Preparation, Characterization Of PH-Sensitive Polymer Nanoparticles And Controlled Drug Release Study

In recent years, polymeric micelles as drug delivery system have received great attention for cancer therapy. They have been shown to greatly improve drug water solubility as well as increase drug accumulation at the tumor sites via the enhanced permeability and retention (EPR) effect, resulting in better drugs’therapeutic efficiencies and reduced side effects. Due to existence of mildly acidic pH in the tumor tissues as well as in the endo/lysosomal compartments of cells, several pH-responsive micelles, such as ortho ester, hydrazone and acetal, have been developed for enhanced drug release and improved the drugs’ therapeutic efficiencies. In this thesis, two kinds of pH sensitive doxorubicin (DOX) polymer nanoparticles were designed. The preparation and characterization of polymeric micelles, pH-responsive release of drug, as well as in vitro anti-tumor activity were investigated.1. A monomer containing hexa-thiols (C-6SH) was synthesized and then modified with MAL-DOX. By using ethylene dimethacrylate (EGDMA) as crosslinker, we synthesized core-crosslinked nanoparticles with polyethylene glycol (PEG) shells and pH-sensitive drug delivery via click reactions of thiol-acrylate. Simply by adjusting the contents of the macromonomer (methoxypolyethylene glycol methacrylate, mPEG-MAC) in its reaction with ethylene diacrylate and a crosslinker containing hexa-thiols groups, the sizes of the nanoparticles could be easily tuned. The size and morphology of nanoparticles were determined by dynamic light scattering (DLS) and transmission electron microscope (TEM). In vitro drug release studies showed that DOX conjugated nanoparticles with hydrazone bond showed a pH-sensitive release behavior. In vitro MTT assays demonstrated that the nanoparticles efficiently inhibited the growth rate of the Hela cancer cells.2. A carboxyl functionalization pH-sensitive prodrug CA-DOX was prepared through the amidation reaction between DOX and cis-aconitic anhydride (CA). Aldehyde modified methoxypolyethylene glycols (mPEG-CHO) were grafted to the poly-L-lysine (PLL) with benzoic-imine linker. The unreacted amide of PLL then further conjugated with CA-DOX by acid sensitive cis-aconityl linkage. These comb-shaped amphiphilic polymers can assembled to form micelles with a hydrophobic DOX inner core and a hydrophilic PEG outer layer in water. The size of nanoparticles was determined by dynamic light scattering (DLS). In vitro drug release studies showed that DOX conjugated nanoparticles with cis-aconityl linkage showed a pH sensitive release phenomenon, that is, the releasing is significantly faster at mildly acidic condition with pH of 5.5 than that at physiological condition.