Research Areas

Our laboratory pursues research in the field of nanoscale chemistry. We explore the novel properties of nanomaterials for their applications in molecular detection, drug delivery and renewable energy devices. Our goal is not only to improve or to develop novel devices for detection and treatment of human diseases, and for conversion of clean energy by using these nanomaterials, but also to understand at the electronic and molecular level the correlation of their performances with the structures of the nanomaterials. To this end, we use a mixture of nanoscopic and macroscopic techniques to characterize the electronic, electrochemical and optical properties of the nanomaterials and to evaluate the performance of the nanodevices made from the nanomaterials. We engage in research in the following three specific areas:

1. Conducting polymer/carbon nanotube (Graphene) composites

We investigate in electronic and molecular level how to fabricate composite materials with dramatically enhanced electronic performance and improved chemical stability. We apply the composite materials in fuel cells, solar cells, and chemical sensing devices.

2. Multiplexed electrical and optical biosensors

We develop electronic sensing devices with individually functionalized and electronically addressable sensing elements for simultaneous detection.

We develop Raman based molecular sensing for early detection of cancer.

3. Nanotechnology for nonviral gene delivery and co-delivery of multiple drugs for efficient cancer therapy

We study DNA (both long plasmid DNA and short therapeutic oligonucleotides) nanoparticles formation mechanism to develop more efficiency gene delivery agents.

We develop co-delivery system for simultaneously delivery of traditional anticancer drugs and gene drugs for efficient cancer therapy.

 
Research Highlights

Labile Catalytic Packaging of DNA/siRNA: Control of Gold Nanoparticles "out" of DNA/siRNA Complexes

Alex M. Chen, Zhang, M., Oleh Taratula, Dongguang Wei, Thresia Thomas, T. J. Thomas, Tamara Minko, and Huixin He., ACS Nano, 2010, 4, 3679-3788.


In this work, we report an interesting finding that Au nanoparticles (NPs) physically anchored with several low generation polypropylenimine (PPI) dendrimers can effectively assemble DNA/siRNA into discrete nanopartcles, where the Au NPs can be controlled "out" of the final DNA/siRNA nanoparticles. Therefore it becomes possible to eliminate the potential toxic problems associated with Au NPs by selectively removing the Au NPs from the resulting nucleic acid complexes before their delivery to targeted cells. This is a new concept of using engineered inorganic nanoparticles for DNA/siRNA condensation and delivery. In contrast to the siRNA nanostructures (mainly random aggregated nanofibers) formed from low generation dendrimer alone (PPI Generation 3), the siRNA complex nanoparticles packaged by this novel approach (Au nanoparticles modified with G3 PPI dendrimers) can be internalized by cancer cells and the delivered siRNAs can effectively silence their targeted mRNA. The efficiency of mRNA silencing by the proposed nanoparticles is even superior to higher generation dendrimers (PPI Generation 5).



Simple Production of Graphene Sheets by Direct Dispersion with Aromatic Doping and Healing Agents

Ming Zhang, Rishi R. Parajuli, Daniel Mastrogiovanni, Boya Dai, Phil Lo, William Cheung, Roman Brukh, Pui Lam Chiu, Tao Zhou, Zhongfan Liu, Eric Garfunkel, and Huixin He. Small, 2010, 6, 1100-1107.


In this work, we report a simple and scalable exfoliation approach to produce high quality single layer graphene sheets. In a typical experimental procedure, graphite powders were exfoliated by sonicating in an aqueous solution of pyrene molecules that had been functionalized with different water soluble groups. Highly conductive graphene sheets stabilized in aqueous suspensions were directly produced without requiring toxic reducing agents and expensive solvents. Most importantly, different from other surfactants and polymers, that has been used to prevent graphene sheets from aggregation in solution, the pyrene molecules also act as nanographene molecules to heal the possible defects in the graphene sheets during annealing. Remarkably, they also appear to act as electrical "glue" soldering adjacent graphene sheets such that electric contacts between graphene sheets can be dramatically improved across the film. Graphene films with conductivity of 181,200 S/m (778 ?/square) with light transmittance greater than 90% in the 400–800 nm wavelength range are reproducibly obtained, which is the highest conductivity values ever achieved for graphene films fabricated by graphite exfoliation approaches (note that graphene films fabricated by chemical vapour deposition (CVD) method can reach 200 ?/square at 80% optical transparency). Nevertheless, this simple and scalable approach is extremely promising to produce high quality graphene films for a wide range of optoelectronic applications, including photovoltaics.



