheres by simply cross-linking the shell chains and subsequent dissolution of the core chains. This procedure could avoid the possible difficulties in the synthesis of the block copolymers and the subsequent degradation of the core chains. Thus, a broad range of common polymers can be used. In addition, the size and the thickness of the hollow spheres can be adjusted easily in a certain range through changing preparation conditions such as the weight ratio of the shell to the core. Using this method, Wang have obtained hollow spheres of cross-linked poly (4-vinylpyridine) in chloroform/nitromethane/DMF.Quite recently, driven by the requirements in biological and medicine sciences, the preparations of biocompatible, biodegradable and stimuli-responsive micelles and hollow spheres, and their solutions at high concentration became the new developing orientations. In the thesis, we first extended the block-copolymer-free strategies to aqueous solutions: biocompatible polymer, pH-responsive polymer and biodegradable polymer were selected to prepare biocompatible and pH-responsive hollow spheres. Combining self-assembly and free radical polymerization, we developed a new "polymerization in situ" method to fabricate core-shell thermo-sensitive nanoparticles and hollow spheres at higher concentration.Further work proved that the method is somewhat versatile and could be used to fabricate different core-shell polymeric nanoparticles. In addition, we studied the loading behavior of the core-shell thermo-sensitive nanoparticles with pyrene and dye DB79. Specifically, five sections of work were carried out as follows:(1) Biocompatible polyvinyl alcohol (PVA) and carboxyl-ended polybutadiene (CPB) self-assembled into non-covalently connected micelles of (CPB)-PVA with CPB core and PVA shell in water/THF (20/1, v/v). By cross-linking the PVA shell with glutaradehyde and cavitation of CPB core by dissolution with THF, PVA hollow nanospheres were obtained. DLS was used to study the pH dependence of CPB nanoparticles and (CPB)-PVA micelles, proving that the micelles were co-stabilized by the electrostatic interactions of ionized carboxyl end groups of CPB and the hydrogen bonding interactions between the unionized carboxyl end groups of CPB and hydroxyl groups of PVA. The influences of dilution, temperature, time and etc. on the stability of the micelles were also studied. Furthermore, we studied the effect of the initial concentration of PVA aqueous solution on the micelles and found that at a certain condition, there is a critical value for the number of PVA chains connected to CPB core through hydrogen bonding, and above the critical value, the surplus PVA chains exist in solution as free chains. DLS and FTIR were used to trace the shell cross-linking process of the micelles, and the influences of glutaradehyde concentration and cross-linking time were studied. The real cross-linking degree of the micelle shell was characterized quantitatively by FTIR. DLS was used to follow the changes in micelle diameter and scattering intensity during the cavitation process, i.e. removal of CPB core by dissolution with THF. The morphologies of the micelles, shell-cross-linked micelles and hollow spheres were observed by TEM, SEM and AFM. The influences of the shell thickness and cross-linking degree on the SEM morphologies of hollow spheres were also studied.(2) pH-responsive polyacrylic acid (PAA) and biodegradable poly (e-caprolactone) (PCL) self-assembled in the selective solvent, leading to the formation of non-covalently connected micelles of (PCL)-PAA with PCL core and PAA shell. The micelle shell was fixed by cross-linking PAA chains with di-amine, followed by cavitation through core-dissolution with DMF or core-biodegradation with enzyme. Thus, pH-responsive PAA hollow nanospheres were obtained. For the first time, it was found that stable nanoparticles formed when PCL solution was added dropwisely into water without surfactant, and it was proved that PCL nanoparticles were stabilized by both the hydrophilic interactions and electrostatic interactions. And the presence of a small amount of organic solvent is the key to the long-term stability of the nanoparticles in solution. The influences of the concentrations of initial PAA aqueous solution and PCL/DMF solution on the micellization were studied and it was found the micelle size has a minimum at a certain concentration of PCL solution. DLS and FTIR were used to trace the process of shell cross-linking and found that due to theinteraction between catalyst ETC for cross-linking reaction and PAA shell, the micelle size first increased and then decreased with the time. Changes in micelle size and scattering intensity during the core degradation process with enzyme were monitored by DLS. The results showed that the enzyme could form complex with PAA chains, leading to an initial increase in scattering intensity. TEM and SEM were used to observe the morphologies of the micelles, shell-cross-linked micelles, hollow spheres, and particularly the morphological change during the core cavitation process with DMF. DLS studies proved that PAA hollow sphere exhibited a large change in the diameter with pH: when pH of the solution raised from 6 to 8, the diameter increased from 126nm to 534nm corresponding to a 75 times volume expansion. Furthermore, this volume-pH dependence is found to be completely reversible provided the effect of ionic strength is excluded. The salt effect on the hollow sphere size was found to depend on pH, and the influences of the shell cross-linking degree and shell thickness on the pH- and salt- dependence of PAA hollow spheres size were also studied.(3) By combining self-assembly and polymerization, we developed a new "polymerization in situ" method to fabricate core-shell thermo-sensitive nanoparticles and hollow spheres. PCL nanoparticles containing a suitable amount of hydrophobic initiator AIBN were prepared by adding PCL/DMF solution in water. Water-soluble monomer N-iso propylacrylamide (NIPAM) and methylene bisacrylamide (MBA) as the cross-linker were introduced to the PCL dispersion, followed by raising temperature to initiate the polymerization. Polymerization mainly takes place on the surface of PCL nanoparticles, and the polymerization and self-assembly occur simultaneously, thus leading to nanoparticles with PCL core and cross-linked PNIPAM shell (PCL/PNIPAM). This method is simple and convenient. Furthermore, it can be used to prepare near mono-dispersed core-shell nanoparticles at higher concentration. The thermo-responsive behavior of the nanoparticles was studied by DLS. The nanoparticles were converted to PNIPAM hollow spheres after the degradation of PCL core. Changes in nanoparticle size and scattering intensity during the core degradation process of nanoparticles with enzyme were monitored by DLS. FTIR, SEM and TEM were used to characterize the change in the structure and morphology of the nanoparticles caused by core degradation with enzyme. A combination of DLS and SLS was used to characterize the temperature dependence of the diameter and structure of the nanoparticles and the corresponding hollow spheres, and it was found that the temperature dependence is completely reversible. Compared with nanoparticle, PNIPAM hollow sphere displays a larger size change with the temperature.(4) The relationship between the reaction conditions and the structure of the nanoparticles PCL/PNIPAM, including the influenences of the weight ratio of the total amount of monomer and cross-linker to that of PCL, target shell cross-linking degree, the concentration of initial PCL/DMF solution, and initiator content etc. on the size and its...