Fabrication Of Multi-functional Polymeric Nano-pharmaceuticals And Their Application In Tumor Theranostics

At present, chemotherapy remain the cornerstones in the therapy of cancer. However, the drug was with poor solubility in aqueous, worse biodistribution, non-specificity to cancer sites and damage to normal tissues, and more importantly, the drug would induce the multidrug resistance(MDR), and it could be cleared through the renal osmosis or pumped out of cells by overexpressed multidrug resistance proteins. So, for alleviating the side effects which was caused by the cytotoxic anticancer drug in the treatment of cancer, the drug delivery system should be designed with multistimuli responsiveness, and passive or active targeted transported to tumor tissues. Furthermore, if the system was decorated with the fluorescent substance, it could achieve the aim of the real-time and noninvasive monitor to tumor tissues. Therefore, this thesis principally discussed the fabrication of multi-functional polymeric nano-pharmaceuticals and their application in tumor theranostics. This dissertation mainly included the following parts.1. The reduction/pH dual stimuli-responsive fluorescent copolymer of PEG-Cys-P(DEAEMAco-Rh6GEAm) was synthesized by RAFT polymerization. The biodegradable disulfide linkages could disintegrate in reductive condition. As a carrier, the amphiphilic PEG-Cys-P(DEAEMA-coRh6GEAm) could easily form micelle in water, DOX was loaded into the PEG-Cys-P(DEAEMAco-Rh6GEAm) micelles by a nanoprecipitation technique. Due to the pH responsiveness of PDEAEMA segments, the leakage of DOX can be controlled, and avoided release in the simulated normal physiological condition. It had a high release ratio with the synergetic effect of reductive agent and pH. Furthermore, the fluorescence intensity of the copolymer was experienced the reversibly transformation in different media pH. The reduction/pH dual stimuli-responsive and the strong fluorescence at faintly acid media had built a platform for the micelles in the application of drug controlled release and real-time fluorescent imaging of tumor tissues.2. The natural polymer drug delivery system FA-PEG-HA-CDs was obtained by two successive steps of amidated reactions, which had perfect biocompatibility, targeting in tumour cells and ideal fluorescence property. Due to the existence of abundant carboxyl groups, the DOX could be loaded by electrostatic interaction. The diameter of the nanoparticles in water was about 43 nm, so it was favorable for the prodrug to enter into the tumour tissues to release medicine. The release ratio of DOX was increased with the increase of the acidity. The biocompatibility of the FA-PEGHA-CDs was better and the cancer kill efficiency of DOX-loaded FA-PEG-HA-CDs was outstanding. Thus, this drug carrier could reach the goal of controlled smart release and real-time fluorescent imaging in the tumor tissues or cancer cells.3. Fluorescent P(MAA-co-PEGMA-co-RhBAh) nanoparticles were synthesized as drug delivery system(DDS) for anti-cancer drug via facile distillation-precipitation copolymerization. Their bio-reducible disulfide crosslinking structure could disintegrate in reductive media, introducing the reduction-responsive degradability. The DOX could be loaded via the strong electrostatic interaction between the carboxyl groups of PMAA segments and the amino group of DOX. Thus a rapid drug release could only take place in acidic reductive media, such as rapid intracellular drug release in tumors via the synergetic effect of GSH and acidic condition. The DOXloaded P(MAA-co-PEGMA-co-RhBAh) nanoparticles could be successfully uptaken by HepG2 cells and the DOX was released and mainly accumulated in cell nucleus. Furthermore, the P(MAAco-PEGMA-co-RhBAh)-a nanoparticles showed strong fluorescence at low pH media. It might be used for the real-time fluorescent imaging in cancer diagnosis.4. The drug delivery system mPEG-OAL/CDs was acquired by two successive steps of amidated reactions based on natural polymer, and it was better biocompatible, pH stimuli-responsive and fluorescent. The DOX was conjugated onto the precursor through reacting with the aldehyde groups to form the Schiff base. The size of the prodrug in water was near to 55 nm, it was transported into the tumor tissues with ease. The release of DOX was controlled without burst release in the tumor microenvironment while the imine bonds were relatively stable to avoid injuring the normal tissues. And then, the special fluorescence characteristic would be applied in the tracing of prodrug. The platform established by the biocompatibility, pH stimulisensibility, and fluorescent responsiveness for the prodrug would be applied in the real-time fluorescent imaging of cancer nidus sites.5. The water-soluble pH stimuli-responsive fluorescent copolymer of P(PEGMA-b-(MAH-coRh6GEAm)) was synthesized by two-step sequential RAFT polymerization. The prodrug was prepared by coupling doxorubicin(DOX) onto the copolymer via acid-cleavable hydrazone bond, formed between the carbonyl group of DOX and abundant hydrazide functional groups in the copolymer. The amphiphilic DOX-conjugated prodrug(P(PEGMA-b-(MAH-DOX-coRh6GEAm))) could easily form a micelle in water with Dh of less than 100 nm. It could be transported into HepG2 cells and release DOX without burst release, while the leakage of DOX can be avoided in the simulated normal physiological media. Furthermore, its fluorescence intensity experienced a reversible change with the transformation of the media pH. The better biocompatibility, pH stimuli-responsiveness, and the strong fluorescence at low pH media make the nanoparticles a potential platform for the controlled release of anticarcinogens and real-time fluorescent imaging of tumor tissues.