Design And Application Of Multifunctional Stimuli-Responsive Nano-Drug Delivery System

At present, cancer has become a severe threaten to human health. The main problems of cancer therapy are to enhance the therapeutic efficiency and improve the quality of patients' life. However, conventional chemotherapeutics suffer many unfavorable disadvantages, such as poor bioavailability, nonselectivity and undesirable side effects. To overcome these drawbacks, scientists have designed a multitude of intelligent nanodrug delivery system for increasing the efficiency of chemotherapeutic drugs. Under these circumstances, we designed a series of multifunctional smart drug delivery systems, which could specifically respond to endogenous or exogenous stimuli of tumor microenvironment and targetedly release the chemotherapeutics in the tumor region for achieving tumor-targeted therapy as well as reducing side effects. The detail is displayed as follow:In chapter one, the endogenous or exogenous stimuli of tumor microenvironment was introduced. Moreover, how to design multifunctional stimuli-responsive drug delivery systems and their application in drug delivery for tumor-targeted therapy was also introduced.In chapter two, a therapeutic system based on functionalized AuNPs which can specifically respond to tumor microenvironment was designed. In the therapeutic system, doxorubicin (DOX) was conjugated to AuNPs via thiol-Au bond by using a peptide substrate, CPLGLAGG, which can be specifically cleaved by the protease. Owing to nanosurface energy transfer effect, the fluorescence of DOX can be quenched by AuNPs. After arriving at tumor sites, the peptide substrate can be hydrolyzed by the overexpressed MMP-2 protease, leading to the pronounced fluorescence of DOX recovered from quenching to exciting state. Obviously, this switchable fluorescence property can be used for tumor imaging and the released DOX can further induce the apoptosis of tumor cells to achieve tumor inhibition.In chapter three, a bioinspired nano-prodrug (BiNp) was constructed by the assembly of an antineoplastic peptidic derivative (FA-KLA-Hy-DOX), which formed by the conjugation of a folate acid (FA) incorporated pro-apoptotic peptide (KLAKLAK)2 (KLA) to doxorubicin (DOX) via an acid-labile hydrozone bond (Hy). The hydrophobic antineoplastic agent DOX was efficiently shielded in the core of nano-prodrug. With the aid of FA targeting moiety, the obtained BiNp showed significant tumor-targeting ability and enhanced cancer cell uptake. Upon the trigger of the intracellular acidic microenvironment in endo/lysosomes, the antineoplastic agent DOX was released on-demand, inducing the apoptosis of cancer cells. Simultaneously, the liberated FA-KLA could induce the dysfunction of mitochondria and evoke mitochondria-dependent apoptosis. Both KLA and DOX collaboratively evoke the apoptosis of tumor cells.In chapter four, a ZnO based nano-cocktail with programmed functions was designed and synthesized for self-synergistic tumor targeted therapy. The nano-cocktail could actively target tumors via specific interaction of hyaluronic acid (HA) with CD44 receptors and respond to HAase-rich tumor microenvironment to induce intracellular cascade reaction for efficient tumor therapy. The exposed cell-penetrating peptide (R8) potentiated the cellular uptake of therapeutic nanoparticles into targeted tumor cells. Then, ZnO cocktail would readily degrade in acidic endo/lysosomes and induce the production of desired reactive oxygen species (ROS) in-situ. The destructive ROS not only led to serious cell damage, but also triggered the on-demand drug release for precise chemotherapy, thus achieving enhanced antitumor efficiency synergistically.In chapter five, to integrate treatments of photothermal therapy (PTT), photodynamic therapy (PDT), and chemotherapy, a multifunctional nanocomposite (MMSGNR-AIPCS4) based on mesoporous silica coated gold nanorod (MSGNR) was developed for high-performance oncotherapy. Gold nanorod (GNR) core was used as the hyperthermal agent and mesoporous silica shell was used as the reservoir of photosensitizer. The mesoporous silica shell was modified with ?-cyclodextrin (?-CD) gatekeeper via redox-cleavable Pt(?) complex for controlled drug release. Furthermore, tumor targeting ligand (lactobionic acid, LA) and long-circulating poly(ethylene glycol) (PEG) chain were introduced via host-guest interaction. In vitro and in vivo experiments revealed the improved tumor accumulation of MMSGNR-AIPcS4 as well as superior tumor growth inhibitory with reduced systemic toxicity. It was found that combining of the GNR-mediated PTT, PS-mediated PDT, and platinum-based chemotherapy makes such a nanocomposite a highly effective strategy for tumor-targeted therapy.