Co-delivery of Doxorubicin and siRNAs into Multidrug Resistant Cancer Cells by Mesoporous Silica Nanoparticles for Enhanced Chemotherapy Efficacy

Alex M. Chen, Min Zhang, Dongguang Wei, Dirk Stueber, Oleh Taratula, Tamara Minko, and Huixin He. Small, 2009, 5, 2673-2677.


In this work, we explored to utilize mesoporous silica nanoparticles (MSNs) to co-deliver doxorubicin (Dox) (as a model apoptosis-inducing anticancer drug), and a siRNA (as a suppressor of cellular antiapoptotic defense) simultaneously into multidrug resistant cancer cells for efficient cancer therapy. As illustrated in Scheme, the MSNs were modified to encapsulate Dox inside the pores to achieve minimal premature drug release. Then the Dox-loaded MSNs were modified with generation 2 (G2) amine-terminated polyamidoamine (PAMAM) dendrimers. The dendrimer-modified MSN can efficiently complex with siRNAs targeted against mRNA encoding Bcl-2 protein, which is the main player for nonpump resistance. We found thus-formed complex can be delivered into multidrug resistant A2780/AD human ovarian cancer cells to induce cell death. The anticancer efficacy of Dox increased 132 times compared to free Dox, mainly because the simultaneously delivered siRNA significantly suppressed the Bcl-2 mRNA, and efficiently overcome the nonpump resistance. Moreover, our data suggested that the delivered Dox by the MSNs are primarily localized in perinuclear region upon internalization, providing additional advantage in possibly bypassing pump resistance, therefore further enhancing the drug efficacy. This result is much different from some liposome co-delivery systems, in which antisense oligonucleotides targeted to pump and nonpump resistances must be simultaneously delivered in order to significantly increase drug efficacy. We attributed this difference to the different internalization pathway and drug release mechanism. We envisioned that this co-delivery system can be generalized to other anticancer drugs and other cancer cell lines.



Anti-HER2 IgY Antibody-Functionalized Single-Walled Carbon Nanotubes for Detection and Selective Destruction of Breast Cancer Cells

Xiao, Y., Gao, X., Taratula, O., Treado, S., Mitra, S., Salva, R., Wagner, P. D., Srivastava, S., He, H. X. BMC Cancer, 2009, 9, 351 (1-11).


In this work, anti-HER2 IgY-SWNT complexes were constructed by covalently conjugating carboxylated SWNTs with anti-HER2 chicken IgY antibodies, which are more specific and sensitive than mammalian IgGs. We demonstrated the dual functionality of the complex for both detection and selective destruction of cancer cells in an in vitro model. Raman signal collected at single-cell level from the complex-treated receptor-positive breast cancer cells was significantly greater than that from various control cells. Near Inferred (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.



Surface-Engineered Targeted PPI Dendrimers for Efficient Intracellular and Intratumoral siRNA delivery

Taratula, O., Garbuzenko, O. B., Kirkpatrick, P., Pandya, I., Savla, S., Pozharov, V. P., He, H. X., Minko, T. Journal of Controlled Release, 2009, 140, 284-293.


Low penetration ability of Small Interfering RNA (siRNA) through the cellular plasma membrane combined with its limited stability in blood plasma, 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(propyleneimmine) (PPI) dendrimers. To provide lateral and steric stability to withstand the aggressive extracellular environment, the formed siRNA nanoparticles were caged with a dithiol containing crosslinker molecules followed by coating them with 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 extracellular stability and intracellular bioavailability, provides for their specific uptake by tumor cells, accumulation of delivered siRNA in the cytoplasm of cancer cells, and the 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.



