Chiao Huang

Inorganic nanoparticles for cancer imaging and therapy.

Inorganic nanoparticles have received increased attention in the recent past as potential diagnostic and therapeutic systems in the field of oncology. Inorganic nanoparticles have demonstrated successes in imaging and treatment of tumors both ex vivo and in vivo, with some promise towards clinical trials. This review primarily discusses progress in applications of inorganic nanoparticles for cancer imaging and treatment, with an emphasis on in vivo studies. Advances in the use of semiconductor fluorescent quantum dots, carbon nanotubes, gold nanoparticles (spheres, shells, rods, cages), iron oxide magnetic nanoparticles and ceramic nanoparticles in tumor targeting, imaging, photothermal therapy and drug delivery applications are discussed. Limitations and toxicity issues associated with inorganic nanoparticles in living organisms are also discussed.

Simultaneous Enhancement of Photothermal Stability and Gene Delivery Efficacy of Gold Nanorods Using Polyelectrolytes

The propensity of nanoparticles to aggregate in aqueous media hinders their effective use in biomedical applications. Gold nanorods (GNRs) have been investigated as therapeutics, imaging agents, and diagnostics. We report that chemically generated gold nanorods rapidly aggregate in biologically relevant media. Depositing polyelectrolyte multilayers on gold nanorods enhanced the stability of these nanoparticles for at least up to 4 weeks. Dispersions of polyelectrolyte (PE)-gold nanorod assemblies (PE-GNRs) demonstrate a stable Arrhenius-like photothermal response, which was exploited for the hyperthermic ablation of prostate cancer cells in vitro. Subtoxic concentrations of PE-GNR assemblies were also employed for delivering exogenous plasmid DNA to prostate cancer cells. PE-GNRs based on a cationic polyelectrolyte recently synthesized in our laboratory demonstrated higher transfection efficacy and lower cytotoxicity compared to those based on polyethyleneimine, a current standard for polymer-mediated gene delivery. Our results indicate that judicious engineering of biocompatible polyelectrolytes leads to multifunctional gold nanorod-based assemblies that combine high stability and low cytotoxicity with photothermal ablation, gene delivery, and optical imaging capabilities on a single platform.

Spatiotemporal temperature distribution and cancer cell death in response to extracellular hyperthermia induced by gold nanorods.

Plasmonic nanoparticles have shown promise in hyperthermic cancer therapy, both in vitro and in vivo. Previous reports have described hyperthermic ablation using targeted and nontargeted nanoparticles internalized by cancer cells, but most reports do not describe a theoretical analysis for determining optimal parameters. The focus of the current research was first to evaluate the spatiotemporal temperature distribution and cell death induced by extracellular hyperthermia in which gold nanorods (GNRs) were maintained in the dispersion outside human prostate cancer cells. The nanorod dispersion was irradiated with near-infrared (NIR) laser, and the spatiotemporal distribution of temperature was determined experimentally. This information was employed to develop and validate theoretical models of spatiotemporal temperature profiles for gold nanorod dispersions undergoing laser irradiation and the impact of the resulting heat generation on the viability of human prostate cancer cells. A cell injury/death model was then coupled to the heat transfer model to predict spatial and temporal variations in cell death and injury. The model predictions agreed well with experimental measurements of both temperature and cell death profiles. Finally, the model was extended to examine the impact of selective binding of gold nanorods to cancer cells compared to nonmalignant cells, coupled with a small change in cell injury activation energy. The impact of these relatively minor changes results in a dramatic change in the overall cell death rate. Taken together, extracellular hyperthermia using gold nanorods is a promising strategy, and tailoring the cellular binding efficacy of nanorods can result in varying therapeutic efficacies using this approach.

Discovery of Cationic Polymers for Non-Viral Gene Delivery Using Combinatorial Approaches

Gene therapy is an attractive treatment option for diseases of genetic origin, including several cancers and cardiovascular diseases. While viruses are effective vectors for delivering exogenous genes to cells, concerns related to insertional mutagenesis, immunogenicity, lack of tropism, decay and high production costs necessitate the discovery of non-viral methods. Significant efforts have been focused on cationic polymers as non-viral alternatives for gene delivery. Recent studies have employed combinatorial syntheses and parallel screening methods for enhancing the efficacy of gene delivery, biocompatibility of the delivery vehicle, and overcoming cellular level barriers as they relate to polymer-mediated transgene uptake, transport, transcription, and expression. This review summarizes and discusses recent advances in combinatorial syntheses and parallel screening of cationic polymer libraries for the discovery of efficient and safe gene delivery systems.

