Core-Shell Micelles With Hydrophilic Polymer As The Shell And Hydrophobic Drug As The Core

Hydrogen bond as important non-covalent force plays an important role instabilizing structure of biological macromolecules and in the process of buildingnanostructures also plays an important role. Because of the special structure of thehydrogen bond, which is a special molecule force between the donor molecules andacceptor molecules, it will be weakened or broken when external environment waschanged, resulting in the changing of molecular structure and properties. Based onthese characteristics, Hydrogen bond can be applied to targeted drug delivery. In thispaper, a hydrophilic carboxymethyl chitosan derivative (Py-CMCS) was preparedfrom chitosan. Based on the hydrogen bonds between pyridine groups and othermolecules, Py-CMCS·BA micelles and Py-CMCS·Mel micelles was prepared andstudied. The main work and conclusions are shown as follows:(1) Py-CMCS prepared from chitosan was characterized by FT-IR, NMR, etc.The degree of substitution, pH stability and Zeta potential were studied.Two different methods have been used for preparation of Py-CMCS forestablishment of a water-soluble well and high degree of substitution method byanalysis of its structure and properties.(2) The Py-CMCS·BA micelles was prepared and its self-assembly mechanism,particle morphology and load capacity to benzoic acid (BA) was studied.The core-shell Py-CMCS·BA micelles were self-assembled by Py-CMCS andBA at pH6.0. The hydrogen bonds between Py-CMCS and BA were confirmed byFT-IR. The core-shell structure of the micelles was confirmed by transmissionelectron microscope (TEM). By studying the load capacity of micelles to benzoic acid,it was fond that the load capacity of micelles to benzoic aci could be controlled bychanging the degree of substitution of pyridine group in Py-CMCS. This was usefulin application of drug loading.(3) The Py-CMCS·Mel micelles was prepared and its self-assembly mechanism,particle morphology, pH sensitivity and Zeta potential was studied.The core-shell Py-CMCS·Mel micelles were self-assembled by Py-CMCS andMelphalan (Mel) at pH7.4. The hydrogen bonds between Py-CMCS and Mel wereconfirmed by FT-IR. The core-shell structure of the micelles was confirmed by TEM and the micelles showed a relatively uniform size. Removal of Mel was conductedusing ethanol wash and hollow nanospheres were formed. The dynamic lightscattering (DLS) result showed that the micelles has a maximum diameter at pH5.0and a minimum diameter at pH7.4, and also the micelles had a lowest zetapotential of-32.5mV at pH7.4.(4) The in vitro release of Py-CMCS·Mel micelles was evaluated at differentpHs.The Py-CMCS·Mel micelles has a high drug loading rate (about24.53%). Themicelles release few drugs at pH7.0and pH7.4(10.04%and8.81%, respectively)due to the hydrogen bonds. But the micelles release drug rapidly (65.1%) at pH5.0due to the broken of hydrogen bonds. The in vitro cytotoxicity of Py-CMCS·Melmicelles showed that the micelles can rapidly release drug via a pH-triggeredmechanism upon entering cancer cells, thus significantly enhancing the therapeuticefficiency of Mel to tumor cells.This approach can achieve the integration of self-assembly and drug-loading ofmicelles-based drug delivery system, avoiding the multiple steps that currently usedin the preparation of drug-loaded micelles and using toxic cross-linkers and organicsolvents. The pH sensitivity of the core-shell micelles can be used in tumor pHtargeting. Furthermore, the carboxylic acid groups located on the surface of thecore-shell micelles could be available as a conjugation site of various targetingligands. Those make it has good application prospects in the field of tumor targeting.