Nanoparticles have received great attention as drug delivery system. It is believed that the nanoparticles can effectively enhance the selectivity and bioavailability of the drugs, thus to improve the efficacy of cancer therapy. However, the design and preparation of functionalized and responsive polymeric materials for the construction of smart drug delivery system has been a great challenge. This dissertation has focused on the fabrication of stimuli-responsive degradable nanoparticles and their applications as drug delivery system. First, we have prepared two amphiphilic functionalized block copolymers with different structures (AB linear-brush and ABC linear copolymer) based on the functionality of polyphosphoesters, and further studied their micellization process, biodegradability and biocompatibility. Second, we have synthesized amphiphilic and stimuli-responsive ABC star polymer and a series of Janus dendrimers, and investigated their stimuli-triggered morphological changes as well as the responsive cargo release. Last, based on the extracellular and intracellular pH conditions, we have constructed pH-responsive drug delivery system to simultaneously enhance cellular uptake of the drug carriers and promote intracellular drug release. This dissertation can be further categorized into five main parts as described below:1. Amphiphilic linear-brush diblock copolymer of poly(ε-caprolatone)-b-polyphosphoester (PCL-b-PPEG) and linear triblock copolymer of poly(ethylene glycol)-b-poly(ε-caprolatone)-b-poly(2-aminoethyl ethylene phosphate) (mPEG-b-PCL-b-PPEEA) based on functionalized polyphosphoesters have been successfully prepared by ring-opening polymerization. This represents the first preparation of well-defined amphiphilic block copolymers based on functionalized polyphosphoesters. The two kinds of amphiphilic copolymers self-assemble into core-shell micelles in aqueous solution and the critical micellization concentration (CMC) increases with the increase of the length of hydrophilic block while decreases with the increase of the length of hydrophobic block. Both of them are biodegradable and biocompatible, showing great potential as drug delivery carriers. In addition, the mPEG-b-PCL-b-PPEEA micelles exhibits positive change due to the presence of amino groups on the polymer, and can be used to deliver small interfering RNA (siRNA) for cancer therapy. They have shown efficient inhibition on tumor growth, which further demonstrates the practical value of functionalized polyphosphoesters.2. We have introduced the concept of UV-induced morphological transition from polymeric micelles to vesicles. Combining ring-opening polymerization and click chemistry, we have successfully prepared a UV-responsive three-armed star polymer ECE, in which a PEG block can be detached from the polymer upon UV irradiation, The UV-driven detachment of PEG from the ECE results in the significant decrease of PEG fraction, thus it promotes the micelle-to-vesicle morphological transition. Compared with the reported thermo-induced morphology change, this UV-responsive methodology shows significant advantages: (1) it remarkably reduces the morphology transition time from several weeks or months to four days; (2) the size and morphology of the resultant vesicles can be maintained without any chemical or physical crosslinking.3. A series of UV-responsive, redox-responsive or pH-responsive amphiphilic Janus dendrimers have been synthesized via the modular syntheses. This represents the first report on stimuli-responsive amphiphilic Janus dendrimers. The structures of all the intermediates and final products have been confirmed by 1H NMR, 13C NMR and ESI-MS analyses. Besides, the expectant responsiveness of each Janus dendrimer has been well validated, demonstrating that the modular syntheses method is potent in construction of responsive amphiphilic Janus dendrimers, which will contribute to the applications of dendrimers. In addition, these Janus dendrimers self-assemble into micellar nanoparticles in aqueous solution and show stimuli-responsive cargo release, which implies their potential for drug delivery application.4. It has long been a significant challenge in cancer therapy to activate the stealth nano-drug carriers at tumor site so as to enhance the internalization by tumor cells. Herein, we have developed a tumor-acidity-activated charge-conversion PAMA-DMMA nanogel that can efficiently solve the problem. Our results demonstrate that the PAMA-DMMA nanogel is negatively charged and does not interact with bovine serum albumin (BSA) at neutral pH (pH 7.4), showing potential for long circulation in blood and enhanced accumulation in tumor site via the enhanced permeability and retention (EPR) effect, whereas at tumoral pH (pH 6.8) the nanogel quickly reverses its charge from negative to positive, which remarkably enhances its interaction with BSA. The confocal laser scanning microscopy (CLSM) and flow cytometry (FACS) measurements demonstrate that the charge-conversionalPAMA-DMMA nanogel can significantly promote the cellular internalization by MDA-MB-435s cells at pH 6.8. The intra-tumoral injection of nanogels also demonstrates that the PAMA-DMMA nanogel is activated by the in situ tumor acidity and the tumor cell uptake is enhanced. More importantly, the nanogel can efficiently encapsulate anticancer drug doxorubicin hydrochloride with high drug loading efficiency above 98%. The cell inhibition assay demonstrates that the drug loaded PAMA-DMMA nanogel has great potency in killing cancer cells. Therefore, we conclude that the tumor-acidity activated charge-conversional PAMA-DMMA nanogel is promising as drug delivery system for cancer therapy.5. To further improve the drug efficacy for cancer therapy, we propose the concept of tailor-made dual pH responsive nanoparticles as drug delivery carriers. With the combination of ring-opening polymerization and post-polymerization modification, we have obtained a polymer-doxorubicin conjugate PPC-Hyd-DOX-DA, which can simultaneously respond to pH environments of both tumor site and endosome/lysosome. PPC-Hyd-DOX-DA conjugate self-assembles into micellar nanoparticles with the diameter of 27 nm in aqueous solution. The nanoparticles reverse their charge from negative to positive under the stimulation of tumor acidity (pH 6.8) and release DOX at endosomal pH value (pH 5.0). The cellular level results detected by CLSM and FACS analyses demonstrate that the dual pH responsive PPC-Hyd-DOX-DA nanoparticles can simultaneous enhance cellular uptake and facilitate the intracellular drug release, whereas single pH responsive controls are not able to achieve such a goal. In addition, it has also been confirmed that the dual pH responsive PPC-Hyd-DOX-DA nanoaprticles enable remarkably inhibition to the sphere formation of SK-3rd cancer stem cells, indicating that the dual pH responsive drug delivery method is potent in killing the drug-resistant cancer stem cells, which further provides a novel strategy for the development of nanoparticular delivery system for cancer therapy. |