Investigation On Preparation, Self-assembly And Drug-loading Property Of Cyclotriphosphazene Derivatives

Polyphosphazenes, macromolecules with an alternative phosphorus and nitrogen backone, provide an ideal background and open the door to a wide range of useful materials for advanced technology, which are among the most versatile of all polymers. This is a consequence of the unique properties of the phosphorus-nitrogen backbone and the ease with which a wide range of different side groups can be introduced mainly by macromolecular substitution and secondary substitutions. This field has reached a stage where the fundamental chemistry now allows the design and synthesis of a broad range of new materials that are valuable for fine-tune properties through different side groups or combinations of groups that led to the development of numerous biomedical initiatives.In this thesis, two types of cyclotriphosphazenes have been synthesized. One type is the hydrophobic cyclotriphosphazenes, such as hexa-[p-(carbonyl tryptophan ethyl ester) phenoxy)] grafted cyclotriphosphazene (HEPCP) and hexa-[p-(carbonyl glycin methyl ester) phenoxy)] substituted cyclotriphosphazene (HGPCP). Another type is the amphiphilic cyclotriphosphazenes, which is grafted with hydrophobic glycin methyl ester and hydrophilic MPEG5000chain with ratio of4:2(MMPCP) and inarched with hydrophobic tryptophan ethyl ester and hydrophilic MPEG1000chain with ration of3:3(EMPCP). The structures of such four products are confirmed by FT-IR,GPC,MS,NMR, and the thermal stability, hydrolysis and fluorescent properties are further researched by DSC,TGA,UV,LS, CLSM. The self-assembly of cyclotriphosphazenes with different structure has been achieved by dialysis, emulsification and desolvation methods, respectively. Also, the multi-functional drug-loaded platform is fabricated by self-assembly of amphiphilic cyclotriphosphazenes, curcumin and magetic nanoparticles of Fe3O4.It is shown by UV and TGA analysis that the synthesized cyclotriphosphazenes are thermal stability and biodegradable. It is also illustrated by DSC and XRD results that both the hydrophobic HGPCP and HEPCP are amorphous structure, and the amphiphilic cyclotirphosphazenes of MMPCP and EMPCP are partially crystalline due to the substitution of MPEG chain. The fluorescent property of hydrophobic cyclotriphosphazenes is explored by LS and both HGPCP and HEPCP exhibit strong fluorescent emission which is easily observed by CLSM. The cell toxicity is also examined for amphiphilic cyclotriphosphazenes, and the results show that the cell toxicity are depended on the concentration of MMPCP and EMPCP, which are distributed in cytoplasm and organelle.The nanoparticles have been fabricated through self-assembly of hydrophobic cyclotriphosphazenes such as HGPCP and HEPCP by desolvation method. The morphology of the nanoparticles is observed by SEM and TEM, and the influence of reaction conditions on the self-assembly process is also explored. The particle size distribution and stability are studied by DLS. All the experimental results show that the self-assembly aggregations from hydrophobic cyclotriphosphazenes are uniform and spherical nanoparticles with smooth surface, exhibiting strong fluorescent emission. It has been found that the nanoparticles in solution could lead to secondary assembly to form nanoparticles monolayer which is indicative of lyophilization for the nanoparticles.The self-assembly process of hydrophobic cyclotriphosphazenes is explored by critical water content (cwc) experiments, and the mechanism is clarified based upon the experimental results with connection of the theoretical and structure simulation. The thermal stability of HEPCP nanoparticles is increased, and the cwc value for self-assembly of HEPCP should be above the solution concentration while which is independent with solution concentration. The self-assembly mechanism of HEPCP is proposed as follows:when the water content is reached to cwc, numerous micro-W/O-system are formed due to the HEPCP molecule is not dissolved in water which is shortened the distance between HEPCP molecule. As the water content is increased up to cwc, the molecular distance was shortened enough to lead to the HEPCP aggregation induced by intermolecular noncovalent interactions. While the thermal stability of the HGPCP nanoparticles is decreased, and the the cwc value for self-assembly of HGPCP is also related to the solution concentration. The self-assembly of HGPCP could be processed even though at diluted solution, which is indicated that the self-assembly of HGPCP molecules to nanoparticles was driven by the intermolecular hydrogen bonds with participation of water molecule.The hydrophobic anti-cancer curcumin can be encapsulated by amphiphilic cyclotirphosphazenes of MMPCP through emulsification because the formation of hydrogen bonds between the amide bonds on the glycinmethylester and cyclotirphosphazene arm and water molecule. Such technique could be fabricated the multi-functional drug-carriers such as dissolution improvement, EPR-targeting and drug-release. The nanoparticles have been also self-assemblied from EMPCP through dialysis method, which is further interacted with curcumin to form drug-loaded nanoparticles. The particle size of EMPCP drug-loading nanoparticles is decreased with narrow size distribution.The magnetic nanoparticles of Fe3O4synthesized by polyol process can easily be dispersed in water media with excellent colloid stability and MRI enhancement effect. It is confirmed by TEM and magnetic measurement that the magnetic nanoparticles and curcumin can be simultaneously capped by amphiphilic cyclotirphosphazenes. Thus, a multi-functional drug-loading platform, with guided delivery by outside magnetic field, MRI imaging, EPR effect, fluorescent tracing, is constructed by interaction between MPEG in amphiphilic cyclotriphosphazene and polyol on the surface of Fe3O4.