Nanomaterials have been widely investigated for improving the treatment of diseases acting as vectors for diverse therapies and as diagnostic tools. Iron-based nanowires possess promising potential for biomedical applications due to their outstanding properties. The combination of different therapeutic and diagnostic strategies into one single platform is an approach for more efficient and safer treatments. In this thesis, I investigate the application of iron-iron oxide core-shell nanowires as therapeutic agents for cancer treatment. In particular, a novel method for multimodal cancer cell destruction was developed combining the optical, magneto-mechanical and chemotherapeutic properties of functionalized nanowires. By functionalizing the nanowires with doxorubicin through a pH-sensitive linker, the first treatment modality was achieved by selective intracellular drug release. The second treatment modality utilizes the mechanical disturbance exerted by the nanowires upon the application of a low-power alternating magnetic field. The third treatment modality exploits the capability of the nanowires to transform optical energy, absorbed from near-infrared irradiation, into heat. The efficiency of the three treatment modalities both independently and combined were tested in breast cancer cells with near complete cell death (90%). The combination of the different strategies can potentially reduce side effects and treatment time. Additionally, I studied the potential of these iron-iron oxide core-shell nanowires as diagnostic tools, included in the Appendix of this dissertation. Specifically, I studied their capability to act as magnetic resonance imaging contrast agents for cell labeling, detection and tracking. Therein, a high performance as T2 contrast agents was confirmed evaluating the effect of oxidation and surface coatings on the T2 contrast in the tailored transverse relaxivities. The detection of nanowire-labeled cancer cells was demonstrated in T2-weighted images of cells implanted in tissue-mimicking phantoms and in mouse brain. Labeling the cells with nanowires enabled high-resolution cell detection after in vivo implantation (~10 cells) over a minimum of 40 days. The capability of these magnetic nanowires of being remotely controllable and detectable make them an attractive option in the treatment and diagnosis of cancer and in cell therapy. Future directions include preclinical studies for testing the nanowire-based photothermal therapy for tumor ablation.

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abstract: Gold nanoparticles as potential diagnostic, therapeutic and sensing systems have a long history of use in medicine, and have expanded to a variety of applications. Gold nanoparticles are attractive in biological applications due to their unique optical, chemical and biological properties. Particularly, gold nanorods (GNRs) are increasingly used due to superior optical property in the near infrared (NIR) window. Light absorbed by the nanorod can be dissipated as heat efficiently or re-emitted by the particle. However, the limitations for clinical translation of gold nanorods include low yields, poor stability, depth-restricted imaging, and resistance of cancer cells to hyperthermia, are severe. A novel high-throughput synthesis method was employed to significantly increase in yields of solid and porous gold nanorods/wires. Stable functional nanoassemblies and nanomaterials were generated by interfacing gold nanorods with a variety of polymeric and polypeptide-based coatings, resulting in unique properties of polymer-gold nanorod assemblies and composites. Here the use of these modified gold nanorods in a variety of applications including optical sensors, cancer therapeutics, and nanobiomaterials were described. / Dissertation/Thesis / Ph.D. Chemical Engineering 2012

Diplomová práce se zabývá výrobou a využitím zlatých koloidních nanotyčinek v biomedicínských aplikacích. Konkrétně se zaměřuje na tři základní funkce nanočástic v analýze - transportní, separační a především zobrazovací. V části o využití nanočástic pro zobrazování je hlavní zájem věnován zejména povrchové plazmonové rezonanci zlatých nantyčinek. Dále je práce zaměřena na využití nanotyčinek pro termální terapii. Následující část je věnována vhodným modifikacím povrchu, hlavně za účelem zmírnění toxicity částic. Závěrem teoretické části jsou způsoby přípravy zlatých koloidních nanotyčinek a techniky jejich následné analýzy. V navazující experimetální části jsou uvedeny postupy, podmínky a výsledky provedených pokusů.

