Browsing by Subject "Gold nanostars"

There is an urgent need to develop practical and effective systems to detect diseases, such as cancer, infectious diseases and cardiovascular diseases.

Nanotechnology is a new, maturing field that employs specialized techniques to detect and diagnose infectious diseases. To this end, there have been a wealth of techniques that have shown promising results, with fluorescence and surface-enhanced Raman scattering being two important optical modalities that are utilized extensively. The progress in this specialized niche is staggering and many research groups in academia, as well as governmental and corporate organizations, are avidly pursuing leads which have demonstrated optimistic results.

Although much fundamental science is still in the pipeline under the guise of both ex-vivo and in-vivo testing, it is ultimately necessary to develop diagnostic devices that are able to impact the greatest number of people possible, in a given population. Such systems make state-of-the-art technology platforms accessible to a large population pool. The development of such technologies provide opportunities for better screening of at-risk patients, more efficient monitoring of disease treatment and tighter surveillance of recurrence. These technologies are also intrinsically low cost, facilitating the large scale screening for disease prevention.

Fluorescence has long been established as the optical transduction method of choice, because of its wealth of available dyes, simple optical system, and long heritage from pathology. The intrinsic limitations of this technique, however, have given rise to a complementary, and more recent, modality: surface-enhanced Raman scattering (SERS). There has been an explosive interest in this technique for the wealth of information it provides without compromising its narrow spectral width.

A number of novel studies and advances are successively presented throughout this study, which culminate to an advanced SERS-based platform in the last chapter.

The finite element method algorithm is critically evaluated against analytical solutions as a potential tool for the numerical modeling of complex, three-dimensional nanostructured geometries. When compared to both the multipole expansion for plane wave excitation, and the Mie-theory with dipole excitation, this algorithm proves to provide more spatially and spectrally accurate results than its alternative, the finite-difference time domain algorithm.

Extensive studies, both experimental and numerical, on the gold nanostar and Nanowave substrate for determining their potential as SERS substrates, constituted the second part of this thesis. The tuning of the gold nanostar geometry and plasmon band to optimize its SERS properties were demonstrated, and significant 3-D modeling was performed on this exotic shape to correlate its geometry to the solution's exhibited plasmon band peak position and large FWHM. The Nanowave substrate was experimentally revived and its periodic array of E-field hotspots, which was until recently only inferred, was finally demonstrated via complex modeling.

Novel gold- and silver- coated magnetic nanoparticles were synthesized after extensive tinkering of the experimental conditions. These plasmonics-active magnetic nanoparticles were small and displayed high stability, were easy to synthesize, exhibited a homogeneous distribution, and were easily functionalizable with Raman dye or thiolated molecules.

Finally, bowtie-shaped cobalt micromagnets were designed, modeled and fabricated to allow the controllable and reproducible concentrating of plasmonics-active magnetic nanoparticles. The external application of an oscillating magnetic field was accompanied by a cycling of the detected SERS signal as the nanoparticles were concentrated and re-dispersed in the laser focal spot. This constituted the first demonstration of magnetic-field modulated SERS; its simplicity of design, fabrication and operation opens doors for its integration into diagnostic devices, such as a digital microfluidic platform, which is another novel concept that is touched upon as the final section of this thesis.

