The Design Of Nanocomposites And Application For Drug Delivery System

Cancer has become one of the major diseases threatening human health because of low cure rate, high recurrence rate and fatality rate. Scientists have been committed to develop efficient methods for cancer treatment. Chemotherapy is the commonly used method in clinical treatment, but it can also cause damage to normal tissues. Photothermal treatment is a method which uses heat to treat tumor. It raises the temperature of local tumor to achieve the goal of killing cancer cells. This becomes the biggest advantage of photothermal therapy compared to chemotherapy. So, the international medical community called photothermal treatment "green therapy", while Japan experts also use "the spring of medicine comes" to describe it. Therefore, development of effective strategies to treat cancer combining small side effects of photothermal therapy with the high efficiency of chemotherapy drugs becomes a research focus. Nanocomposites have manyadvantages such as easy synthesis, controllable morphology, easy to modify, strong absorption in near infrared region, high drug loadings. These features made them good choices as drug carriers and photothermal therapy materials. In this paper, we synthesized many nanocomposites based on gold nanoparticles, graphene, mesoporous silica nanoparticles and so on. Then we built three drug delivery systems used for the treatment of cancer. The drug controlled release can be realized in particular stimulation, which provides new methods for the diagnosis and treatment of cancer.Chapterl. IntroductionIn this chapter, we first introduced some commonly used nano-drug carriers, including carbon nanoparticles, gold nanoparticles, mesoporous silica nanoparticels etc. Then we presented some basic knowledge of DNA. Lastly, we elaborated the purpose and meaning of our work.Chapter2. Construction and Applications of NRGO@DOX Nano -Drug Delivery SystemIn this work, nano-sized graphene oxide (NGO) was firstly reduced with dopamine (PDA-NRGO). And then, gold nanostars (GNSs) were loaded on PDA-NRGO to enhance its absorbance at NIR region via the formation of Au-catechol as well as Au-N bonds with PDA coating layer (NRGO-GNS). The resultant NRGO-GNS was then modified with thiolated poly(ethylene glycol) via formation of Au-thiol bonds with GNS and Schiff base reaction with PDA (PEG-NRGO). A chemotherapeutic drug of doxorubicin (DOX) was finally loaded on PEGylated NRGO-GNS to obtain GNS and DOX co-loaded NRGO (denoted as NRGO@DOX) via π-π stacking and hydrophobic interactions with NRGO. The as-prepared GNS and DOX co-loaded NRGO@DOX can be internalized into cancer cells via endocytosis owing to its nano-scaled particle size. The DOX molecules are unpackaged from NRGO in lysosome vesicles in an acid environment or laser irradiation-triggered manner. In a synergistic mechanism, NRGO@DOX hybrid nanoparticles inhibit the growth of primary tumor and prevent its metastasis by inducing cellular apoptosis and necrosis owing to DOX-mediated DNA degradation and laser irradiation caused hyperthermia effect. The NRGO@DOX can realize combinational chemotherapy and photothermal treatment of metastatic breast cancers. The TEM images, UV-vis spectra and FTIR spectra were used to characterize the nanocomposites. According to the fluorescence titration curve, the maximal DOX loading ratio is over 200%. In acid environment (pH=5.0), DOX releasing accumulation can reach 70%. Given laser irradiation, it can release over 80% in 9 h, even at low laser power (1.6 W·cm-2). Surprisingly, the speed of drug release was accelerated. Using 4.0W·cm-2 laser irradiate NRGO@ DOX for 90s, the temperature rose about 25℃. At the same time, our materials showed the concentration dependence and power dependence. Higher concentration and greater power can induce higher temperature rise. When injecting this nanocomposite into mice bore breast cancer and given near infrared laser, cancer cells can efficiently be killed. Meanwhile, metastasis was also inhibited.Chapter3. Construction and Applications of GNR@Pt Nano-Drug Delivery SystemIn this chapter, a novel polypeptide-wrapped gold nanorod (PGNR) platform with cisplatin (CDDP) loading for anti-cancer drug delivery was constructed. In the first step, we synthesized the poly (L-glutamic acid) (PGA), and then poly (ethylene glycol) and cysteamine were covalently grafted to get PEG-g-PGA-SH. Next, we introduced the folic acid to target cancer cells to get the FA-PEG-g-PGA-SH. The PGNRs were prepared by covalently coating the CTAB-protected GNRs with FA-PEG-g-PGA-SH copolymer. The resultant PGNRs were then loaded with CDDP to obtain GNR@Pt hybrid nanoparticles by forming coordination bonds between platinum and the carboxyl groups of PGA outer layer. The PEG corona improved the colloidal stability and biocompatibility of GNR-PGA nanoparticles and ready for ligand modification. When given laser irradiation, the hyperthermia effect induced by GNR upon laser illumination can inhibit the angiogenesis of solid tumor by destroying the endothelia cells. At the same time, the cytotoxic drug CDDP can also kill the cancer cells. Therefore, the nanocomposite we designed may realize the combination therapy of tumor treatment.Chapter 4. Construction of MSN@DOX Nano -Drug Delivery SystemIn this work, a drug delivery system based on mesoporous silica nanoparticlesand DNA was built. Firstly, we synthesized mesoporous silica nanomaterials (MSN). And then, we used APTES to obtain amino modified mesoporous silica (NH2-MSN). This NH2-MSN can be used as the carrier of drug molecules. After loading DOX into the NH2-MSN, we used DNA as a "gatekeeper" to block the drug in the hole. The single-stranded DNA (Si-DNA) we designed composed of 44 bases. Asymmetric hairpin structure was formed after annealing. There are 20 bases of unpaired state on the 3’ end, and 22 bases on the 5’ end formed double-stranded DNA. The single DNA can absorb on the surface of NH2-MSN because of electrostatic interactions, as a result, the DNA we used here can block drugs. Under the acid condition, the DNA formed triplex secondary structure, and divorced away from NH2-MSN surface to achieve controlled drug release.