title: Stepwise orthogonal click chemistry toward fabrication of paclitaxel/galactose functionalized fluorescent nanoparticles for HepG2 cell targeting and delivery.
abstract: In this report, we used stepwise orthogonal click chemistry (SOCC) involving strain-promoted azide-alkyne cycloaddition (SPAAC) and microwave-assisted Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) to assemble an anticancer drug (paclitaxel, PTX) and a targeting ligand (trivalent galactoside, TGal) on a fluorescent silicon oxide nanoparticle (NP) by using dialkyne linker 8 as a bridge. The fluorescent NH2@Cy3SiO2NP was fabricated using a competition method to incorporate Cy3 without loss of the original surface amine density on the NPs. The concept of SOCC was first investigated in a solution-phase model study that showed quantitative reaction yield. In the fabrication of TGal-PTX@Cy3SiO2NP, the expensive compound azido-functionalized PTX 12 used in SPAAC can be easily recovered due to the absence of other reagents in the reaction mixture. High loading of the sugar ligand on the NP surface serves a targeting function and also overcomes the low water solubility of PTX. Confocal fluorescence microscopy and cytotoxicity assay showed that TGal-PTX@Cy3SiO2NP was taken up by HepG2 cells and was affected by the microtubule skeleton in these cells and inhibited the proliferation of these cells in a dose-dependent manner. The presence of a fluorescent probe, a targeting ligand, and an anticancer drug on the multifunctional TGal-PTX@Cy3SiO2NP allows for real-time imaging, specific cancer-cell targeting, and the cell-killing effect which is better than free PTX.
authors.affiliation: Department of Chemistry and ‡Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University , 101 Sec. 2, Kuang Fu Road, Hsinchu 300, Taiwan.
authors.forename: Chian-Hui
authors.initials: CH
authors.lastname: Lai
authors.forename: Tsung-Che
authors.initials: TC
authors.lastname: Chang
authors.forename: Yung-Jen
authors.initials: YJ
authors.lastname: Chuang
authors.forename: Der-Lii
authors.initials: DL
authors.lastname: Tzou
authors.forename: Chun-Cheng
authors.initials: CC
authors.lastname: Lin
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D057930:Click Chemistry; D016503:Drug Delivery Systems; D005456:Fluorescent Dyes / Q000737:chemistry*; D005690:Galactose / Q000737:chemistry*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy; D053758:Nanoparticles / Q000737:chemistry*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005456:Fluorescent Dyes; D017239:Paclitaxel; D005690:Galactose