The prevalence of cancer has increasingly become a significant threat to human health and as such, there exists a strong need for developing novel methods for early detection and effective therapy. Nanotheranostics, a combination of diagnostic and therapeutic functions into a single nanoplatform, has great potential to be used for cancer management by allowing detection, real-time tracking, image-guided therapy and therapeutic response monitoring. Gold nanostars (GNS) with tip-enhanced plasmonics have become one of the most promising platforms for cancer nanotheranostics. This work is aimed at addressing the challenges of sensitive cancer detection, metastasis treatment and recurrence prevention by combining state-of-the-art nanotechnology, molecular imaging and immunotherapy. A multifunctional GNS nanoprobe is developed with capabilities ranging from non-invasive, multi-modality cancer detection using positron emission tomography (PET), magnetic resonance imaging (MRI) and X-ray computed tomography (CT), to intraoperative tumor margin delineation with surface enhanced Raman spectroscopy (SERS) and high-resolution nanoprobe tracking with two-photon photoluminescence (TPL), as well as cancer treatment with photoimmunotherapy. The GNS nanoprobe with PET scans is particularly exceptional in detecting brain malignancies as small as 0.5 mm. To the best of our knowledge, the developed GNS nanoprobe for PET imaging provides the most sensitive means of brain tumor detection reported so far. In addition, the GNS nanoprobe exhibits superior performance as photon-to-heat transducer and can be used for specific photothermal therapy (PTT). More importantly, GNS-mediated PTT combined with checkpoint inhibitor immunotherapy has been found to trigger a memorized immunoresponse to treat cancer metastasis and prevent recurrence in mouse model studies. Furthermore, a 6-month in vivo toxicity study including body weight monitoring, blood chemistry test and histopathology examination demonstrate GNS nanoparticles’ biocompatibility. Therefore, the multifunctional GNS nanoprobe exhibits superior cancer detection and treatment capabilities and has great promise for future clinical translation in cancer management.

Bladder cancer has been ranked as one of the top ten and top twenty most commonly occurring cancers in men and women, respectively, with approximately half of the diagnoses being late stage and/or metastatic disease. The current standard-of-care treatment for metastatic bladder cancer is cisplatin-based chemotherapy, but only about 60% of patients qualify for this treatment option and the remaining cohort have few alternatives available. In fact, the only widely considered alternative is immune checkpoint blockades, or immunotherapies, which work to reactivate inhibited functions of immune cells. Unfortunately, these alone have not proven effective against metastatic malignancies. We believe that we can enhance the effects of clinically available immunotherapies with the addition of nanostar mediated photothermal therapy to the primary tumor. In fact, this combination of anti-PD-L1 immune checkpoint blockade and gold nanostar mediated photothermal therapy, henceforth called SYnergistic iMmuno PHOtothermal NanotherapY (SYMPHONY), was previously tested in a pilot study where C57BL/6 mice were injected with MB49 bladder cancer cells at two locations. One of the sites was treated with one of five treatments and the second remained untreated. Both tumor volumes were measured over time and the survival of the mice was also documented. This study resulted in one of the five SYMPHONY mice having complete tumor control after treatment and no other treatment group had this outcome. Upon rechallenge of the same tumor cell line, a tumor did not grow suggesting long-term immunity to this cancer. Along with a proof of concept, these studies were successful in identifying that macrophages and T-cells are associated with the tumor eradication. However, there is still little known about the quantification of the immune response at the distant tumor site after treatment. Our long-term goal is to develop an effective alternative treatment option for patients with metastatic bladder cancer. The overall objective of this application was to quantify the immune response of transgenic mice with fluorescent reporter genes on monocytes, natural killer cells, and dendritic cells undergoing one of four treatments (SYMPHONY, photothermal therapy alone (GNS), immunotherapy alone (anti-PD-L1) or no treatment (control)) as well as identify time points within the week following therapy in which additional studies could be conducted. Our central hypothesis was that mice treated with SYMPHONY would exhibit an elevated immune cell infiltration at the site of the distant tumor within ~48 hours post treatment, and that SYMPHONY will induce a greater immune response at the distant tumor site compared to anti-PD-L1 alone. This hypothesis was tested by implanting a primary flank tumor and a smaller, untreated distant tumor in 14 mice. The distant tumor cells were first stained with a far-red DiD fluorescent dye before injection into the center of a dorsal skinfold window chamber. The primary tumors were treated with one of the four treatment modalities and the window chamber was imaged using intravital microscopy for 7 days after the treatment. From this study, we found that the greatest change in the immune signal for any group occurred in the SYMPHONY group on the day of treatment and this immune signal remained elevated throughout the 7-day imaging period. This change was greater than all other treatment groups, including the anti-PD-L1 group, therefore, we accept our hypothesis. Further work should focus on assessing the immune response in mice on the day of treatment, looking at other immune cell types and by quantifying the effects of laser treatment on this day. It is noted that using the immune signal surrounding the distant tumor to predict an immune response within the tumor requires imaging at intervals more frequent than every 24 hours because of estimated macrophage travel velocity in tissue, where a more suitable frequency would be every 1.5-2 hours.