Huixin He

Co‐delivery of Doxorubicin and Bcl‐2 siRNA by Mesoporous Silica Nanoparticles Enhances the Efficacy of Chemotherapy in Multidrug‐Resistant Cancer Cells

Development of multidrug resistance in cancer cells and adverse side effects are the major obstacles for effective cancer chemotherapy.[1-3] Therapeutic strategies to overcome drug resistance and specific tumor targeting with minimal premature drug release should have a great impact on the treatment of cancer. The term multidrug resistance (MDR) is used to define a resistance phenotype where cancer cells become resistant simultaneously to multiple drugs with no obvious structural resemblance and with different molecular targets.[4, 5] The multidrug resistance can be divided into two distinct classes, pump and nonpump resistance.[3] The pump resistance is caused by certain proteins that form membrane-bound ATP-dependent active drug efflux pumps, which significantly decrease the intracellular concentration of the drug and thereby the efficacy of the treatment. Membrane proteins, P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP) have been shown to be the main players for pump resistance to a broad range of structurally and functionally distinct cytotoxic agents.[6] The main mechanism of nonpump resistance is an activation of cellular antiapoptotic defense, mainly by Bcl-2 protein. Most of the anticancer drugs trigger apoptosis and simultaneously activate both pump and nonpump cellular defense of multidrug resistance, which prevents cell death. Therefore, to effectively suppress the overall resistance to chemotherapy, it is essential to simultaneously inhibit both pump and nonpump mechanisms of cellular resistance by targeting all the intracellular molecular targets.[3, 7-9]

Surface-Engineered Targeted PPI Dendrimer for Efficient Intracellular and Intratumoral siRNA Delivery

Low penetration ability of Small Interfering RNA (siRNA) through the cellular plasma membrane combined with its limited stability in blood, limits the effectiveness of the systemic delivery of siRNA. In order to overcome such difficulties, we constructed a nanocarrier-based delivery system by taking advantage of the lessons learned from the problems in the delivery of DNA. In the present study, siRNA nanoparticles were first formulated with Poly(Propyleneimine) (PPI) dendrimers. To provide lateral and steric stability to withstand the aggressive environment in the blood stream, the formed siRNA nanoparticles were caged with a dithiol containing cross-linker molecules followed by coating them with Poly(Ethylene Glycol) (PEG) polymer. A synthetic analog of Luteinizing Hormone-Releasing Hormone (LHRH) peptide was conjugated to the distal end of PEG polymer to direct the siRNA nanoparticles specifically to the cancer cells. Our results demonstrated that this layer-by-layer modification and targeting approach confers the siRNA nanoparticles stability in plasma and intracellular bioavailability, provides for their specific uptake by tumor cells, accumulation of siRNA in the cytoplasm of cancer cells, and efficient gene silencing. In addition, in vivo body distribution data confirmed high specificity of the proposed targeting delivery approach which created the basis for the prevention of adverse side effects of the treatment on healthy organs.

Surface-Modified and Internally Cationic Polyamidoamine Dendrimers for Efficient siRNA Delivery

A novel internally quaternized and surface-acetylated poly(amidoamine) generation four dendrimer (QPAMAM-NHAc) was synthesized and evaluated for intracellular delivery of siRNA. The proposed dendrimer as a nanocarrier possesses the following advantages: (1) modified neutral surface of the dendrimer for low cytotoxicity and enhanced cellular internalization; (2) existence of cationic charges inside the dendrimer (not on the outer surface) resulting in highly organized compact nanoparticles, which can potentially protect nucleic acids from degradation. The properties of this dendrimer were compared with PAMAM-NH 2 dendrimer, possessing surface charges, and with an internally quaternized charged and hydroxyl-terminated QPAMAM-OH dendrimer. Atomic force microscopy studies revealed that internally charged and surface neutral dendrimers, QPAMAM-OH and QPAMAM-NHAc, formed well-condensed, spherical particles (polyplexes) with siRNA, while PAMAM-NH 2 resulted in the formation of nanofibers. The modification of surface amine groups to amide significantly reduced cytotoxicity of dendrimers with QPAMAM-NHAc dendrimer showing the lowest toxicity. Confocal microscopy demonstrated enhanced cellular uptake and homogeneous intracellular distribution of siRNA delivered by the proposed QPAMAM-NHAc nanocarrier. The results clearly demonstrated distinct advantages of developed QPAMAM-NHAc/siRNA polyplexes over the existing nucleic acid dendrimeric carriers.

