| Drug delivery system (DDS) exhibits many fascinating features, including changing drug biodistribution in the body and targeting drug to tumor tissue, improving the efficiency of drugs and decreasing the therapeutic side effects of drugs, which will become an effective means of treatment of cancer, and bring new opportunities for the detection and personalized treatment of cancer. With the development of science, the function of the conventional DDS cannot be enough to fulfill the development of pharmaceutical industry. Therefore, to achieve the best curing effect, we have to combine the materials of drug delivery and consider all kinds of factors, develop multi-functioned DDS.Polysaccharides from plants are not only good biocompatible, low toxicity, but also ease of biodegradable, absorption and metabolism within cell and living organism. Furthermore, sulfated modification of polysaccharide can enhance antitumor activity. If they can be used as the materials of drug carriers, it will be more effective to treat a disease by the cooperation of carriers and drugs. Gold nanomaterials (Au NMs) have unique advantages in physical, chemical and optical properties, which can achieve biological imaging and destroy the tumor cells by photo-thermal therapy. In recent years, Au NMs is used widely in the field of biomedicine and DDS. In this study, we synthesized several types of the novel multifunctional DDS used sulfated polysaccharide and Au NMs. They have attracted attention in the diagnosis and treatmeat of cancer. The details showed as followed:1. A water-soluble polysaccharides (POP1) was isolated from Portulaca oleracea L. Four sulfated derivatives of POP1(POP1-S1, POP1-S2, POP1-S3and POP1-S4) were prepared by chlorosulfonic acid method with N, N'-Dicyclocarbodiimide (DCC) as catalyst. FTIR spectra and C NMR spectra indicated the sulfated groups had been introduced at the C-6and C-2positions of POP1. Four kinds of sulfated polysaccharides had different degree of substitution (DS) ranging from1.01to1.81, and different weight-average molecular mass (Mw) ranging from41.4to48.5KDa. Sulfated polysaccharides except POP1-S5inhibited the growth of HepG2cells and Hela cells in vitro significantly, which indicated that sulfated modification could enhance cytotoxicity of POP1on tumor cells. Flow cytometric studies revealed that sulfated polysaccharides could mediate the cell-cycle arrest of Hela cells in the S phase.2. Sulfated derivatives of polysaccharide (GPP2) which was isolated from Gynostemma pentaphyllum Makino were prepared by chlorosulfonic acid method with ionic liquids (ILs) as solvent and4-dimethylaminopyridine (DMAP) as catalyst. The structures of the sulfated polysaccharides (GPP2-S) were analyzed by FTIR spectra and13C NMR spectra, which indicated that the sulfated groups were introduced mainly at the C-6position as well as at the C-2position. Four kinds of GPP2-S (GPP2-S1, GPP2-S2, GPP2-S3and GPP2-S4) with different DS were obtained by the different amount of CISO3H added into the reaction system. The products showed different DS ranging from0.79to1.34, and different Mw ranging from8.64to11.2Da. Compared with GPP2, the molecular mass decrease of GPP2after sulfated modification had not been observed. On the contrary, Mw of GPP2-S1and GPP2-S2had been a little increase. The sulfated polysaccharides inhibited the growth of HepG2cells and Hela cells in vitro significantly. However, they had no obvious influence on293cells, which indicated that they had low toxicity. Flowcytometric studies revealed that treatment of GPP2-S with Hela cells could mediate the cell-cycle arrest in the S phase.3. A kind of core-shell structured multifunctional nanocarriers (NCs) of ZnO quantum dots-conjugated gold nanoparticles (Au NPs) as core and folate (FA)-conjugated amphiphilic hyperbranched block copolymer as shell based on poly(L-lactide)(PLA) inner arm and FA-conjugated sulfated polysaccharide (GPPS-FA) outer arm (ZnO-Au-PLA-GPPS-FA) were synthesized for targeted drug delivery. The structure and properties of ZnO-Au-PLA-GPPS-FA NCs were characterized and determined by UV-visible spectra, FT-IR spectra, X-ray diffraction (XRD), dynamic light scattering (DLS), fluorescence spectroscopy and transmission electron microscopic (TEM) analyses. The anticancer drug, camptothecin (CPT) was used as a hydrophobic model anticancer drug. In vitro drug loading, release and cytotoxicity studies showed that ZnO-Au-PLA-GPPS-FA NCs not only had excellent capability in targeted drug loading and release, but also had certain antitumor activities, which would be more effective to kill tumor cells by the cooperation of carriers and drugs, and had an assistant role in the treatment of cancer.4. A kind of multifunctional nanocarriers of gold nanoclusters (Au NCs) as core and folate (FA)-conjugated amphiphilic hyperbranched block copolymer as shell based on poly(L-lactide)(PLA) inner arm and FA-conjugated sulfated polysaccharide (GPPS-FA) outer arm (Au NCs-PLA-GPPS-FA) were synthesized for targeted drug delivery. Au NCs-PLA-GPPS-FA copolymers showed highly fluorescence and good water solubility. The structure and properties of Au NCs-PLA-GPPS-FA copolymers were characterized and determined by1H NMR spectrum, FT-IR spectra, DLS, fluorescence spectroscopy and TEM analyses. In vitro the release results indicated that CPT release from the nanocarriers at pH9.6was much greater than that at pH5.3and7.4. The cytotoxicity studies showed that the empty nanocarriers had certain antitumor activities, which would be more effective to kill tumor cells by the cooperation of carriers and drugs. In vitro FA targeting showed that FA-conjugated nanocarriers exhibited higher inhibition ratio against Hela cells, compared with nanocarriers without FA molecule, but it had no obvious influence against A549cells. The results showed that FA-conjugated nanocarriers could be internalized in the target cell via FA-receptor-mediated endocytosis and kill tumor cells. The scanning confocal images studies showed that the nanocarriers could track at the cellular level for advance therapy.5. We described the design of a kind of multifunctional nanocarriers (ARPG/APPDCF nanostructures) as a dual delivery system that was completely stabilized via electrostatic self-assembly. ARPG/APPDCF nanostructures were created through electrostatic interactions by mixing nanocarriers of gold nanorods as core (Au NRs-PLA-GPPS copolymers) and nanocarriers of gold nanoparticles as core (Au NPs-P(LG-DOX)-CS-FA copolymers) in the ratio of1:4(m/m). The structure and properties of ARPG/APPDCF nanostructures were characterized by1H NMR spectrum, FT-IR spectra and TEM analyses. The anticancer drug, CPT and doxorubicin (DOX) were used as a hydrophobic model anticancer drug. In vitro we studied two kinds of drug loading yield, release behavior and cytotoxicity using ARPG/APPDCF nanostructures. The results indicated that ARPG/APPDCF nanostructures not only showed high drug loading contents, tumor-targeted drug delivery and photoactivated therapy of Au NRs, but also could be more effective to kill tumor cells by the cooperation of two kinds of drugs and reduce use of nanocarriers. However, Au NPs-P(LG-DOX)-CS-FA copolymers was less around Au NRs-PLA-GPPS copolymers due to weaker electrostatic attraction, which did not achieve the initial plan. To obtain preferable structure, we must find stronger interaction for self-assembly of ARPG/APPDCF nanostructures. |
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