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Thesis advisor: Krzysztof Kempa / It is well established that molecules can be driven to dissociation via ionizing radiation, and this has various uses in medicine. The drawback is that ionizing radiation has little spectral resolution when applied to the human body. Consequentially, ionizing radiation damages target biological cells and healthy biological cells indiscriminately. If a truly non-invasive and selective dissociation method is desired, it is necessary to consider non-ionizing radiation for additional specificity. The first part of this thesis proposes that a selective dissociation of biomolecules is possible with non-ionizing electromagnetic radiation on the basis of nonlinear driving of molecular resonances. The second part is devoted to a “Trojan horse”-type of strategy. Experimentally, we demonstrate that visible light at moderate power levels damages metastatic cancer cells when they are sensitized with biocompatible polymeric nanoparticles. Efficient photothermal conversion of nanoparticles triggers hyperthermia-induced lysis in cells in a target-selective manner. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Physics.

published_or_final_version / Physics / Master / Master of Philosophy

Thesis (M. Phil.)--University of Hong Kong, 1995. / "9th September 1994." Includes bibliographical references.

Almost a decade has passed ever since the first time nanoparticles were proposed to be used for tumor/cancer diagnosis and treatment. For tumor/cancer treatments, nanoparticles are usually engineered to be the photo-thermal agent to promote the selectivity of the photo-thermal therapy while the most promising diagnostic applica- tion for nanoparticles might be being used as the exogenous optical contrast agent for optical imaging technique. This study is targeted at developing numerical modeling & simulation to be a subsidiary tool of experimental investigation of diagnostic & therapeutic applications of nanoparticles, particularly, gold-silica nanoshells. Around this goal, the present study is comprised with four sub-projects, each would be presented as an independent chapter. Firstly, an alternative method for calculating the spatial distribution of interstitial fluence rate in laser-induced interstitial thermo-therapy is introduced. The method originates from the un-simplified integral-differential radiant transport equa- tion, which is then solved by the radial basis function collocation technique. Validation of the method against the stochastic Monte Carlo and the numerical finite volume method has been done. Secondly, the nanoparticle assisted laser-induced interstitial thermo-therapy for tumor/cancer treatments is numerically investigated, which was targeted at exploring the therapeutic effects of a variety of treatment conditions including laser wavelength, power, exposure time, concentrations of tailored nanoparticles, and optical/thermal properties of the tissue that is under the treatment. Thirdly, the feasibility of extending nanoparticle assisted photo-thermal therapy from treating subcutaneous tumors to treating organ tumors, particularly, tumors growing in the clearance organ liver has been investigated. For organ tumors, nanoparticles could not recognize tumors from the surrounding normal organ tissue very well, as what has been for subcutaneous tumors. And last, how gold-silica nanoshells alter the diffuse reflectance signature of tissue phantoms has been numerically investigated, for the purpose of exploring how to engineering nanoshells to be good exogenous optical contrast agent for early-staged cancer diagnostic imaging.

Providing molecular fingerprint information, vibrational spectroscopy is a powerful tool for chemical analysis. In the mid-infrared window, FT-IR spectroscopy and microscopy have been routinely used for sample characterization. In the near-IR window, near-infrared spectroscopy has been widely used for tissue analysis and for the detection of lipids in the arterial walls. Yet, these traditional linear spectroscopies have intrinsic limitations. FT-IR spectroscopy suffers from a poor spatial resolution and strong water absorption for the study of living systems. Near-infrared spectroscopy avoids water absorption, yet it suffers from a poor, millimeter-scale spatial resolution in tissue analysis. My thesis focuses on breaking these limitations through photoacoustic and photothermal detection approaches. The first part of my thesis is on improving the spatial resolution in catheter-based intravascular photoacoustic (IVPA) imaging. By near-infrared excitation of lipids and acoustic detection, IVPA allows depth-resolved identification of lipid-laden atherosclerotic plaque. Thus far, most IVPA endoscopes use multimode fibers, which do not allow tight focusing of photons. Recent experiments on pulse propagation in multimode graded-index fibers have shown a nonlinear improvement in beam quality. Here, we harness this nonlinear phenomenon for the fiber-delivery of nanosecond laser pulses. We built a photoacoustic catheter 1.4 mm outer diameter, offering a lateral resolution as fine as 30 μm within a depth range of 2.5 mm. Such resolution is one order of magnitude better than current multi-mode fiber-based intravascular photoacoustic catheters. At the same time, the delivered pulse energy can reach as high as 20 μJ, which is two orders of magnitude higher than that of an optical resolution photoacoustic endoscope built with single-mode fiber. These improvements are expected to promote the biomedical application of photoacoustic endoscopes which require both high resolution and high pulse energy. Based on the technical advances, my thesis work further demonstrated longitudinal imaging of the same plaque in the same living animal. Recently developed mid-infrared photothermal (MIP) microscopy overcomes the limitations in FT-IR microscopy by probing the IR absorption-induced photothermal effect using visible light. MIP microscopy yields sub-micrometer spatial resolution with high spectral fidelity and much-reduced water background. The second part of my thesis work pushes the physical limits of MIP microscopy in aspects of detection sensitivity and imaging speed using two approaches. First, taking advantage of the interference scattering effect, the scattering signal from the sample can be greatly enhanced. Together with the relatively large infrared absorption coefficient, the sensitivity of the infrared spectrum is greatly improved, and single virus detection is achieved. Second, by using fluorescence as a thermo-sensitive probe, the temperature raise by infrared absorption can be retrieved in a more efficient way and much higher imaging speed and sensitivity are thus accomplished.

