Preparation Of Stimuli-responsive Nanomaterials And Their Application In Controlled Drug Delivery

Cancer remains one of the biggest challenges in the medical field with chemotherapy being the major treatment modality. However, conventional chemotherapy suffers the disadvantages of strong side effect, low drug bioavailability, inability to bypass biological carriers, and lack of specific recognition, which maybe the cause of treatment failure in cancer. Nanomaterials have been emerged as an effective tool for the diagnosis and treatment of cancer and widely used in biomedical field due to their unique characteristics, such as small size, large surface area, chemical reactivity, mechanical property and optical property. Stimuli-responsive controlled drug delivery systems constructed from nanomaterials have shown the potential to overcome these problems existing in conventional chemotherapy, which can achieve targeted delivery of the anticancer drug to the tumor site, improve the therapeutic effect, and decrease the side effect. In the stimuli-responsive delivery system, the anticaner agent can be released by an appropriate stimulus (for example, pH, redox, thermal, light, magnetic field, and enzyme). Among all the applied stimuli, pH and redox have been considered as ideal triggers for the selective release of anticancer drugs.In the past decades, mesoporous silica nanoparticle (MSNs) and block copolymer have received continous and wide attentions as the typical inorganic and organic materials, respectively. MSNs have been developed to be novel biocompatible drug nanocarriers owing to their unique mesoporous structure, large surface areas, tunable pore and convenient modification, which show great potential in controlled drug delivery. Block copolymers can self-assemble into micelles, which can be utilized as ideal nanocarriers for drugs with many advantages, such as excellent biodegradability and biocompatibility, uniform size, ability of loading hydrophobic drugs, and convenient pegylation. However, drug delivery systems based on both MSNs and block copolymes are facing the similary problem, that they cannot avoid release drug before reaching the targeted cells or tissues. Based on the research background as above, four novel types of controlled drug delivery systems that triggered release of anticancer drugs including doxorubicin (DOX) and paclitaxel (PTX) by pH or redox stimuli were designed and evaluated in vitro. In summary, this dissertation includes four parts as follows:(1) pH responsive polymer poly(acrylic acid)(PAA) was covalently grafted onto the surface of mesoporous silica nanoparticles via the amidation reaction between PAA homopolymer and amino group functionalized MSNs. The resultant PAA-MSNs were uniform spherical nanoparticles with a mean diameter of approximately150nm, and could be well dispersed in aqueous solution. Doxorubicin hydrochloride (DOX), a well-known anticancer drug, could be effectively loaded into the channels of PAA-MSNs with drug loading reaching up to48%. The drug release rate of DOX@PAA-MSNs was pH dependent and increased with the decrease of pH.(2) A PTX prodrug based on a disulfide linker was synthesized, and its drug delivery mechanism was determined through HPLC characterization. Utilizing the carboxyl group of the prodrug, PTX was covalently conjugated to the surface of amino-functionalized FMSN, with a disulfide linker as a spacer to bridge between PTX and FMSN. The most important feature of this nanoscale CDDS is that the PTX prodrug modules conjugated with FMSN can be activated to its cytotoxic form inside the tumor cells upon internalization and in situ drug release. To prove the efficacy of this CDDS, glutathione-mediated intracellular drug delivery was investigated against the HeLa cell line, and the results indicated that our CDDS showed higher cellular proliferation inhibition against glutathione monoester pretreated cells than against untreated cells and the cytotoxicity increased with increasing intracellular glutathione concentration. The result indicates that CDDS can release PTX molecules to kill cancer cells and the release behavior is GSH-dependent.(3) A series of well-defined amphiphilic triblock copolymers, PEG-b-P/BA-b-PHEMA, were synthesized via successive atom transfer radical polymerization (ATRP) using a PEG-based macroinitiator. The critical micelle concentrations (CMC) of obtained amphiphilic triblock copolymers were determined by fluorescence spectroscopy using N-phenyl-1-naphthylamine as probe. The morphology and size of formed aggregates were investigated by transmission electron microscopy and dynamic light scattering, respectively. Finally, an acid-sensitive PEG-b-PtBA-b-P(HEMA-CAD) polymer-drug conjugate via cis-aconityl linkage between doxorubicin and hydroxyls of triblock copolymers with a high drug loading content up to38%, was prepared to preliminarilyexplore the application of triblock copolymer in drug delivery. The in vitro experiment demonstrated that the drug release of conjugate was pH-dependent and the release rate was much faster at lower pH.(4) PEG-b-PHEMA was synthesized via ATRP and the PTX prodrug synthesized in the above was grafted onto the polymer chain of PEG-b-PHEMA. This new polymer-drug conjugate PEG-b-P(HEMA-PTX) can self-assemble into spherical micelles with a mean diameter of approximately200nm. In vitro cytotoxicity showed that the cytotoxicity of PEG-b-P(HEMA-PTX) micelles showed higher cellular proliferation inhibition against glutathione monoester pretreated HeLa cells than that of the nonpretreated ones, and increased with the concentration of GSH inside cells.