Improved Conductivity of Carbon Nanotube Networks by In-situ Polymerization of a Thin Skin of Conducting Polymer

Ma, Y. F., Cheung, W., Wei, D. G., Bogozi, A., Chiu, P. L., Wang, L., Pontoriero, F., Mendelshon, R. and He, H. X. ACS Nano, 2008, 2, 1197-1204.



There is increasing enthusiasm for the use of carbon nanotube network films as conductive flexible electrodes for a wide variety of applications. However, all the reported conductivities of the single walled carbon nanotubes (SWNTs) network films were significantly lower than the conductivity of a carbon nanotube rope (axial conductivity). This has been attributed to the high contact resistance between the tubes in the networks. Tremendous efforts have been made over the past decade to prepare polymer and carbon nanotube composites with an aim to synergistically combine the merits of each individual component. However, all the reported composites show enhanced conductivity over the polymeric side, much lower electronic performance when compared to the carbon nanotube network film side. In this work, we have demonstrated experimentally, for the first time, that in-situ polymerization of a thin “skin” of highly conductive polymer around and along the SWNTs can greatly decrease the contact resistance. The polymer skin also acts as “conductive glue” effectively assembling the SWNTs into a conductive network, which decreased the amount of SWNTs needed to reach the high conductive regime of the network. The highly conductive composite network and the method to fabricate the highly conductive composite can be widely used for large area flexible electronics, including flexible solar cells, and organic light emitting devices.  



The Electronic Role of DNA Functionalized Carbon Nanotubes: Efficacy for In-situ Fabrication of Conducting Polymer Nanocomposites

Ma, Y. F., Chiu, P. L., Serrano, A., Ali, S. K., Chen, A. M, and He, H. X. J. Am. Chem. Soc. 2008, 130, 7921-7928.



To truly synergistically combine the merits of each individual component in the conducting polymer nanocomposites, it is essential to understand the monomer-nanotube interfacial chemical and electronic interactions during polymerization and polymer-nanotube interfacial interactions after the polymerization, which has not been fully addressed.

Taking advantages of the well-documented surface chemistry and electronic structure of single stranded DNA dispersed and functionalized single walled carbon nanotubes (ss-DNA-SWNTs), we systematically studied the impacts of the electronic structure of a carbon nanotube and the monomer-nanotube interfacial interaction on the kinetics of the nanocomposite fabrication and the quality of the obtained composites. For the first time, we found that the polymerization process can be 4,500 times faster and much less oxidant needed to initiate the reaction when a conducting polymer was polymerized in the presence of intact ss-DNA-SWNTs, which are electron rich. More importantly, the quality of the composite was synergistically improved, as demonstrated by the significantly enhanced electrical performance of the obtained nanocomposite. However, the synergistic conductance enhancement cannot be obtained by simply mixing a preformed conducting polymer with the ss-DNA/SWNTs. Surprisingly, the enhancement was not achievable by in-situ polymerization with pre-oxidized SWNTs, which are electron deficient. In addition, the polymerization process is also much slower in the presence of pre-oxidized ss-DNA-SWNTs. Understanding these reaction characteristics is important to effectively optimize the fabrication parameters and ensure the formation of composites in a controllable fashion for a variety of potential applications. Based on these remarkable observations, currently they are developing a “greener” approach for the fabrication of nanocomposites.

 

In-situ Fabrication of A Water-Soluble, Self-Doped Polyaniline Nanocomposite: the Unique Role of DNA Functionalized Single-Walled Carbon Nanotubes

Yufeng Ma, Shah K Ali, Ling Wang, Pui Lam Chiu, Richard Mendelsohn and Huixin He, J. Am. Chem. Soc. 2006, 128, 12064-12065.


