Arsonium and phosphonium-functionalized gold nanoparticles for mitochondria targeted therapeutics

This thesis presents a body of original research describing the synthesis, characterisation and biological properties of novel arsonium- and phosphonium- alkylthiosulfate zwitterions and thioacetate salts and gold nanoparticles functionalized with triphenylarsoniumpropylthiolate ligands. Chapter 1 presents a systematic literature review of the preparation of functionalized gold nanoparticles, their biomedical properties, the biological applications of phosphonium and arsonium ions and phosphonium-functionalized nanomaterials. Details of the analytical methods employed to characterize all the compounds produced in this study are outlined in chapter 2. Chapter 3 reports the synthesis of the triphenylarsoniopropylthiosulfate zwitterion and ω- thioacetylpropyl(triphenyl)arsonium bromide salt. Both compounds have been characterized spectroscopically and by single crystal X-ray diffraction. The thiosulfate group of the triphenylarsoniopropylthiosulfate zwitterion and the thioacetate group of the ω- thioacetylpropyl(triphenyl)arsonium salt undergo reductive cleavage, forming the corresponding triphenylarsoniumpropylthiolate ions that attach to the surface of gold in a modification of the established Brust-Schiffrin method for preparing gold nanoparticles. TEM studies show the triphenylarsonium-functionalized gold nanoparticles to be spherical with diameters of c.a. 3nm. The presence of the triphenylarsonium groups has been confirmed by Raman and XPS spectroscopy and mass spectrometry. It also describes the synthesis, characterisation and biological properties of a family of phosphoniopropylthiosulfate zwitterions and ω-thioacetylpropyl(triaryl)phosphonium salts derived from tri(4-methoxyphenyl)phosphine, tri(2,6-dimethoxyphenyl)phosphine and tri(2,4,6-trimethoxyphenyl)phosphine. The IC50 values of the triphenylarsoniopropylthiosulfate zwitterion, ω-thioacetylpropyl- (triphenyl)arsonium bromide salt, triphenylarsonium-functionalized gold nanoparticles and family of phosphoniopropylthiosulfate zwitterions and ω- thioacetylpropyl(triaryl)phosphonium salts derived from tri(4-methoxyphenyl)phosphine, tri(2,6-dimethoxyphenyl)phosphine and tri(2,4,6-trimethoxyphenyl)phosphine have been determined against PC3 prostate cancer cells using MTT and CellTiter-Glo assays and are reported in Chapter 4. The uptake of the triphenylarsonium-functionalized gold nanoparticles by PC3 and Human Fibroblast cells has also been determined by ICP-OES spectroscopy

Measurement and Correlation of the Solubility of Hexaquonickel(II) Bis(<i>p</i>‑toluenesulfonate) in Water + Ethanol Solvents within 288.15–333.15 K

The solubilities of hexaquonickel­(II) bis­(<i>p</i>-toluenesulfonate) [Ni­(OTs)₂·6H₂O] in an ethanol–water mixture containing a mole fraction of 0−0.342 ethanol were measured at temperatures ranging from 288.15 to 333.15 K by using a synthetic method. The experimental data were fitted using the van’t Hoff plot, the modified Apelblat equation, the general single model, and the hybrid model. All of these models show good agreement with the experimental data. The solubility of Ni­(OTs)₂·6H₂O increases with an increase of the temperature and the initial mole fraction of ethanol in the mixed solvents. Further, the molecular modeling studies using <i>Materials Studio DMol³</i> (Accelrys Software Inc.) indicated that the solubility of Ni­(OTs)₂·6H₂O depends not only on the polarities of the solvents but also on the interactions between Ni­(OTs)₂·6H₂O and solvent molecules. The enthalpy, Gibbs energy, and entropy of the solution process were derived by the modified van’t Hoff equation

Proteomic analysis for the impact of hypercholesterolemia on expressions of hepatic drug transporters and metabolizing enzymes

<p>1. Our objective is to investigate the alterations of hepatic drug transporters and metabolizing enzymes in hypercholesterolemia. Male Sprague–Dawley rats were fed high-cholesterol chows for 8 weeks to induce hypercholesterolemia. Protein levels of hepatic drug transporters and metabolizing enzymes were analyzed by iTRAQ labeling coupled with LC TRIPLE-TOF.</p> <p>2. Total 239 differentially expressed proteins were identified using proteomic analysis. Among those, protein levels of hepatic drug transporters (MRP2, ABCD3, OAT2, SLC25A12, SCL38A3, SLC2A2 and SLC25A5) and metabolizing enzymes (CYP2B3, CYP2C7, CYP2C11, CYP2C13, CYP4A2 and UGT2B) were markedly reduced, but the levels of CYP2C6 and CYP2E1 were increased in hypercholesterolemia group compared to control. Decreased expressions of drug transporters MRP2 and OAT2 were further confirmed by real time quantitative PCR (RT-qPCR) and western blot.</p> <p>3. Ingenuity pathway analysis revealed that these differentially expressed proteins were regulated by various signaling pathways including nuclear receptors and inflammatory cytokines. One of the nuclear receptor candidates, liver X receptor alpha (LXRα), was further validated by RT-qPCR and western blot. Additionally, LXRα agonist T0901317 rescued the reduced expressions of MRP2 and OAT2 in HepG2 cells in hypercholesterolemic serum treatment.</p> <p>4. Our present results indicated that hypercholesterolemia affected the expressions of various drug transporters and metabolizing enzymes in liver via nuclear receptors pathway. Especially, decreased function of LXRα contributes to the reduced expressions of MRP2 and OAT2.</p