Internally Cationic Polyamidoamine PAMAM-OH Dendrimers for siRNA Delivery: Effect of the Degree of Quaternization and Cancer Targeting

A novel cancer targeted, internally cationic and surface neutral polyamidoamine (PAMAM) dendrimer, was designed, synthesized, and evaluated as a nanocarrier for the targeted intracellular delivery of siRNA. The dendrimer contained a synthetic analog of Luteinizing hormone-releasing hormone as cancer targeting moiety. The proposed delivery system possesses the following advantages: (1) internal cationic charges for complexation with siRNA and enhanced siRNA protection; (2) low cytotoxicity; (3) lesser degree of quaternization offering free tertiary amines for potential proton sponge effect; and (4) targeting specifically to cancer cells for enhancing siRNA uptake and efficiency and potential limitation of adverse side effects of chemotherapy on healthy organs. Both nontargeted and targeted dendrimer-siRNA complexes formed compact nanometer size spherical particles, exhibited very low cytotoxicity even at the higher concentration, and efficiently penetrated cancer cells in vitro. However, only the targeted dendrimer-siRNA complex was able to substantially decrease the expression of a targeted BCL2 gene.

Production of Graphene Sheets by Direct Dispersion with Aromatic Healing Agents

Graphene exhibits remarkable properties for various novel applications. One of many appealing applications of graphene would be to fabricate transparent conductive films to replace indium tinoxide (ITO).Theuseof graphene is promisingdue to its high optical transmittance, low resistance, high chemical stability, and high mechanical strength. This, as well as other applications, requires a large quantity of high-quality graphene as the basic component. Among the reported methods to prepare graphene, liquid-phase methods have drawn tremendous attention due to their scalability and ease of functionalization. Compared to chemical vapor deposition (CVD) approaches, which produce graphene films with the highest conductivity yet obtained, one advantage of liquid-phase methods is that the produced graphene can be conveniently deposited on any substratewith simple processing, such as spincoating or inkjet-printing on plastic substrates. Therefore, liquid-based techniqueshave thepotential to realize large-scale organic devices including photovoltaic cells.

Molecular detection based on conductance quantization of nanowires

We have studied molecular adsorption onto stable metallic nanowires fabricated with an electrochemical method. Upon the adsorption, the quantized conductance decreases, typically, to a fractional value, which may be attributed to the scattering of the conduction electrons by the adsorbates. The further conductance change occurs when the nanowire is exposed to another molecule that has stronger adsorption strength. Because the quantized conductance is determined by a few atoms at the narrowest portion of each nanowire, adsorption of a molecule onto the portion is enough to change the conductance, which may be used for chemical sensors.

DNA and carbon nanotubes as medicine

The identification of disease-related genes and their complete nucleotide sequence through the human genome project provides us with a remarkable opportunity to combat a large number of diseases with designed genes as medicine. However, gene therapy relies on the efficient and nontoxic transport of therapeutic genetic medicine through the cell membranes, and this process is very inefficient. Carbon nanotubes, due to their large surface areas, unique surface properties, and needle-like shape, can deliver a large amount of therapeutic agents, including DNA and siRNAs, to the target disease sites. In addition, due to their unparalleled optical and electrical properties, carbon nanotubes can deliver DNA/siRNA not only into cells, which include difficult transfecting primary-immune cells and bacteria, they can also lead to controlled release of DNA/siRNA for targeted gene therapy. Furthermore, due to their wire shaped structure with a diameter matching with that of DNA/siRNA and their remarkable flexibility, carbon nanotubes can impact on the conformational structure and the transient conformational change of DNA/RNA, which can further enhance the therapeutic effects of DNA/siRNA. Synergistic combination of the multiple capabilities of carbon nanotubes to deliver DNA/siRNAs will lead to the development of powerful multifunctional nanomedicine to treat cancer or other difficult diseases. In this review, we summarized the current studies in using CNT as unique vehicles in the field of gene therapy.