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Background: Photothermal therapy is an actively researched cancer treatment alternative to chemotherapy and resection due to its potential as a minimally invasive treatment with fewer health complications than high energy radiation therapies. The effectiveness of photothermal therapy may be enhanced with the use of photoabsorbtive nanoparticles by increasing heat generation and improving spatial selectivity. While photothermal therapy is a spatially distributed treatment, traditional experimental analysis methods used to assess photothermal therapy have either lacked spatial assessment such as is the case with standard viability assays of cell monolayers, or they only provide macroscopic treatment information, such as the measurement of the diameters of implanted mice flank tumors post-treatment. Goals: This work aims to accomplish two major goals. The first is to determine the therapeutic impact of combining Single Walled Carbon Nanohorns (SWNHs) with photothermal therapy. The second is to advance the measurement tools used to assess photothermal therapy by developing viability measurement methods which incorporate detailed quantitative spatial information Methods: Photothermal therapy was tested with and without SWNHs in in vitro cell monolayers, in vitro tissue phantoms, and ex-vivo tissue. Digital image analysis methods were developed which allowed for the use of viability assays and histological information to be identified and organized spatially. These methods were then used to compare the impact of cellular microenvironment and heating method on Arrhenius parameters. Results: The inclusion of SWNHs dramatically increased the temperatures reached in each experiment. Digital image analysis methods were shown to quantify spatial viability with a high degree of accuracy and precision in 2D and 3D. Experimental data indicated that there were areas of collateral damage (partially treated tissue) surrounding areas of completely treated tissue ranging which were between 46% and 78% of the completely treated volume. In each case the heat transfer properties of the experimental system had a large impact on the area of treatment. Variation in the temperature and viability response of photothermal therapy for specific laser and nanoparticle treatment parameters was quantified. Conclusions: This research has brought an experimental cancer treatment procedure from experiments in cell monolayers to tests in ex-vivo tissue to analyze viability response. The strengths of photothermal therapy such as its minimally invasive nature, and effectiveness at killing cells were experimentally demonstrated. This research has also developed the tools necessary to assess the spatial impact in vitro and lay the foundations for assessing spatial impact in vivo. These tools may be used to assess other treatments beyond photothermal therapy, and serve as a basis for improving the analysis of biological systems both in vitro and in vivo. / Ph. D.

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Cancer accounts for nearly 1 out of every 4 deaths in the United States, and because conventional treatments are limited by morbidity and off-target toxicities, improvements in cancer management are needed. This thesis further develops nanoparticle-assisted photothermal therapy (NAPT) as a viable treatment option for cancer patients. NAPT enables localized ablation of disease because heat generation only occurs where tissue permissive near-infrared (NIR) light and absorbing nanoparticles are combined, leaving surrounding normal tissue unharmed. Two principle approaches were investigated to improve the specificity of this technique: multimodal imaging and molecular targeting. Multimodal imaging affords the ability to guide NIR laser application for site-specific NAPT and more holistic characterization of disease by combining the advantages of several diagnostic technologies. Towards the goal of image-guided NAPT, gadolinium-conjugated gold-silica nanoshells were engineered and demonstrated to enhance imaging contrast across a range of diagnostic modes, including T1-weighted magnetic resonance imaging, X-Ray, optical coherence tomography, reflective confocal microscopy, and two-photon luminescence in vitro as well as within an animal tumor model. Additionally, the nanoparticle conjugates were shown to effectively convert NIR light to heat for applications in photothermal therapy. Therefore, the broad utility of gadolinium-nanoshells for anatomic localization of tissue lesions, molecular characterization of malignancy, and mediators of ablation was established. Molecular targeting strategies may also improve NAPT by promoting nanoparticle uptake and retention within tumors and enhancing specificity when malignant and normal tissue interdigitate. Here, ephrinA1 protein ligands were conjugated to nanoshell surfaces for particle homing to overexpressed EphA2 receptors on prostate cancer cells. In vitro, successful targeting and subsequent photothermal ablation of prostate cancer cells was achieved with negligible nanoshell binding to normal cells. In vivo however, ephrinA1-nanoshells did not promote enhanced therapeutic outcomes in mice bearing subcutaneous prostate cancer tumors treated with NAPT compared to nontargeted particles. Nonetheless, both treatment groups demonstrated effective ablation of prostate tumors, as evidenced by tumor tissue regression. Further investigation is warranted to overcome probable protein immunogenicity that offsets ephrinA1 targeting in vivo. With future study, photothermal therapy with multimodal gadolinium-conjugated and molecularly targeted nanoshells may offer a viable treatment option for cancer patients in the clinic.