Dispersion of carbon nanotubes into solvents affects their surface chemistries, electronic structures, and subsequent functionalization. In this communication, a water-soluble self-doped polyaniline nanocomposite was fabricated by in-situ polymerization of the 3-aminophenylboronic acid monomers in the presence of single-stranded DNA dispersed- and functionalized- single-walled carbon nanotubes. For the first time, we found that the carbon nanotubes became novel active stabilizers due to the DNA functionalization. The nanotubes reduced the polyaniline backbone from the unstable, degradable, fully oxidized pernigraniline state to the stable, conducting emeraldine state due to their reductive ability, which could improve the chemical stability of the self-doped polyaniline. Electrical measurements demonstrate that the conductivity of the nanocomposite was much higher than that of the pure self-doped polyaniline in both acidic and neutral solutions.



Enhanced Sensitivity for Biosensors: Multiple Functions of DNA Wrapped Single Walled Carbon Nanotubes in Self-Doped Polyaniline Nanocomposites

Yufeng Ma, Shah R Ali, Afua S. Dodoo, and Huixin He, J. Phys. Chem. B, 2006, 110, 16359-16365.

 


A nanocomposite of poly(anilineboronic acid), a self-doped polyaniline, with ss-DNA wrapped single walled carbon nanotube (ss-DNA/SWNTs) was fabricated on a gold electrode by in-situ electrochemical polymerization of 3-aminophenylboronic acid monomers in the presence of ssDNA/SWNTs. We used this nanocomposite to detect nanomolar concentrations of dopamine and found that the sensitivity increased four orders of magnitude compared to the detection only neat poly(anilineboronic acid) was used to modify the electrode. For the first time, this work reports the multiple functions of the ss-DNA/SWNTs in the fabrication and biosensor application of a self-doped polyaniline/ssDNA/SWNT nanocomposite. First, the ssDNA/SWNTs acted as effective molecular templates during polymerization of self-doped polyanline so that not only was the polymerization speed increased, but also the quality of the polymer was greatly improved. Second, they functioned as novel active stabilizers after the polymerization, which significantly enhanced the stability of the film. Furthermore, the ss-DNA/SWNTs also acted as conductive polyanionic doping agents in the resulting polyaniline film, which showed enhanced conductivity and redox activity. Finally, the large surface area of carbon nanotubes greatly increased the density of the functional groups available for sensitive detection of the target analyte. We envision that polyaniline with other functional groups, as well as other conducting polymers, may be produced for different targeted applications by this approach.



Oligodeoxynucleotide nanostructure formation in the presence of polypropyleneimine dendrimers and their uptake in breast cancer cells

Alex M. Chen, Latha M. Santhakumaran, Sandhya K. Nair, Peter S. Amenta, Thresia Thomas, Huixin He, and T. J. Thomas, Published in Nanotechnology, 2006, 17, 5449-5460.

This is a collaboration study with Drs. Thomas at University of Medicine and Dentistry at New Jersey. We studied the efficacy of 5 generations of polypropyleneimine (PPI) dendrimers to provoke nanoparticle formation from a 21-nt antisense oligodeoxynucleotide (ODN). Nanoparticle formation was observed with all generations of dendrimers by light scattering and microscopic techniques. The efficacy of the dendrimers increased with generation number. Atomic force microscopy (AFM) was used to study the morphology of the structures at different condensation stages. Based on the observed nanofibers in the beginning of condensation, we propose a zipping condensation mechanism, which is very different from the condensation pathways of high molecular weight DNA polymers. Electron microscopy showed the presence of toroidal nanoparticles. Confocal microscopic analysis showed that the nanoparticles formed with G-4 and G-5 dendrimers could undergo facile cellular uptake in a breast cancer cell line, MDA-MB-231, whereas particles formed with G-1 to G-3 dendrimers lacked this ability.  Nanoparticles formed with G-1 to G-3 dendrimers showed significantly lower zeta potential (5.2-6.5 mV) than those (12-18 mV) of particles formed with G-4 and G-5 dendrimers. These results show that the structure and charge density of the dendrimers are important in ODN nanoparticle formation and cellular transport and that G-4 and G-5 dendrimers are useful in cellular delivery of antisense ODN.