Progress has been made in using human serum albumin nanoparticles (HSAPs) as carrier systems for targeted treatment of cancer. Human serum albumin (HSA), the most abundant human blood protein, can form HSAPs via a desolvation and crosslinking method, with the size of the HSAPs having crucial importance for drug loading and in vivo performance. Gold nanoparticles have also gained medicinal attention due to their ability to absorb near-infrared (NIR) light. These relatively non-toxic particles offer combinational therapy via imaging and photothermal therapy (PPTT) capabilities. A desolvation and crosslinking approach was employed to encapsulate gold nanoparticles (AuNPs), hollow gold nanoshells (AuNSs), and gold nanorods (AuNRs), into efficiently sized HSAPs for future tumor heat ablation via PPTT. The AuNR-HSAPs, AuNP-HSAPs and AuNS-HSAPs had average particle diameters of 222 ± 5, 195 ± 9 and 156 ± 15, respectively. We simultaneously encapsulated AuNRs and the anticancer drug paclitaxel (PAC), forming PAC-AuNR-HSAPs with overall average particle size of 299 ± 6 nm. Loading of paclitaxel into PAC-AuNR-HSAPs reached 3μg PAC/mg HSA. PAC-AuNR-HSAPs experienced photothermal heating of 46 ˚C after 15 minutes of NIR laser exposure; the temperature necessary to cause severe cellular hyperthermia. There was a burst release of paclitaxel up to 188 ng caused by the irradiation session, followed by a temporal drug release. AuNR-HSAPs were tested for ablation of renal cell carcinoma using NIR irradiation in vitro. Particles created with the same amount of AuNRs, but varying HSA (1, 5 or 20 mg) showed overall particle size diameters 409 ± 224, 294 ± 83 and 167 ± 4 nm, respectively. Increasing HSAPs causes more toxicity under non-irradiated treatment conditions: AuNR-HSAPs with 20 mg versus 5 mg HSA caused cell viability of 64.5% versus 87%, respectively. All AuNR-HSAPs batches experienced photothermal heating above 42 ˚C. Coumarin-6, was used to visualize the cellular uptake of AuNR-HSAPs via fluorescence microscopy. Finally, camptothecin (CPT) an antineoplastic agent and BACPT (7-butyl-10-aminocamptothecin) were loaded into HSAPs to combat their aqueous insolubility. BACPT-HSAPs loaded up to 5.25 micrograms BACPT/ mg of HSA. CPT encapsulation could not be determined. BACPT-HSAPs and CPT-HSAPs showed cytotoxicity to human sarcoma cells in vitro.

Ce travail démontre l'utilité des propriétés photothermiques dans le proche Infrarouge (NIR) des complexes de nickel-bis(dithiolène) neutres pour des applications en science des matériaux et biotechnologies. Des complexes Ni-bis(dithiolène) neutres hydrophiles et hydrophobes ont été élaborés et leur effet photothermique, sous irradiation laser NIR, a été quantifié pour la première fois. Grâce à cette propriété remarquable et à leur grande stabilité sous irradiation, il a été mis en évidence, que ces complexes pouvaient trouver des applications pour la thérapie photothermique, la libération contrôlée de médicament mais également pour le développement de nanomatériaux photosensibles à un stimulus externe. En effet, cet effet photothermique, sous irradiation laser NIR, permet de détruire des cellules cancéreuses, d'augmenter la perméabilité de nanoparticules polymériques ou de liposomes contenant des principes actifs et de désagréger des métallogels à base de complexes Ni-bis(dithiolène). Enfin, nous avons montré que les complexes [Ni(R2-timdt)2]0 ayant une haute efficacité photothermique sont de nouveaux candidats très prometteurs pour ce type d'applications. / The photothermal properties in the near Infrared (NIR) of neutral nickel-bis(dithiolene) complexes were used in materials science and for the first time in biotechnology. Hydrophilic and hydrophobic neutral Ni-bis(dithiolene) complexes were developped and for the first time, their photothermal effect under NIR laser irradiation was quantified. Thanks to this remarkable property and their high stability under irradiaton, it has been demonstrated that these complexes could find applications to photothermal therapy, controlled drug delivery but also in the developpement of stimuli responsive nanomaterials. Indeed, this photothermal effect, under NIR laser irradiation, allow to destroy malignant cells, increase the permeability of polymeric nanoparticles or liposomes containing active ingredients and disintegrate métallogels based on Ni-bis(dithiolene) cores. Finally, we showed that the [Ni(R2-timdt)2]0 complexes having higher phothothermal activity are very promising new candidates for these applications.