Anti-HER2 IgY antibody-functionalized single-walled carbon nanotubes for detection and selective destruction of breast cancer cells.

BackgroundNanocarrier-based antibody targeting is a promising modality in therapeutic and diagnostic oncology. Single-walled carbon nanotubes (SWNTs) exhibit two unique optical properties that can be exploited for these applications, strong Raman signal for cancer cell detection and near-infrared (NIR) absorbance for selective photothermal ablation of tumors. In the present study, we constructed a HER2 IgY-SWNT complex and demonstrated its dual functionality for both detection and selective destruction of cancer cells in an in vitro model consisting of HER2-expressing SK-BR-3 cells and HER2-negative MCF-7 cells.MethodsThe complex was constructed by covalently conjugating carboxylated SWNTs with anti-HER2 chicken IgY antibody, which is more specific and sensitive than mammalian IgGs. Raman signals were recorded on Raman spectrometers with a laser excitation at 785 nm. NIR irradiation was performed using a diode laser system, and cells with or without nanotube treatment were irradiated by 808 nm laser at 5 W/cm2 for 2 min. Cell viability was examined by the calcein AM/ethidium homodimer-1 (EthD-1) staining.ResultsUsing a Raman optical microscope, we found the Raman signal collected at single-cell level from the complex-treated SK-BR-3 cells was significantly greater than that from various control cells. NIR irradiation selectively destroyed the complex-targeted breast cancer cells without harming receptor-free cells. The cell death was effectuated without the need of internalization of SWNTs by the cancer cells, a finding that has not been reported previously.ConclusionWe have demonstrated that the HER2 IgY-SWNT complex specifically targeted HER2-expressing SK-BR-3 cells but not receptor-negative MCF-7 cells. The complex can be potentially used for both detection and selective photothermal ablation of receptor-positive breast cancer cells without the need of internalization by the cells. Thus, the unique intrinsic properties of SWNTs combined with high specificity and sensitivity of IgY antibodies can lead to new strategies for cancer detection and therapy.

Conductance of polymer nanowires fabricated by a combined electrodeposition and mechanical break junction method

We electrochemically deposit conducting polymer to bridge two closely placed electrodes, and then form a polymer nanowire by stretching the polymer bridge with the electrodes. During stretching, the conductance increases initially as the polymer chains are aligned in parallel, and then decreases in a stepwise fashion, due to abrupt changes in the nanowire thickness. We study the current–voltage (I–V) characteristics of the nanowire as a function of its electrochemical potential in an analogous fashion to the control of the gate voltage in semiconductor devices. Depending on the potential, the I–V curves vary from ohmic to rectifying characteristics.

Self-Assembled Organic Nanowires for High Power Density Lithium Ion Batteries

The electroactive organic materials are promising alternatives to inorganic electrode materials for the new generation of green Li-ion batteries due to their sustainability, environmental benignity, and low cost. Croconic acid disodium salt (CADS) was used as Li-ion battery electrode, and CADS organic wires with different diameters were fabricated through a facile synthetic route using antisolvent crystallization method to overcome the challenges of low electronic conductivity of CADS and lithiation induced strain. The CADS nanowire exhibits much better electrochemical performance than its crystal bulk material and microwire counterpart. CADS nanowire with a diameter of 150 nm delivers a reversible capability of 177 mAh g(-1) at a current density of 0.2 C and retains capacity of 170 mAh g(-1) after 110 charge/discharge cycles. The nanowire structure also remarkably enhances the kinetics of croconic acid disodium salt. The CADS nanowire retains 50% of the 0.1 C capacity even when the current density increases to 6 C. In contrast, the crystal bulk and microwire material completely lose their capacities when the current density merely increases to 2 C. Such a high rate performance of CADS nanowire is attributed to its short ion diffusion pathway and large surface area, which enable fast ion and electron transport in the electrode. The theoretical calculation suggests that lithiation of CADS experiences an ion exchange process. The sodium ions in CADS will be gradually replaced by lithium ions during the lithiation and delithiation of CADS electrode, which is confirmed by inductively coupled plasma test.