Figure 1. AFM images of condensates formed by the 21-nt ODN in the presence of PPI dendrimers after 10-minute condensation.  ODN had a concentration of 0.4 µM and dendrimer was 2.5 µM in a solution containing the approximate physiological concentration of salts. Panels are (A) G-1, (B) G-2, (C) G-3, (inset) Phase image with the same scale of the main image indicated by a red arrow.  (D) G-4, (E) G-5, and (F) G-5. Bar represents 250 nm in all panels.  

Figure 2. AFM images of condensates formed by the 21-nt ODN in the presence of PPI dendrimers after 1 hour of condensation (panels A, B, C, D, E and F).  ODN had a concentration of 0.4 µM and dendrimer was 2.5 µM in a solution containing the approximate physiological concentration of salts. (A) G-1, (B) G-1 (zoom image of one part of panel (A)), (C) G-2, (D) G-3, (E) G-4, (F) G-5. Bar represents 4 µm in panel (A), 1 µm in panels (B, C, D, F) and 300 nm in panel (E).

Figure 3. Representative images of cellular uptake of fluorescein-labeled 21-nt ODN by MDA-MB-231 cell by confocal microscopy. ODN uptake in the absence (A, B, C, D) or the presence (E, F, G, H) of G-4 dendrimer is shown. Differential interference contrast (DIC) images of cells are shown in panels A and E. Nuclei stained with DAPI (B and F), detection of fluorescein-labeled oligonucleotide (C and G) and overlay of images (D and H) are shown. Final concentration of ODN and G-4 dendrimer in the cell culture medium were 0.2 µM each.  

Figure 4. Schematic representation of the proposed zipping mechanism for the condensation of the 21-nt ODN by PPI dendrimers. PPI dendrimers first "zip" the ODN molecules by electrostatic interactions to form extended chains. The extended chains could wrap around to form aggregated complex structures, which then further condense into spheroidal structures. The extended chains could also interact with each other in parallel to form ribbon- and rod-like structures and then wrap around to form toroidal structures.



Assembly of Highly Aligned DNA Strands onto Si Chips

Zhang, J. M., Ma, Y. F., Stachura, S. He, H. X., Langmuir, 2005, 21, 4180-4184.



This work  reports a robust and efficient approach to assemble highly aligned DNA strands onto Si chips. The method combines advantages from molecular combing and microcontact printing to realize controlling both the density and direction of DNA strands on the Si chip. In addition, it also can be utilized to prepare stretched DNA structures on solid surfaces. Compared to approaches that use molecular combing directly on silanated surfaces, the stretched single-chain DNA structures are straighter. Furthermore, by exploiting the hydrophobic property of the intrinsic poly(dimethylsiloxane) (PDMS) stamp, this study also describes a simple way to simply produce straight bundled DNA arrays on Si and other substrates.



Polyaniline Nanowires on Si Surfaces Fabricated with DNA Templates

Yufeng Ma, Jianming Zhang, Guojin Zhang and Huixin He*, J. Am. Chem. Soc. 2004, 126, 7097–7101.



It is essential to put individual, freestanding nanowires onto insulating substrates and integrate them to useful devices. Here we report a strategy for fabrication of conducting polymer nanowires on thermally oxidized Si surfaces using DNA as templates. The direct use of stretched and immobilized DNA strands as templates avoided the agglomeration of DNA caused by shielding of charges on DNA when polyaniline/DNA complexes formed in solution. Most importantly, the oriented DNA strands immobilized on Si surface predetermined the position and the orientation of the nanowires. The approach described here is the first step toward uniting the programmable-assembly ability of DNA with the unique electronic properties of conducting polymers for high-density functional nanodevices. The conductivity of the nanowires is very sensitive to the proton doping-undoping process suggesting that the nanowires hold a great promise for sensitive chemical sensor applications.