This thesis reports new gold nanoparticle-based methods to treat chemotherapy-resistant and metastatic tumors that frequently evade conventional cancer therapies. Gold nanoparticles represent an innovative generation of diagnostic and treatment agents due to the ease with which they can be tuned to scatter or absorb a chosen wavelength of light. One area of intensive investigation in recent years is gold nanoparticle photothermal therapy (PTT), in which gold nanoparticles are used to heat and destroy cancer. This work demonstrates the utility of gold nanoparticle PTT against two categories of cancer that are currently a clinical challenge: trastuzumab-resistant breast cancer and metastatic cancer. In addition, this thesis presents a new method of gold nanoparticle delivery using T cells that increases gold nanoparticle tumor accumulation efficiency, a current challenge in the field of PTT. I ablated trastuzumab-resistant breast cancer in vitro for the first time using anti-HER2 labeled silica-gold nanoshells, demonstrating the potential utility of PTT against chemotherapy-resistant cancers. I next established for the first time the use of T cells as gold nanoparticle vehicles in vivo. When incubated with gold nanoparticles in culture, T cells can internalize up to 15000 nanoparticles per cell with no detrimental effects to T cell viability or function (e.g. migration and cytokine secretion). These AuNP-T cells can be systemically administered to tumor-bearing mice and deliver gold nanoparticles four times more efficiently than by injecting free nanoparticles. In addition, the biodistribution of AuNP-T cells correlates with the normal biodistribution of T cell carrier, suggesting the gold nanoparticle biodistribution can be modulated through the choice of nanoparticle vehicle. Finally, I apply gold nanoparticle PTT as an adjuvant treatment for T cell adoptive transfer immunotherapy (Hyperthermia-Enhanced Immunotherapy or HIT) of distant tumors in a melanoma mouse model. The results presented in this thesis expand the potential of gold nanoparticle PTT from only chemotherapy-sensitive or localized cancers to chemotherapy-resistant non-localized cancers that currently defy conventional therapies.

Gold nanoparticles exhibit a combination of physical, chemical, optical, and electronic properties unique from all other nanotechnologies. These structures can provide a highly multifunctional platform with which to diagnose and treat diseases and can dramatically enhance a variety of photonic and electronic processes and devices. The work herein highlights some newly emerging applications of these phenomena as they relate to the targeted diagnosis and treatment of cancer, improved charge carrier generation in photovoltaic device materials, and strategies for enhanced spectrochemical analysis and detection. Chapter 1 introduces the reader to the design, synthesis, and molecular functionalization of gold nanotechnologies, and provides a framework from which to discuss the unique photophysical properties and applications of these nanoscale materials and their physiological interactions in Chapter 2. Chapter 3 discusses ongoing preclinical research in our lab investigating the use of near-infrared absorbing gold nanorods as photothermal contrast agents for laser ablation therapy of solid tumors. In Chapter 4, we present recent work developing a novel strategy for the targeted treatment of hormone-dependent breast and prostate tumors using multivalent gold nanoparticles that function as highly selective and potent endocrine receptor antagonist chemotherapeutics. In Chapter 5, we discuss a newly-emerging tumor-targeting strategy for nanoscale drug carriers which relies on their selective delivery to immune cells that exhibit high accumulation and infiltration into breast and brain tumors. Using this platform, we further investigate the interactions of nanoscale drug carriers and imaging agents to a transmembrane protein considered to be the single most prevalent and single most important contributor to drug resistance and the failure of chemotherapy. Chapter 6 presents work from a series of studies exploring enhanced charge carrier generation and relaxation in a hybrid electronic system exhibiting resonant interactions between photovoltaic device materials and plasmonic gold nanoparticles. Chapter 7 concludes by presenting studies investigating the contributions from so-called “dark” plasmon modes to the spectrochemical diagnostic method known as surface enhanced Raman scattering.