Laser Welding of Ruptured Intestinal Tissue Using Plasmonic Polypeptide Nanocomposite Solders

Approximately 1.5 million people suffer from colorectal cancer and inflammatory bowel disease in the United States. Occurrence of leakage following standard surgical anastomosis in intestinal and colorectal surgery is common and can cause infection leading to life-threatening consequences. In this report, we demonstrate that plasmonic nanocomposites, generated from elastin-like polypeptides (ELPs) cross-linked with gold nanorods, can be used to weld ruptured intestinal tissue upon exposure to near-infrared (NIR) laser irradiation. Mechanical properties of these nanocomposites can be modulated based on the concentration of gold nanorods embedded within the ELP matrix. We employed photostable, NIR-absorbing cellularized and noncellularized GNR-ELP nanocomposites for ex vivo laser welding of ruptured porcine small intestines. Laser welding using the nanocomposites significantly enhanced the tensile strength, leakage pressure, and bursting pressure of ruptured intestinal tissue. This, in turn, provided a liquid-tight seal against leakage of luminal liquid from the intestine and resulting bacterial infection. This study demonstrates the utility of laser tissue welding using plasmonic polypeptide nanocomposites and indicates the translational potential of these materials in intestinal and colorectal repair.

High-throughput templated multisegment synthesis of gold nanowires and nanorods.

A cost-effective, high-throughput method for generating gold nanowires and/or nanorods based on a multisegment template electrodeposition approach is described. Using this method, multiple nanowires/nanorods can be generated from a single pore of alumina template membranes by alternately depositing segments of desirable (e.g., gold) and non-desirable metals (e.g., silver), followed by dissolution of the template and the non-desirable metal. Critical cost analysis indicates substantial savings in material requirements, processing times, and processing costs compared to the commonly used single-segment method. In addition to solid gold nanowires/nanorods, high yields of porous gold nanowires/nanorods are obtained by depositing alternate segments of gold-silver alloy and silver from the same gold-silver plating solution followed by selective dissolution of the silver from both segments. It is anticipated that this high-throughput method for synthesizing solid and porous gold nanowires and nanorods will accelerate their use in sensing, electronic, and biomedical applications.

Investigation of Phase Separation Behavior and Formation of Plasmonic Nanocomposites from Polypeptide-Gold Nanorod Nanoassemblies

Genetically engineered elastin-like polypeptides (ELP) can be interfaced with cetyltrimethyl ammonium bromide (CTAB)-stabilized gold nanorods (GNRs) resulting in the formation of stable dispersions (nanoassemblies). Increasing the dispersion temperature beyond the ELP transition temperature results in phase separation and formation of solid-phase ELP-GNR matrices (nanocomposites). Here, we investigated different physicochemical conditions that influence nanocomposite formation from temperature-induced phase separation of ELP-GNR nanoassemblies. The presence of cetyltrimethyl ammonium bromide (CTAB), used to template the formation of gold nanorods, plays a significant role in the phase separation behavior, with high concentrations of the surfactant leading to dramatic enhancements in ELP transition temperature. Nanocomposites could be generated at 37 °C in the presence of low CTAB concentrations (<1.5 mM); higher concentrations of CTAB necessitated higher temperatures (60 °C) due to elevated transition temperatures. The concentration of gold nanorods, however, had minimal influence on the phase separation behavior and nanocomposite formation. Further analysis of the kinetics of nanocomposite formation using a mathematical model indicated that CTAB largely influenced the early event of coacervation of ELP-GNR nanoassemblies leading to nanocomposites, but had minimal effect on nanocomposite maturation, which is a later-stage longer event. Finally, nanocomposites prepared in the presence of low CTAB concentrations demonstrated a superior photothermal response following laser irradiation compared to those generated using higher CTAB concentrations. Our results on understanding the formation of plasmonic/photothermal ELP-GNR nanocomposites have significant implications for tissue engineering, regenerative medicine, and drug delivery.