Synthesis of Cyclic Porphyrin Trimers through Alkyne Metathesis Cyclooligomerization and Their Host–Guest Binding Study

Cyclic porphyrin trimers were synthesized through one-step cyclooligomerization via alkyne metathesis from diyne monomers. These macrocycles show interesting host–guest binding interactions with fullerenes, selectively binding C₇₀ (6 × 10³ M^–1) over C₆₀ and C₈₄ (no binding observed). The fullerene-encapsulated host–guest complex can undergo guest or host exchange in the presence of another guest (2,4,6-tri­(4-pyridyl)-1,3,5-triazine) or host (cage COP5) molecule with higher binding affinity

YAP/TEAD Co-Activator Regulated Pluripotency and Chemoresistance in Ovarian Cancer Initiated Cells

<div><p>Recent evidence suggests that some solid tumors, including ovarian cancer, contain distinct populations of stem cells that are responsible for tumor initiation, growth, chemo-resistance, and recurrence. The Hippo pathway has attracted considerable attention and some investigators have focused on YAP functions for maintaining stemness and cell differentiation. In this study, we successfully isolated the ovarian cancer initiating cells (OCICs) and demonstrated YAP promoted self-renewal of ovarian cancer initiated cell (OCIC) through its downstream co-activator TEAD. YAP and TEAD families were required for maintaining the expression of specific genes that may be involved in OCICs' stemness and chemoresistance. Taken together, our data first indicate that YAP/TEAD co-activator regulated ovarian cancer initiated cell pluripotency and chemo-resistance. It proposed a new mechanism on the drug resistance in cancer stem cell that Hippo-YAP signal pathway might serve as therapeutic targets for ovarian cancer treatment in clinical.</p></div

Solvent-Controlled, Tunable β‑OAc and β‑H Elimination in Rh(III)-Catalyzed Allyl Acetate and Aryl Amide Coupling via C–H Activation

The Heck reaction between arenes and allyl acetate has led to cinnamyl derivatives and allyl products depending on the regioselectivity of β-elimination. The regioselectivity can be controlled by the solvent in the Rh­(III)-catalyzed arene–allyl acetate coupling via C–H activation: (1) in THF, cinnamyl derivatives via β-H elimination were generated; (2) in MeOH, allyl products via β-OAc elimination were produced. Both routes have advantages such as excellent γ-selectivity toward allyl acetate, good to excellent yields, and broad substrate scope

YAP and TEAD are required for maintaining OCIC pluripotency.

<p><b>A-C</b>: Real-time RT-PCR (A), immunofluorescence staining (B), and Western blotting (C) results for YAP and TEAD1-4 expression levels in primary ovarian cancer cells (control) and OCICs. Nuclei were stained with DAPI. <b>D</b>: Real-time RT-PCR results for mRNA levels of known YAP/TEAD target genes, including <i>Runx2</i>, <i>Itgb2</i>, and <i>Erbb4</i>, in primary ovarian cancer cells (control) and OCIC cells. <b>E-F</b>: Real-time RT-PCR results for the RNAi depletion efficiencies of YAP, TEAD1, TEAD3, and TEAD4, after using two different shRNAs for each gene.</p

OCICs have stronger tumorigenic capability than primary ovarian cancer cells.

<p><b>A</b>: Images of nude mice showing xenograft ovarian tumor formation after injecting OCIC spheres. Cell concentrations used 10⁴ in each group. <b>B</b>: H&E staining results showing the histology of tumors derived from subcutaneously transplanted OCIC spheroids. <b>C</b>: Representative IHC results for CA125 and YAP expression in human xenograft tumors derived from OCICs. Specific protein expression is indicated by the brown color and nuclei (blue) were counterstained with DAPI. <b>D</b>: Representative IHC results for the expression of the pluripotency markers OCT4, SOX2, and NANOG in xenograft ovarian tumors derived from OCIC spheroids. <b>E</b>: Representative IHC results for phosphorylated AKT and pMAPK (ERK1/2) expression in the xenograft tumors derived from OCICs. Scale bar  = 200 µM for B-E panels.</p

YAP-TEAD confers chemotherapeutic drug resistance to OCICs by regulating specific target genes' expression.

<p><b>A.</b> Survival rates of primary ovarian cancer cells (control) and OCICs after treatment with cisplatin (CDDP), taxol, or bleomycin at the indicated concentrations. OCICs and control cells were treated with drugs for 48 h. *, P<0.01, compared with the corresponding control group. **, P<0.001, compared with the corresponding control group. <b>B.</b> Survival rates of OCICs with or without <i>Yap</i> and <i>Tead1/3/4</i> knockdown after treatment with CDDP, taxol, or bleomycin at the indicated concentrations for 48 h. ns, not significant; *, P<0.01; **, P<0.001. <b>C-D</b>: Real-time RT-PCR results showing that the indicated genes were expressed in OCICs at higher levels than in primary ovarian cancer cells (C). Indicated genes' expression levels in OCICs were significantly down-regulated with <i>Yap</i> and <i>Tead1/3/4</i> RNAi (D). *, P<0.01; **, P<0.001. <b>E.</b> Western blotting results for AKT and pAKT levels in OCICs with or without <i>Yap/Tead1/3/4</i> shRNA treatment.</p

A High Efficient Waveguide Display with Space-variant Volume Holographic Gratings

This video shows the dynamic display results of the waveguide display based on space-variant volume holographic gratings. In-door and out-door scene are both tested